Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

EURETINA – Review

Free Access

Genetic Factors Associated with Age-Related Macular Degeneration

Leveziel N.a, b · Tilleul J.a · Puche N.a · Zerbib J.a · Laloum F.a · Querques G.a · Souied E.H.a, b

Author affiliations

Departments of Ophthalmology,aHôpital Intercommunal de Créteil, University of Paris XII, and bFaculté de Médecine Henri-Mondor, UPEC, Créteil, France

Corresponding Author

Dr. Nicolas Leveziel

Service d’Ophtalmologie, Hôpital Henri-Mondor

51, avenue du Maréchal-de-Lattre-de-Tassigny

FR–94010 Créteil Cedex (France)

Tel. +33 1 45 17 52 22, E-Mail nicolas.leveziel@chicreteil.fr

Related Articles for ""

Ophthalmologica 2011;226:87–102

Abstract

Age-related macular degeneration (AMD) is a complex, multifactorial disease associated with environmental and genetic factors. This review emphasizes the clinical impact of the major genetic factors mainly located in the complement factor H gene and on the 10q26 locus, and their current and future implications for the management of AMD.

© 2011 S. Karger AG, Basel


Introduction

Age-related macular degeneration (AMD) is the main cause of visual loss among elderly people in developed countries. Indeed, the prevalence of age-related maculopathy, defined by drusen and pigment alteration located in the macular area, and late AMD, defined by atrophic or exudative AMD, is 9.8% among individuals aged ≥65 years and 12.0% (8.7–15.4) among individuals aged ≥80 years [1,2]. Many factors, including environmental and genetic factors, are associated with the disease. Indeed, several studies have established a link between some modifiable environmental factors (mainly cigarette smoking, higher body mass index, increased plasma fibrinogen levels, poor carotenoid, omega-3 and fish consumption and higher trans-unsaturated fat intake) and AMD [1,3,4,5,6]. On the other hand, multiple genetic factors play a major role in the disease, leading to a population-attributable risk >50% if 1 complement factor H (CFH) risk allele is involved to 87% with a combination of 6 risk single-nucleotide polymorphisms (SNPs) [7,8,9]. Moreover, some of these genetic susceptibility factors could influence disease progression [10,11], and estimates of the combined effects of major genetic factors with modifiable environmental or biological factors are consistent with a multiplicative or an additive effect that may be considered as a public health concern [7,12,13,14]. The aim of this review is to analyze the influence of different genetic study designs and to investigate the impact of major genetic factors in AMD.

Because AMD occurs late in life, the parents are usually deceased and the offspring are often too young to be affected by the disease. Since only one informative generation is usually available for familial genetic studies of AMD, the design and the interpretation of these studies can be problematic. Under these conditions, familial aggregation studies, twin studies and segregation analyses are obviously difficult to perform because parental data on the index cases and because the offspring are not old enough to suffer from the disease.

Genetic Studies

Familial Aggregation Analysis and Twin Studies

Family and twin studies have been useful as a first step to establish genetic determinants in AMD. Indeed, a higher concordance rate of AMD has been demonstrated in both study designs including monozygotic twins or relatives of AMD patients. Twin studies have strongly suggested underlying genetic factors in AMD, showing that the concordance of the disease was higher among monozygotic than dizigotic twins [15,16,17,18,19,20]. In a study based on 406 twin pairs with 226 monozygotic and 280 dizygotic twins, Hammond et al. [18] calculated a heritability of age-related maculopathy and late AMD of 0.45 and 0.81, respectively. This was confirmed by Seddon et al. [20] based on the analysis of 840 elderly male twins including 210 monozygotic and 181 dizygotic complete twin pairs and 58 singletons, showing heritability rates for grade 3 and 5 AMD of 0.67 and 0.71, respectively.

Similarly, the first familial aggregation studies have consistently demonstrated familial aggregation in AMD [21,22,23,24,25,26]. Gass wrote that ‘more careful questioning of the patient and investigation of the few relatives available during this study has revealed a significant incidence of familial involvement for drusen and disciform detachment’ [22]. The risk of AMD in relatives of AMD patients based on these studies is presented in supplementary table 1 (www.karger.com?doi=10.1159/000328981). However, because environmental and/or genetic factors can explain any familial aggregation, the results of familial aggregation studies should be interpreted cautiously.

Segregation Studies

These studies investigate the mode of inheritance of a disease by comparing the transmission patterns of inheritance observed within families with genetic and nongenetic models. A segregation approach can also be used to analyze the effect of any SNP among relatives of multiplex families with affected cases to measure the segregation rate between the SNP and the disease trait.

In a segregation study including 546 sibships with an average size of 2.43 (2–9), Heiba et al. showed that a major gene effect in age-related maculopathy could be expected from their data [27]. In another study, Souied et al. analyzed the segregation of 6 heterozygous missense substitutions in different families, some members of which were affected with exudative AMD [28]. This approach enabled to conclude that the P940R and L1970F codon changes in the ATP-binding cassette transporter (ABCA4) gene could be implicated in a small proportion of cases with exudative AMD. In a study that successively used a candidate gene approach with 689 cases and 544 controls and a segregation approach in 5 multiplex Australian families, Guymer et al. analyzed the implications of the G1961E or D2177N variants of the ABCA4 gene in AMD [29]. This dual approach led to the exclusion of an association of these variants with AMD. In order to identify the causative genes of AMD, potentially located between LAMB2 and D1S3469 in the 1q25–31 region, Schultz et al. analyzed 49 variants of 20 genes for segregation with the disease haplotype in a multiplex family (4 generations and 40 subjects) [30]. They identified the G5345R variant of hemicentin-1 that exclusively segregated with the disease haplotype, showing that this variant might be associated with AMD in some cases.

Linkage Analysis

Linkage studies focused on the inheritance of loci in family pedigrees using polymorphic markers located across the genome. Because these studies require multiplex families and have less power in case of complex inheritance with incomplete penetrance, it was initially expected that they would lead to relatively weak results related to screening of genetic factors in AMD, considered to be a complex-trait disease.

However, in most of these studies, consistent evidence for linkage was established for the 1q [31,32,33,34,35,36] and 10q26 [34,35,36,37]loci. These converging results may be explained by the fact that although AMD is polygenic in nature, two major genetic factors are mainly involved in AMD. Other genes sometimes associated with the disease do not seem to play a major role because of their relatively small allele frequency in the general population or because of their weak genetic effect. The results of the main linkage analyses are presented in supplementary table 2.

Candidate Gene Approach

This approach is based on a hypothesis-driven pathway in contrast to genome-wide association studies (GWAS), generally considered as more ‘agnostic’ in the field of genetic studies [38].

The candidate gene approach is a useful study design to validate previous associations or to demonstrate associations of a gene with a disease in different populations.

Because previous experimental studies, particularly immunochemical analyses of soft drusen, have generated strong hypotheses on specific biochemical pathways potentially involved in AMD, this approach has been useful to establish associations between genetic susceptibility factors and AMD. The genetic susceptibility factors associated with AMD in more than 2 studies using this hypothesis-driven pathway approach are listed in supplementary table 3.

Some studies published years or months before the first publications that have emphasized the implication of the complement cascade genes in AMD pointed out the potential key role of the complement pathway in the biogenesis of drusen and AMD [39,40,41,42,43,44,45]. Moreover, 6 linkage studies published before 2006 showed a consistent association between the 1q31 locus and AMD [46]. Using a candidate gene approach, Hageman et al. [47 ]identified a common haplotype in 8 most informative SNPs located in the CFH and studies based on previous GWAS also identified the CFH gene as a major genetic factor for AMD the same year [48,49,50]. This example emphasizes the need for candidate gene analyses to combine biochemical data with previously identified loci obtained through linkage studies in order to select ideal SNPs for analysis. However, it seems more useful to screen millions of SNPs in a GWAS than to screen few SNPs in a candidate gene approach, because a higher rate of positive association is obviously more frequently observed in the first case. In such studies, functional SNPs with a minor allele frequency cutoff usually >0.05 and potentially associated with modifications of the protein activity profile are usually preferred. Because a tagging-haplotype approach, facilitated by the International HapMap project (http://www.hapmap.org/), allows wide coverage of functional SNPs in a gene using few tagging SNPs, the choice of SNPs for a candidate gene approach can be improved. This deductive approach for targeted potential functional SNPs based on biochemical data, potentially crossed with physical data obtained from previous linkage analysis, provides advantages over GWA studies as it also offers the ability of studying smaller populations in case of a rare disease, and lower minor allele frequencies (MAFs) or SNPs associated with minor genetic effects, with a cost-efficiency advantage.

Genome-Wide Association Studies

The classical stepwise approach with familial aggregation/twin studies – segregation – linkage association studies and candidate gene approach, as successive steps to identify genetic factors, has been useful, although time consuming in the case of AMD.

Advances in genotyping technologies allowing the performance of scans of up to one million SNPs and in genome analyses with the completion of the Human Genome Project have led to large-scale GWAS. If most of the common variants identified through GWAS in common complex-trait diseases individually confer small increments in risk and usually leave a large proportion of missing heritability [51], these studies have been successful in AMD mainly because few high-effect common variants [CFH, age-related maculopathy susceptibility 2 (ARMS2)/LOC387715-HtrA serine peptidase 1 (HTRA1) and hepatic lipase (LIPC) genes], characterize the genetics of this disease. Moreover, the putative causative role of these genes significantly associated with AMD in GWAS is strengthened when expression data confirm that they are also expressed in the retina [49,52].

Genetic Factors Associated with AMD

Numerous genetic factors associated with AMD have been described since the identification of ApoE in 1998. Some of them might be involved in sporadic AMD cases or play a minor role as a risk factor, and few of them are responsible for a greater proportion of AMD cases. Indeed, the effect sizes of the two major risk genes for AMD (CFH Y402H and ARMS2/LOC387715) are dramatically larger than for other risk genes identified in most late-onset complex diseases [53,54,55], leading to potential primary preventive perspectives by genetic screening.

Numerous studies in different ethnic groups mainly emphasize the role of genetic factors as susceptibility factors for AMD, but only few studies have analyzed their effect on the incidence, progression, treatment response, or clinical features of the disease.

The pathogenesis of AMD seems to involve different biological pathways, such as inflammation, lipid, apoptosis and oxidation. These pathways can obviously share common networks and cannot be considered as completely dissociated.

Genes Involved in the Inflammatory Pathway

Previous immunohistochemical studies focusing on drusen or choroidal neovascular membranes implicated the inflammatory pathway and specifically the complement pathways in AMD [56,57]. Since 2005, this hypothesis has been demonstrated by numerous genetic studies.

The CFH Gene

The four activation pathways of the complement cascade lead to formation of the cytolytic membrane attack complex (MAC). The CFH gene encodes a protein acting as a regulator of the basal activation of the alternative pathway of the complement cascade. The Y402H polymorphism of the CFH gene (rs1061170) has been associated with all forms of AMD in different populations worldwide and the odds ratios (ORs) in large case-control studies are summarized in supplementary figure 1. This SNP, which is located in the short consensus repeat 7, results in an amino acid substitution of histidine for tyrosine in a particular domain of factor H that contains binding sites for C-reactive protein, heparin, and streptococcal M6 protein [58].

Differences in binding properties on various cellular surfaces have been reported between the risk variant 402H and the wild variant 402Y [59,60], but no differences in either CFH or CRP immunolabeling in drusen were detected between homozygous carriers for both variants [61].

The Y402H SNP of CFH as a genetic risk factor for AMD is not consistently replicated in some case-control studies in the Asian population [62,63,64,65,66,67,68,69,70,71,72]. This lack of a consistent association could be explained by the lower MAF in this population compared with Caucasian populations. Indeed, the C allele frequency is 0.282 in Europeans, 0.067 in Han Chinese in Beijing and 0.057 in Japanese subjects in Tokyo (http://hapmap.ncbi.nlm.nih.gov/biomart). However, other SNPs of the CFH gene are associated with AMD in Asians. Furthermore, some of these SNPs are also associated with polypoidal choroidal vasculopathy, which is sometimes considered as a frontier form of AMD (same age of onset, frequent association with occult choroidal neovascularization (CNV) in Asian patients) [62,73,74,75]. The main results of case-control studies analyzing SNPs of the CFH gene in AMD in Chinese and Japanese populations are summarized in supplementary table 4.

Complement Component 2 and Factor B Genes

Activation of the alternative pathway is initiated by cleavage of C3b-bound factor B, leading to the formation of the C3Bb complex. Factor B (BF) and complement component 2 (C2), an activator of the classical complement pathway, are paralogous genes located only 500 bp apart on human chromosome 6p21. Risk haplotype and protective haplotypes have been identified [76]. Indeed, the H10 (L9H with E318D) and H7 (ISV10 with R32Q) haplotypes independently exert a protective effect in Caucasian populations with respective ORs of 0.45 (95% CI 0.33–0.61; p < 0.0001) and 0.36 (95% CI 0.23–0.56; p < 0.0001), whereas the H1 haplotype is associated with an increased risk of AMD with an OR of 1.32; p = 0.0013) in the study by Gold et al.. Moreover, taking into account only 3 genes, C2, BF and CFH, Gold et al. consider that this could predict the clinical outcome in 74% of affected individuals [76].

The protective effect of some variants of C2 and BF has been confirmed in other studies [77,78]. The protective effect of the 32Q variant of the BF could be linked to its decreased affinity for C3b, leading to a decreased amplification of complement activation due to lower production of convertase [79].

Complement C3

In two replicated case-control studies on Scottish (n = 244 cases and 351 controls) and English (n = 603 cases and 350 controls) individuals, Yates et al. showed that the rs2230199 (R80G) functional polymorphism in exon 3 of the C3 gene is a risk factor for both exudative and atrophic AMD, with ORs of 1.7 (95% CI 1.3–2.1) and 2.6 (95% CI 1.6–4.1) for heterozygous or homozygous carriers of the risk allele, respectively [80]. Similar results were also published by Maller et al. confirming that rs2230199 is associated with both forms of the disease, and excluding an association of C5 gene polymorphisms with the disease [81].

The MAF of rs2230199 (R80G) is 0.2 in Europeans, and this SNP is in almost complete linkage disequilibrium (LD) with rs1047286 (P292L) in exon 9 of the C3 gene (r2 = 0.8; D′ = 1) (http://www.broadinstitute.org/mpg/snap/ldsearch.php). However, in the studies by Yates et al. [80 ]and Spencer et al. [82], stepwise logistic-regression analyses confirmed that the R80G SNP is more likely to be the causative SNP of AMD than the P292L SNP.

In a study based on participants of the Rotterdam study (n = 6,418 individuals) and an independent case-control cohort (n = 357 cases and 173 controls), haplotype analysis showed that carriers of the 80G and the 292L variants exhibited the highest difference in frequency between cases and controls (0.245 vs. 0.207; p = 0.006) compared with the 3 other haplotypes. Moreover, this study demonstrated that these risk alleles in LD are independent of the major risk alleles of CFH and LOC387715; they are also independent of smoking, with a population-attributable risk of 14.6% [83]. This independent effect from other known genetic factors has been confirmed in other studies [84,85,86,87].

Similarly to the Y402H allele of the CFH gene, the 80G variant of rs2230199 is not associated with exudative AMD in the Chinese population, likely because of the lower MAF – almost 0 for the C allele in the HapMap of Han Chinese in Beijing and 0.175 of the Centre d’Etude du Polymorphisme Humain (CEPH) population. However, the C3 IVS2 rs2250656 polymorphism appeared to be protective for exudative AMD in the Chinese population, the G allele conferring an OR of 0.58 (95% CI 0.35–0.96; p = 0.033) [88]. As mentioned by the authors, the low frequencies of the risk alleles of the rs2230199 of C3 and the rs1061170 of CFH could, to some extent, partly explain the lower prevalence of AMD in the Chinese population.

In a recent study combining immunochemical and case-control genetic analyses (478 AMD cases and 300 controls), the authors have identified other SNPs located in the C3 (MRD_4273), the C9 (rs476569), and the ficolin (collagen/fibrinogen domain containing) 1 (FCN1) genes (rs10117466, rs10120023, MRD_4502) that showed borderline associations with AMD [61].

The Complement Factor I Gene

The complement factor I (CFI) gene encodes a molecule containing a serine protease domain that cleaves and inactivates C3b and C4b. Based on a case-control analysis (n = 1,228 cases and 825 controls) of 1,500 SNPs selected among the complement pathway genes and on the meta-analysis of previous whole-genome linkage studies Fagerness et al. identified rs10033900 and rs13117504, and their combined haplotype of the CFI gene that are associated with AMD [89]. However, because these SNPs are unlikely to be functional, it is possible that these SNPs tag an undiscovered functional variant as mentioned by the authors. The role of a putative functional variant of the CFI gene associated with AMD is also supported by other studies [90,91].

The VEGFA Gene

In a recent meta-analysis of GWAS for advanced AMD with follow-up replication of most significant signals in 5,640 cases and 52,174 controls, the rs4711751 SNP located nearby VEGFA and the rs1999930 SNP located nearby FRK/COL10A1 were associated with AMD with ORs of 1.15 (95% CI 1.1–1.21; p = 8.7 × 10–9) and 0.87 (95% CI 0.83–0.91; p = 1.1 × 10–8), respectively. These variants suggest that VEGFA involved in angiogenesis/inflammatory process genes involved in extracellular collagen matrix could contribute to AMD development [92].

The 10q26 Locus

Based on previous whole-genome analyses that have identified this locus associated with AMD [34,35,36,37], several studies focused more thoroughly on this region, which led to the identification of the other major genetic factor(s) of AMD, the LOC387715/age-related maculopathy susceptibility 2 (ARMS2) [93,94], and the HtrA serine peptidase 1 (HTRA1) genes [52,95]. In the 10q26 locus, a total of 15 variants are in strong LD and tag a single-risk haplotype, leaving statistical analyses with insufficient power to obtain enough discrimination between ARMS2 and HTRA1 variants [96]. Both associations of ARMS2 have been replicated through different population case-control studies, and the main results of these studies are presented in supplementary table 4. For the time being, it seems difficult to identify the causal variant associated with AMD because both variants are in strong LD in different populations (r2 = 1 and D′ = 1 in CEU; r2 = 0.88 and D′ = 1 in Africans, and r2 = 0.863 and D′ = 0.929 in Asians; http://www.broadinstitute.org/mpg/snap/ ldsearch.php).

ARMS2 mRNA was detected in the human retina and could encode a putative protein whose expression and cellular location are still under debate. Indeed, the putative protein was initially observed in the mitochondrial outer membrane [97], and later in the cytosol and extracellular compartment [98,99]. In a recent study, the authors showed that the risk haplotype in 10q26 is associated with a dramatic effect on ARMS2 but not on HTRA1 expression levels. Moreover, the rs2736911 variant also leads to significant reduction in ARMS2 transcript levels and is not associated with AMD. From these results, it seems unlikely that ARMS2 protein deficiency could be the direct pathogenic mechanism responsible for AMD [100]. The main results of case-control studies on ARMS2 are summarized in supplementary figure 2.

HTRA1 encodes a 50-kDa secreted protein belonging to the high-temperature requirement A family of serine proteases. Although the first studies associated the rs11200638 promoter variant of the HTRA1 gene with increased expression of the protein [95,52], other studies have not replicated these results [97,101]. However, a recent study showed that HTRA1 mRNA expression is higher in cultured retinal pigment epithelial cells homozygous for the risk allele of HTRA1, and that some molecules involved in the complement pathway, such as clusterin, vitronectin and fibromodulin, are substrates for HTRA1 serine protease [102]. Other results have reinforced the idea that HTRA1 could be the causal gene [103,104]. The main results of case-control studies on HTRA1 are summarized in supplementaryfigure 3.

Considering the interaction between major risk variants of the CFH and the ARMS2/LOC387715-HTRA1 genes, different studies suggest an independent multiplicative joint effect in AMD [13,105].

The Lipid Pathway

The putative role of the lipid pathway in AMD has been suggested by the presence of cholesterol and esterified cholesterol accumulating in Bruch’s membrane and drusen in AMD patients [106,107]. Different genes involved in the lipid pathway are associated with AMD.

ApoE

ApoE is located at locus 19q13.2 and encodes a glycoprotein of 34.2 kDa. ApoE is located on lipoproteins and interacts with the cellular receptors of ApoE, the LDL receptors and other LDL receptor-related proteins (i.e. LRP1, LRP5 and LRP8), whose interactions enable a turnover of cellular lipids and the clearance of different lipoproteins from the circulation [108,109]. Three main isoforms of ApoE, i.e. E3, E4, and E3, are described. The ε3 allele is most frequently observed in different populations leaving on agriculture or on agriculture-derived occupations (70–80%), whereas the frequency of the ε4 allele, the ancestral allele, is higher among Pygmies (0.407), Malaysian aborigines (0.240), Australian aborigines (0.260), Khoi San (0.370), Papuans (0.368), some Native Americans (0.280) and Lapps (0.310) [110].

Apo-ε is the first genetic factor identified in AMD through candidate gene approaches [111]. These results have been replicated in other studies [112,113,114,115,116,117,118,119,120,121,122] and confirmed by a meta-analysis [123]. However, likely because of the weak allele effects of Apo-ε, and because of the low allele frequencies of both the ε2 and ε4 alleles, some studies could not demonstrate any association between this gene and AMD [124,125,126,127,128,129]. The ε4 allele is associated with a reduced risk of developing different subtypes of the disease (exudative or atrophic forms) [115,116], with sometimes a gender-specific protective effect reported for men [117], whereas a gender effect of the ε2 isoform might confer an increased risk mainly for men [115]. These gender effects are not yet precisely clarified. Other specific gender effects have been observed for the Apo-ε4 allele in late-onset familial Alzheimer’s disease with a higher risk for women [130] and in cardiovascular diseases with a higher risk for men [131]. Moreover, the relative rate of Apo-ε expression, in conjunction with functional differences of the respective isoforms, might also be associated with AMD [122].

The Scavenger Receptor Class B Type 1 Gene

The scavenger receptor class B type 1 (SCARB1) gene located on 12q24.31 encodes a protein (SRB1) of 509 amino acids that mediates the transfer of cholesterol between cells and high-density lipoproteins (HDL) and is also involved in the metabolism of vitamin E and lutein [132,133].

In a collaborative case-control study including 1,241 + 1,732 AMD cases compared with 297 + 1,257 controls, the CT heterozygotes for the rs5888 SNP of SCARB1 were at increased risk of developing exudative AMD, with an OR of 3.6 (95% CI 1.7–7.6; p < 0.0015) compared with the CC genotype [134]. Although this genetic finding has not been widely replicated up to now, this association is interesting when considering the underlying role of cholesterol, lutein and vitamin E in AMD established by epidemiological studies.

The LIPC and Other Genes Associated with Lipid Metabolism

Hepatic triglyceride lipase (HL) and the cholesteryl ester transfer protein (CETP) are proteins that play a major role in the regulation of plasma lipids. HL is encoded by the LIPC gene located at 15q21–q23, and the CETP gene is encoded on 16q21.

Two GWAS based on large independent cohorts of 2,157 AMD cases/1,150 controls (Michigan-Mayo Clinic-AREDS-Pennsylvania GWAS) and of 821 AMD cases/ 1,709 controls (Tufts/MGH GWAS) identified 30 SNPs with consistent evidence for association. These SNPs were genotyped in additional samples of 7,749 AMD cases/4,625 controls. Among them, rs9621532 and nearby markers of the inhibitor of metalloproteinase 3 (TIMP3) gene, and both common rs493258 SNP located 35 kb upstream of the LIPC gene and rs3764261 SNP near the CETP gene were associated with an increased risk of AMD with ORs of 1.41 (95% CI 1.27–1.57; p = 1.1 × 10–11), 1.14 (95% CI 1.09–1.20; p = 1.3 × 10–7) and 1.19 (95% CI 1.12–1.27; p = 7.4 × 10–7), respectively [135]. As mentioned in the Discussion of that paper, it is noteworthy that the two latter risk SNPs for AMD are also associated with higher HDL cholesterol levels [136,137]. Among other SNPs associated with modifications of HDL cholesterol levels also investigated in that study, rs12678919 near the LPL gene and rs1883025 near the ABCA1gene were associated with an increased risk of AMD, with ORs of 1.26 (p = 0.003) and 1.15 (p = 5.6 × 10–4). Other SNPs, i.e. rs173539 near the CETP gene, and rs10468017, near the LIPC gene, also revealed evidence for an association with AMD [132].

The Tufts/MGH GWAS with 979 AMD cases/1,709 controls and replication cohorts of 5,789 AMD cases/4,234 controls showed that rs493258 SNP, near the LIPC gene, is unlikely to be the causative SNP, but that a functional variant, rs10768017, located on the proximal promoter of the LIPC gene and in LD with the previous rs493258 SNP, might be the causative variant [138]. The rs10768017 SNP previously associated with reduced LIPC expression and higher HDL demonstrates a protective effect for both forms of AMD with an OR of 0.82 (95% CI 0.77–0.88). In the latter study, immunoprecipitation and real-time PCR showed that both LIPC protein and mRNA are present in human retinas.

A recent study investigated serum lipids and LIPC rs10768017 in 318 advanced AMD cases/140 controls [139]. In this study, HDL cholesterol is lower in AMD cases than in controls (49 vs. 53 mg/dl; p = 0.05), LDL cholesterol is higher in AMD cases than in controls (144 vs. 135 mg/dl; p = 0.03) and the protective T allele of LIPC rs10768017 is associated with increased HDL levels (p = 0.05). As mentioned by the authors, because of the independent associations of LIPC and HDL when considered simultaneously, the HDL level unlikely mediates the association between LIPC and AMD [139]. No other interaction of LIPC has been demonstrated up to now between other environmental factors, such as smoking, body mass index and lutein intake [140].

Other Genetic Mechanisms Potentially Involved in AMD

Most of the genetic studies on AMD focused on SNPs, but this mechanism probably does not explain the entire genetic component of this disease. Indeed, other mechanisms including epigenomic (i.e. DNA methylation, histone methylation, acetylation status and transcrip- tion factors) variants of mitochondrial DNA (mtDNA), mtDNA alterations [141] and copy number variation might be potentially involved in the pathophysiology of the disease.

mtDNA Variants

The maternally inherited mtDNA is 16,569 pb in size and is composed of 37 genes encoding 13 protein subunits involved in oxidative phosphorylation, 2 ribosomal RNAs and 22 transfer RNAs. Inherited variants located in the mtDNA T2 haplogroup and characterized by 2 variants in complex I gene (A11812G of MT-ND4 and A14233G of MT-ND6) have been associated with advanced AMD, with an OR of 2.54 (95% CI 1.36–4.80; p ≤ 0.004) [142]. Other variants associated with mitochondrial haplogroups J (T16126C, G13708A and C16069T SNP), T (A4917G, G13368A and A73G SNPs) and U (A12308G, G9055A_SNP) have also been associated with AMD [143]. This latter study seems to confirm the findings of a previous study showing that haplogroups J and U are connected with some clinical features associated with age-related maculopathy, with ORs of 1.80 (95% CI 1.18–2.73) and 1.45 (95% CI 1.11–1.91), respectively [144].

Copy Number Variation

Copy number variation, including duplications, tandem repeats and deletions of 1 kb or more of genomic DNA could be associated with AMD [145,146] through increased or decreased gene expression [147].

Complement factor H-related 1 (CFHR1) and complement factor H-related 3 (CFHR3) share significant amino acid sequence homology, and similar binding properties with CFH. However, unlike CFH that regulates C3 convertase, CFHR1 modulates the activity of C5 convertase and inhibits the formation of MAC. A protective effect of a haplotype carrying deletions of CFHR1 and CFHR3, with an OR of 0.4 (95% CI 0.3–0.5), independent of rs1061170 of the CFH gene, has been described. These deletions were associated with a lack of the proteins encoded by these genes among homozygotes for these deletions [148]. These results were replicated in other independent cohorts [149,150]. However, this common CNV could be associated with other protective haplotypes located in the CFH gene as suggested by some authors [151]. The protective effect of deletions located in the CFHR1/CFHR3 genes could be mediated by removal of the C5a blockade and disinhibition of MAC formation [152].

Genetic Factors and Progression of AMD

Some genetic susceptibility factors for AMD have also demonstrated an impact upon the progression from intermediate to advanced AMD. Based on the AREDS cohort, Seddon et al. have analyzed the impact of CFH and LOC387715/ARMS2 risk SNPs and environmental factors on the progression of AMD [153]. Among 1,466 participants, 281 progressed from grades 2 or 3 (drusen and/or pigment anomalies and/or noncentral geographic atrophy) to grades 4 (unilateral exudative or atrophic AMD) or 5 (bilateral exudative or atrophic AMD) or from grade 4 to grade 5. For the Y402H SNP of CFH, the ORs for AMD progression were 1.6 (95% CI 1.1–2.4) and 2.6 (95% CI 1.7–3.9) for the heterozygous and homozygous risk genotypes, respectively. For the A69S SNP of LOC387715/ARMS2, the ORs for AMD progression were 2.7 (95% CI 1.9–3.7) and 4.1 (95% CI 2.7–6.3) for the heterozygous and homozygous risk genotypes, respectively. In this same study, the risks of progression attributable to these genotypes were 71.8% for both SNPs and 81.2% for both SNPs combined with smoking and body mass index. Moreover, the rate of progression to the exudative form in homozygotes with the risk allele of LOC387715/ARMS2 was higher than the rate of progression to the atrophic form (ORs 6.1 and 3, respectively). This effect was not observed with the CFH risk allele, with similar rates of progression for both forms of the disease [153].

In another study also based on 1,446 individuals from the AREDS cohort of whom 279 progressed during a 6.3-year follow-up, multivariate analysis between demographic, genetic and environmental factors showed that age >70, baseline grade 3, current smoking and body mass index >25 were significantly associated with progression, with ORs of 1.5, 11, 3.1 and 1.6, respectively. In this study, rs1061170 of CFH, rs10490924 of ARMS2 and rs2230199 of C3 were also associated with a higher risk of progression, with ORs of 2 (1.1–3.5; p = 0.019), 4 (2.6–6.1; p < 0.001) and 1.8 (1–3.2; p = 0.044) for homozygous risk alleles. rs9332739 of C2 was associated with a lower risk of progression, with an OR of 0.4 (0.2–0.8; p = 0.01) [10].

In a study based on 3 different cohorts, Francis et al. analyzed progression from grade 3 (intermediate AMD) to advanced AMD (grade 4), or from advanced AMD in one eye (grade 4) to advanced AMD in both eyes among 889 patients from the AREDS cohort [121]. In this study, the protective alleles rs9332739/rs4151667 of C2/CFB (both in high LD) were associated with a reduced progression rate from intermediate AMD to atrophic or exudative forms, with an OR of 0.32 (95% CI 0.14–0.73; p = 0.004) for heterozygotes and the risk allele rs2230199 of the C3 gene was associated with an increased progression rate, with an OR of 3.32 (95% CI 1.46–7.59; p = 0.004) in homozygotes [121].

The effect of variants of CFH, LOC387715/ARMS2, C2, C3, APOE and TLR3 on the progression of the area of geographic atrophy (GA) has been recently investigated by Klein et al. in a cohort of 114 participants from the AREDS [154]. Whereas the mean growth rate of GA was 1.79 mm2/year (0.17–4.76), extension of GA was higher among homozygotes with the LOC387715/ARMS2 risk genotype (2.34 mm2/year) compared with homozygotes with the nonrisk genotype (1.51 mm2/year) (p = 0.014).

Genetic Factors and Clinical Features of AMD

An earlier age of onset of AMD is the most common phenotypic manifestation associated with the LOC387715/ARMS2 genetic predisposition reported in few studies [155,156,157,158,159].

Studies also also established that a larger size of the choroidal neovascular lesion is associated with the LOC387715/ARMS2 or HTRA1risk alleles [155,159,160]. We previously analyzed the clinical features of AMD correlated to CFH and ARMS2 after genotypic selection. Significant associations were found for earlier disease onset (p < 0.014), fibrovascular scar (p < 0.001), bilateral CNV and lower visual acuity at presentation (p = 0.02) among patients homozygous for both risk alleles. An association was also found between ARMS2 and classical CNV (p < 0.026) [161]. These results have been partly confirmed by a recent study showing that progression of CNV and bilaterality of CNV are more consistently associated with the HTRA1/ARMS2 SNPs than with CFH SNP [162]. On the contrary, other groups established a positive association between homozygosity for the risk allele of rs1061170 SNP of CFH and predominantly classical CNV [163,164,165]. However, these latter studies did not include the major ARMS2 or HTRA1 gene in their analyses. In a recent publication, the ARMS2 gene conferred differential susceptibility to exudative and atrophic forms of the disease, with the risk allele of the rs10490924 SNP being more frequently observed for patients with exudative AMD (n = 3,139) than for patients with geographic atrophy (n = 731), with an OR of 1.37 (95% CI 1.21–1.51; p = 4.2 × 10–7). In this study, other genes, such as CFH, C2/CFB, C3, CFI, LIPC and TIMP3, did not confer differential susceptibility to both forms of the disease [166].

When considering the rs2230199 SNP of the C3 gene, it is rather associated with GA than with exudative AMD in a study including 341 patients with GA, 994 patients with CNV and 509 controls [162]. Indeed, the ORs for GA and for exudative AMD were, respectively, 3.86 (95% CI 1.77–8.40; p = 0.001) and 2.39 (95% CI 1.23–4.63; p = 0.01) for homozygous individuals. Considering the Y402H variant of the CFH gene, no difference was observed between ORs for exudative or GA AMD (3.75 vs. 3.12), but the rs2274700 of the CFH gene was significantly associated with bilateral forms of GA compared with unilateral forms. As to the ARMS2 gene, the OR for CNV was 2-fold higher than the OR for GA in that study (13.49 vs. 6.57) [162]. Similar results with a higher effect of ARMS2 on exudative forms compared with atrophic forms have also been reported elsewhere [153].

Other particular clinical features or borderline forms of AMD have also been associated with genetic factors. Indeed, in a study comparing 62 cases of polypoidal choroidal vasculopathy (PCV) with 93 controls in the Chinese population, PCV was associated with rs3753394 of the CFH promoter and the rs800292 of the CFH gene, with individuals homozygous for the risk genotypes having ORs of 4.05 (95% CI 1.38–13.13; p = 0.0055) and of 4.49 (95% CI 1.29–20.15; p = 0.011) for both SNPs, respectively. ARMS2 and HTRA1 common risk alleles were also associated with a higher risk of PCV, with ORs of 3.97 (1.50–11.06; p = 0.0025) and 4.53 (95% CI 1.69–12.87; p = 0.0011) for homozygosity for both SNPs, respectively [73]. In the Japanese population, PCV has been found to be associated with ARMS2 and the Y402H SNP of the CFH gene [167]. In another Japanese study (100 PCV and 190 controls), the rs2241394 of the C3 gene, the rs800292 of the CFH gene and the rs10490924 of the ARMS2 gene were associated with an increased risk of PCV with ORs of 3.47 (1.48–8.38), 2.00 (1.37–2.92), and 4.16 (2.89–5.99). Other SNPs of the CFH gene were also associated with a higher risk of PCV in this genome-wide screening [75].

Other phenotypes, such as peripheral anomalies including reticular pigment changes and peripheral drusen, have been associated with both rs1061170 and rs1410996 of the CFH gene [168,169].

Basal laminar drusen (also called cuticular drusen) are characterized by a typical ‘stars in the sky’ appearance in fluorescein angiography. This particular clinical feature has been associated with the 402H variant of the CFH gene [170] and with compound heterozygosity for the R1078S and R567G missense variants or the Q408X nonsense mutation with the Y402H variant [171].

Relation between Genetic and Environmental Factors

In the classical model of complex diseases, numerous genes and environmental factors with small effects contribute to overall risk. In AMD, this model has been complicated by potential dominant or negative effects of some genes, potential gene-environment and gene-gene interactions, and by large genetic heterogeneity.

As smoking is the major environmental factor of exudative and atrophic AMD, accounting for 20% of the population-attributable risk, interaction analyses have been performed between this factor and various genetic factors [13]. Joint effects of the CFH gene and smoking, both independent from each other, are consistent with a multiplicative model [13,172], whereas conflicting data for an interaction between smoking and ARMS2/HTRA1 have been reported, some studies showing a strong interaction [13,105] while others found no interaction between ARMS2/HTRA1 and smoking [10,173,174,175]. However, most of these studies described a strong synergistic effect of smoking with these variants [10,13,105,174,175,176].

A higher body mass index has been associated with a higher incidence, prevalence and progression rate of AMD when combined with genetic factors [177,178,179,180]. Furthermore, although no interaction has been established between any particular genetic risk factor and body mass index up to now, this modifiable environmental factor increases the incidence and prevalence of AMD when combined with genetic factors [174,181].

Genetic Factors and Response to Preventive Medication or Treatments

It is likely that the ‘standard of care’ concept for AMD treatment or prevention in which all patients receive similar interventions might rapidly be replaced by a more personalized approach, based on the molecular characteristics of individual patients as developed in cancer therapy [182,183]. Predictive biomarkers including genomic, demographic and environmental parameters for increased risks of developing the disease can be used in primary prevention, might be used to evaluate the severity of the disease, and might also be used for secondary and tertiary prevention. Other biomarkers might be used to reflect sensitivity or resistance to existing therapies.

Preventive Medication and Genetic Biomarkers

The AREDS study demonstrated that a combination of zinc and antioxidants (β-carotene, vitamin C and vitamin E) leads to a 25% reduction in the development of advanced AMD over 5 years [184]. An ancillary study of the AREDS investigated whether genetic factors might influence the effect of the AREDS nutritional supplements on AMD [185]. This study is based on 876 individuals randomized to different subgroups (placebo, n = 204; antioxidants, n = 219; zinc, n = 217; antioxidants + zinc, n = 236) with a mean duration of treatment of 6.3 years. A greater reduction in AMD progression in the antioxidant + zinc group compared with the placebo group was observed in homozygous individuals with the wild allele (TT) compared with homozygous individuals with the risk allele (CC) of the CFH gene (reduction in the progression of 68 vs. 11%; p = 0.004). If the results of this study are confirmed, the preventive strategy using antioxidants and zinc could be considered as pointless in patients homozygous for the C risk allele, and very effective in patients homozygous for the T wild allele of rs1061170 of the CFH gene.

AMD Treatments and Genetic Biomarkers

In a recent study based of the analysis of baseline and posttreatment logMAR best corrected visual acuity of 110 Japanese patients with exudative AMD treated with photodynamic therapy (PDT) with a follow-up of 12 months, the authors demonstrated that the risk allele of rs11200638 of HTRA1 was associated with worse visual acuity outcomes (p = 1.10 × 10–3) and a 6-fold greater risk of CNV recurrence at 12 months (p = 5.58 × 10–3). Furthermore, both rs1410996 and rs2274700 of the CFH gene were also associated with a shorter interval between PDT treatment and CNV recurrence (p = 8.5 × 10–3) [186].

In another study including 309 eyes with exudative AMD of 267 patients treated with ranibizumab, patients carrying the CT or TT genotypes of rs1061170 of the CFH gene (Y402H variant) had better visual acuity outcomes at 12 months than those with the CC genotype, with an OR of 3.42 (95% CI 1.4–9.42; p = 0.006) [187].

In a study based on 168 eyes of 168 patients with exudative AMD treated with intravitreal injections of ranibizumab only or with a combination of ranibizumab and bevacizumab, the ApoE4 allele was associated with better visual acuity outcomes at 3 months, with an OR of 4.04 (95% CI 1.11–14.70; p = 0.03). Although not significant, a similar trend was reported between better visual acuity outcomes at 6 and 12 months and ApoE4 carriers, with an OR of 3.26 (95% CI 0.76–13.90; p = 0.11) and of 2.54 (95% CI 0.61–10.52; p = 0.2), respectively [188].

Toward Personalized Medicine for AMD

The era of personalized medicine has just begun, with commercialization of genomics testing along with genetic profiling for a wide panel of disorders, with the aim of obtaining individualized disease risk estimates in apparently healthy people with potential genetic risks of developing a disease (e.g. Parkinson’s disease, Alzheimer’s disease, type 2 diabetes or AMD). Presymptomatic risk assessment for AMD and personalized care to extend a healthy life span are now global priorities. Indeed, unraveling the genetics of AMD could lead to personalized treatment/preventive procedures or follow-up as in cancer therapy [189].

The area under the ROC curve, widely used as a usefulness measure of the discrimination power for a classifier, should be greater than 0.75 for an individual at increased risk of disease, and greater than 0.99 for the general population to predict the risk of developing the disease [190]. As regards AMD, because risk genotypes for both CFH and ARMS2/HTRA1 are strong (OR ≥2 for 1 risk allele in most studies) and common (with an MAF of 0.28 and 0.2/0.2, respectively, in the CEU population), good discriminative accuracy should be expected. Other proteomic or genomic biomarkers could perhaps increase the discrimination rate between AMD and controls with higher accuracy [191]. However, one should keep in mind that because of the lack of long-term prospective investigations in genetic epidemiology, genetic profiling is up to now mainly based on hypothetical models of simulation studies.

Conclusion

Genetic factors of AMD are now considered as reliable genomic biomarkers to predict the risk of developing the disease and to predict both disease severity and progression. Hitherto a binary therapeutic approach to exudative AMD has been available with two anti-VEGF therapies available. However, other therapeutic strategies will be developed and the response to each treatment should be considered in further studies taking into account genomic markers to define personalized treatment for each individual.

Disclosure Statement

There are no conflicts of interest.


References

  1. Chakravarthy U, Wong TY, Fletcher A, Piault E, Evans C, Zlateva G, Buggage R, Pleil A, Mitchell P: Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol 2010;10:31.
  2. Klein R, Cruickshanks KJ, Nash SD, Krantz EM, Javier Nieto F, Huang GH, Pankow JS, Klein BE: The prevalence of age-related macular degeneration and associated risk factors. Arch Ophthalmol 2010;128:750–758.
  3. Chong EW, Robman LD, Simpson JA, Hodge AM, Aung KZ, Dolphin TK, English DR, Giles GG, Guymer RH: Fat consumption and its association with age-related macular degeneration. Arch Ophthalmol 2009;127:674–680.
  4. Seddon JM, George S, Rosner B: Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-related Macular Degeneration. Arch Ophthalmol 2006;124:995–1001.
  5. Delcourt C, Carrière I, Delage M, Barberger-Gateau P, Schalch W; POLA Study Group: Plasma lutein and zeaxanthin and other carotenoids as modifiable risk factors for age-related maculopathy and cataract: the POLA Study. Invest Ophthalmol Vis Sci 2006;47:2329–2335.
  6. Age-Related Eye Disease Study Research Group, San Giovanni JP, Chew EY, Clemons TE, Ferris FL 3rd, Gensler G, Lindblad AS, Milton RC, Seddon JM, Sperduto RD: The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No 22. Arch Ophthalmol 2007;125:1225–1232.
  7. Despriet DD, Klaver CC, Witteman JC, Bergen AA, Kardys I, de Maat MP, Boekhoorn SS, Vingerling JR, Hofman A, Oostra BA, Uitterlinden AG, Stijnen T, van Duijn CM, de Jong PT: Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA 2006;296:301–309.
  8. Seitsonen SP, Onkamo P, Peng G, Xiong M, Tommila PV, Ranta PH, Holopainen JM, Moilanen JA, Palosaari T, Kaarniranta K, Meri S, Immonen IR, Järvelä IE: Multifactor effects and evidence of potential interaction between complement factor H Y402H and LOC387715 A69S in age-related macular degeneration. PLoS One 2008;3:e3833.
  9. Gibson J, Cree A, Collins A, Lotery A, Ennis S: Determination of a gene and environment risk model for age-related macular degeneration. Br J Ophthalmol 2010;94:1382–1387.
  10. Seddon JM, Reynolds R, Maller J, Fagerness JA, Daly MJ, Rosner B: Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci 2009;50:2044–2053.
  11. Wang JJ, Rochtchina E, Smith W, Klein R, Klein BE, Joshi T, Sivakumaran TA, Iyengar S, Mitchell P: Combined effects of complement factor H genotypes, fish consumption, and inflammatory markers on long-term risk for age-related macular degeneration in a cohort. Am J Epidemiol 2009;169:633–641.
  12. Schaumberg DA, Hankinson SE, Guo Q, Rimm E, Hunter DJ: A prospective study of 2 major age-related macular degeneration susceptibility alleles and interactions with modifiable risk factors. Arch Ophthalmol 2007;125:55–62.
  13. Schmidt S, Hauser MA, Scott WK, Postel EA, Agarwal A, Gallins P, Wong F, Chen YS, Spencer K, Schnetz-Boutaud N, Haines JL, Pericak-Vance MA: Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet 2006;78:852–864.
  14. Robman L, Baird PN, Dimitrov PN, Richardson AJ, Guymer RH: C-reactive protein levels and complement factor H polymorphism interaction in age-related macular degeneration and its progression. Ophthalmology 2010;117:1982–1988.
  15. Meyers SM: A twin study on age-related macular degeneration. Trans Am Ophthalmol Soc 1994;92:775–843.
  16. Meyers SM, Greene T, Gutman FA: A twin study of age-related macular degeneration. Am J Ophthalmol 1995;120:757–766.
  17. Gottfredsdottir MS, Sverrisson T, Musch DC, Stefánsson E: Age related macular degeneration in monozygotic twins and their spouses in Iceland. Acta Ophthalmol Scand 1999;77:422–425.
  18. Hammond CJ, Webster AR, Snieder H, Bird AC, Gilbert CE, Spector TD: Genetic influence on early age-related maculopathy: a twin study. Ophthalmology 2002;109:730–736.
  19. Grizzard SW, Arnett D, Haag SL: Twin study of age-related macular degeneration. Ophthalmic Epidemiol 2003;10:315–322.
  20. Seddon JM, Cote J, Page WF, Aggen SH, Neale MC: The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 2005;123:321–327.
  21. Bradley AE: Dystrophy of the macula. Am J Ophthalmol 1966;61:1–24.
  22. Gass JDM: Drusen and disciform macular detachment and degeneration. Arch Ophthalmol 1973;90:206–217.
  23. Hyman LG, Lilienfeld AM, Ferris FL 3rd, Fine SL: Senile macular degeneration: a case-control study. Am J Epidemiol 1983;118:213–227.
  24. Silvestri G, Johnston PB, Hughes AE: Is genetic predisposition an important risk factor for age-related macular degeneration? Eye 1995;8:564–568.
    External Resources
  25. Seddon JM, Ajani UA, Mitchell BD: Familial aggregation of age-related maculopathy. Am J Ophthalmol 1997;123:199–206.
  26. Klaver CC, Wolfs RC, Assink JJ, van Duijn CM, Hofman A, de Jong PT: Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophthalmol 1998;116:1646–1651.
  27. Heiba IM, Elston RC, Klein BE, Klein R: Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam Eye Study. Genet Epidemiol1994;11:51–67.
  28. Souied EH, Ducroq D, Rozet JM, Gerber S, Perrault I, Munnich A, Coscas G, Soubrane G, Kaplan J: ABCR gene analysis in familial exudative age-related macular degeneration. Invest Ophthalmol Vis Sci 2000;41:244–247.
  29. Guymer RH, Héon E, Lotery AJ, Munier FL, Schorderet DF, Baird PN, McNeil RJ, Haines H, Sheffield VC, Stone EM: Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration. Arch Ophthalmol 2001;119:745–751.
  30. Schultz DW, Klein ML, Humpert AJ, Luzier CW, Persun V, Schain M, Mahan A, Runckel C, Cassera M, Vittal V, Doyle TM, Martin TM, Weleber RG, Francis PJ, Acott TS: Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. Hum Mol Genet 2003;12:3315–3323.
  31. Abecasis GR, Yashar BM, Zhao Y, Ghiasvand NM, Zareparsi S, Branham KE, Reddick AC, Trager EH, Yoshida S, Bahling J, Filippova E, Elner S, Johnson MW, Vine AK, Sieving PA, Jacobson SG, Richards JE, Swaroop A: Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease. Am J Hum Genet 2004;74:482–494.
  32. Schick JH, Iyengar SK, Klein BE, Klein R, Reading K, Liptak R, Millard C, Lee KE, Tomany SC, Moore EL, Fijal BA, Elston RC: A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study. Am J Hum Genet 2003;72:1412–1424.
  33. Klein ML, Schultz DW, Edwards A, Matise TC, Rust K, Berselli CB, Trzupek K, Weleber RG, Ott J, Wirtz MK, Acott TS: Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Arch Ophthalmol 1998;116:1082–1088.
  34. Iyengar SK, Song D, Klein BE, Klein R, Schick JH, Humphrey J, Millard C, Liptak R, Russo K, Jun G, Lee KE, Fijal B, Elston RC: Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. Am J Hum Genet 2004;74:20–39.
  35. Majewski J, Schultz DW, Weleber RG, Schain MB, Edwards AO, Matise TC, Acott TS, Ott J, Klein ML: Age-related macular degeneration – a genome scan in extended families. Am J Hum Genet 2003;73:540–550.
  36. Seddon JM, Santangelo SL, Book K, Chong S, Cote J: A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions. Am J Hum Genet 2003;73:780–790.
  37. Weeks DE, Conley YP, Mah TS, Paul TO, Morse L, Ngo-Chang J, Dailey JP, Ferrell RE, Gorin MB: A full genome scan for age-related maculopathy. Hum Mol Genet 2000;9:1329–1349.
  38. Jorgensen TJ, Ruczinski I, Kessing B, Smith MW, Shugart YY, Alberg AJ: Hypothesis-driven candidate gene association studies: practical design and analytical considerations. Am J Epidemiol 2009;170:986–993.
  39. Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH: A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 2000;70:441–449.
  40. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF: An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705–732.
  41. Mullins RF, Aptsiauri N, Hageman GS: Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye (Lond) 2001;15:390–395.
  42. Umeda S, Suzuki MT, Okamoto H, Ono F, Mizota A, Terao K, Yoshikawa Y, Tanaka Y, Iwata T: Molecular composition of drusen and possible involvement of anti-retinal autoimmunity in two different forms of macular degeneration in cynomolgus monkey (Macaca fascicularis). FASEB J 2005;19:1683–1685.
  43. Anderson DH, Mullins RF, Hageman GS, Johnson LV: A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134:411–431.
  44. Bora PS, Sohn JH, Cruz JM, Jha P, Nishihori H, Wang Y, Kaliappan S, Kaplan HJ, Bora NS: Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization. J Immunol 2005;174:491–497.
  45. Kijlstra A, La Heij E, Hendrikse F: Immunological factors in the pathogenesis and treatment of age-related macular degeneration. Ocul Immunol Inflamm 2005;13:3–11.
  46. Swaroop A, Branham KE, Chen W, Abecasis G: Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Hum Mol Genet 2007;16:174–182.
    External Resources
  47. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R: A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.Proc Natl Acad Sci USA 2005;102:7227–7232.
  48. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA: Complement factor H polymorphism and age-related macular degeneration. Science 2005;308:421–424.
  49. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J: Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–389.
  50. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA: Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419–421.
  51. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM: Finding the missing heritability of complex diseases. Nature 2009;461:747–753.
  52. Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, Tam PO, Chan WM, Lam DS, Snyder M, Barnstable C, Pang CP, Hoh J: HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 2006;314:989–992.
  53. Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research, et al: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331–1336.
  54. Easton DF, Pooley KA, Dunning AM, et al: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007;447:1087–1093.
  55. Klein C, Ziegler A: From GWAS to clinical utility in Parkinson’s disease. Lancet 2011;377:613–614.
  56. Johnson LV, Leitner WP, Staples MK, Anderson DH: Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res 2001;73:887–896.
  57. Baudouin C, Peyman GA, Fredj-Reygrobellet D, Gordon WC, Lapalus P, Gastaud P, Bazan NG: Immunohistological study of subretinal membranes in age-related macular degeneration. Jpn J Ophthalmol 1992;36:443–451.
  58. Giannakis E, Jokiranta TS, Male DA, Ranganathan S, Ormsby RJ, Fischetti VA, Mold C, Gordon DL: A common site within factor H SCR 7 responsible for binding heparin, C-reactive protein and streptococcal M protein. Eur J Immunol 2003;33:962–969.
  59. Sjöberg AP, Trouw LA, Clark SJ, Sjölander J, Heinegård D, Sim RB, Day AJ, Blom AM: The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells. J Biol Chem 2007;282:10894–10900.
  60. Skerka C, Lauer N, Weinberger AA, Keilhauer CN, Sühnel J, Smith R, Schlötzer-Schrehardt U, Fritsche L, Heinen S, Hartmann A, Weber BH, Zipfel PF: Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol Immunol 2007;44:3398–3406.
  61. Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, Hancox LS, Hu J, Ebright JN, Malek G, Hauser MA, Rickman CB, Bok D, Hageman GS, Johnson LV: The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 2010;29:95–112.
  62. Hayashi H, Yamashiro K, Gotoh N, Nakanishi H, Nakata I, Tsujikawa A, Otani A, Saito M, Iida T, Matsuo K, Tajima K, Yamada R, Yoshimura N: CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 2010;51:5914–5919.
  63. Dong L, Qu Y, Jiang H, Dai H, Zhou F, Xu X, Bi H, Pan X, Dang G: Correlation of complement factor H gene polymorphisms with exudative age-related macular degeneration in a Chinese cohort. Neurosci Lett 2011;488:283–287.
  64. Xu Y, Guan N, Xu J, Yang X, Ma K, Zhou H, Zhang F, Snellingen T, Jiao Y, Liu X, Wang N, Liu N: Association of CFH, LOC387715, and HTRA1 polymorphisms with exudative age-related macular degeneration in a northern Chinese population. Mol Vis 2008;14:1373–1381.
  65. Fuse N, Miyazawa A, Mengkegale M, Yoshida M, Wakusawa R, Abe T, Tamai M: Polymorphisms in complement Factor H and hemicentin-1 genes in a Japanese population with dry-type age-related macular degeneration. Am J Ophthalmol 2006;142:1074–1076.
  66. Mori K, Gehlbach PL, Kabasawa S, Kawasaki I, Oosaki M, Iizuka H, Katayama S, Awata T, Yoneya S: Coding and noncoding variants in the CFH gene and cigarette smoking influence the risk of age-related macular degeneration in a Japanese population. Invest Ophthalmol Vis Sci 2007;48:5315–5319.
  67. Kim NR, Kang JH, Kwon OW, Lee SJ, Oh JH, Chin HS: Association between complement factor H gene polymorphisms and neovascular age-related macular degeneration in Koreans. Invest Ophthalmol Vis Sci 2008;49:2071–2076.
  68. Chen LJ, Liu DT, Tam PO, Chan WM, Liu K, Chong KK, Lam DS, Pang CP: Association of complement factor H polymorphisms with exudative age-related macular degeneration. Mol Vis 2006;12:1536–1542.
  69. Ng TK, Chen LJ, Liu DT, Tam PO, Chan WM, Liu K, Hu YJ, Chong KK, Lau CS, Chiang SW, Lam DS, Pang CP: Multiple gene polymorphisms in the complement factor H gene are associated with exudative age related macular degeneration in Chinese. Invest Ophthalmol Vis Sci 2008;49:3312–3317.
  70. Lau LI, Chen SJ, Cheng CY, et al: Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. Invest Ophthalmol Vis Sci 2006;47:3242–3246.
  71. Gotoh N, Yamada R, Hiratani H, Renault V, Kuroiwa S, Monet M, Toyoda S, Chida S, Mandai M, Otani A, Yoshimura N, Matsuda F: No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese. Hum Genet2006;120:139–143.
  72. Uka J, Tamura H, Kobayashi T, Yamane K, Kawakami H, Minamoto A, Mishima HK: No association of complement factor H gene polymorphism and age-related macular degeneration in the Japanese population. Retina 2006;26:985–987.
  73. Lee KY, Vithana EN, Mathur R, Yong VH, Yeo IY, Thalamuthu A, Lee MW, Koh AH, Lim MC, How AC, Wong DW, Aung T: Association analysis of CFH, C2, BF, and HTRA1 gene polymorphisms in Chinese patients with polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2008;49:2613–2619.
  74. Kondo N, Honda S, Kuno S, Negi A: Coding variant I62V in the complement factor H gene is strongly associated with polypoidal choroidal vasculopathy. Ophthalmology. 2009;116:304–310.
  75. Goto A, Akahori M, Okamoto H, Minami M, Terauchi N, Haruhata Y, Obazawa M, Noda T, Honda M, Mizota A, Tanaka M, Hayashi T, Tanito M, Ogata N, Iwata T: Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population. J Ocul Biol Dis Infor 2009;2:164–175.
  76. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT; AMD Genetics Clinical Study Group, Hageman GS, Dean M, Allikmets R: Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006;38:458–462.
  77. Spencer KL, Hauser MA, Olson LM, Schmidt S, Scott WK, Gallins P, Agarwal A, Postel EA, Pericak-Vance MA, Haines JL: Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Hum Mol Genet 2007;16:1986–1992.
  78. Jakobsdottir J, Conley YP, Weeks DE, Ferrell RE, Gorin MB: C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes. PLoS One 2008;3:e2199.
  79. Montes T, Tortajada A, Morgan BP, Rodríguez de Córdoba S, Harris CL: Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc Natl Acad Sci USA 2009;106:4366–4371.
  80. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT; Genetic Factors in AMD Study Group: Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 2007;357:553–561.
  81. Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM: Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 2007;39:1200–1201.
  82. Spencer KL, Olson LM, Anderson BM, Schnetz-Boutaud N, Scott WK, Gallins P, Agarwal A, Postel EA, Pericak-Vance MA, Haines JL: C3 R102G polymorphism increases risk of age-related macular degeneration. Hum Mol Genet 2008;17:1821–1824.
  83. Despriet DD, van Duijn CM, Oostra BA, Uitterlinden AG, Hofman A, Wright AF, ten Brink JB, Bakker A, de Jong PT, Vingerling JR, Bergen AA, Klaver CC: Complement component C3 and risk of age-related macular degeneration. Ophthalmology 2009;116:474–480.
  84. Park KH, Fridley BL, Ryu E, Tosakulwong N, Edwards AO: Complement component 3 (C3) haplotypes and risk of advanced age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50:3386–3393.
  85. Bergeron-Sawitzke J, Gold B, Olsh A, Schlotterbeck S, Lemon K, Visvanathan K, Allikmets R, Dean M: Multilocus analysis of age-related macular degeneration. Eur J Hum Genet 2009;17:1190–1199.
  86. Scholl HP, Fleckenstein M, Fritsche LG, Schmitz-Valckenberg S, Göbel A, Adrion C, Herold C, Keilhauer CN, Mackensen F, Mössner A, Pauleikhoff D, Weinberger AW, Mansmann U, Holz FG, Becker T, Weber BH: CFH, C3 and ARMS2 are significant risk loci for susceptibility but not for disease progression of geographic atrophy due to AMD. PLoS One 2009;4:e7418.
  87. Zerbib J, Richard F, Puche N, Leveziel N, Cohen SY, Korobelnik JF, Sahel J, Munnich A, Kaplan J, Rozet JM, Souied EH: R102G polymorphism of the C3 gene associated with exudative age-related macular degeneration in a French population. Mol Vis 2010;16:1324–1330.
  88. Pei XT, Li XX, Bao YZ, Yu WZ, Yan Z, Qi HJ, Qian T, Xiao HX: Association of C3 gene polymorphisms with neovascular age-related macular degeneration in a Chinese population. Curr Eye Res 2009;34:615–622.
  89. Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM: Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 2009;17:100–104.
  90. Ennis S, Gibson J, Cree AJ, Collins A, Lotery AJ: Support for the involvement of complement factor I in age-related macular degeneration. Eur J Hum Genet 2010;18:15–16.
  91. Kondo N, Bessho H, Honda S, Negi A: Additional evidence to support the role of a common variant near the complement factor I gene in susceptibility to age-related macular degeneration. Eur J Hum Genet 2010;18:634–635.
  92. Yu Y, Bhangale TR, Fagerness J, Ripke S, Thorleifsson G, Tan PL, Souied EH, Richardson AJ, Merriam JE, Buitendijk GH, Reynolds R, Raychaudhuri S, Chin KA, Sobrin L, Evangelou E, Lee PH, Lee AY, Leveziel N, Zack DJ, Campochiaro B, Campochiaro P, Smith RT, Barile GR, Guymer RH, Hogg R, Chakravarthy U, Robman LD, Gustafsson O, Sigurdsson H, Ortmann W, Behrens TW, Stefansson K, Uitterlinden AG, van Duijn CM, Vingerling JR, Klaver CC, Allikmets R, Brantley MA Jr, Baird PN, Katsanis N, Thorsteinsdottir U, Ioannidis JP, Daly MJ, Graham RR, Seddon JM: Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum Mol Genet 2011, Epub ahead of print.
  93. Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB: Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 2005;77:389–407.
  94. Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, Weber BH: Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 2005;14:3227–3236.
  95. Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K: A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006;314:992–993.
  96. Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, Weber BH: Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 2008;40:892–896.
  97. Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, He S, Lyons R, Abecasis GR, Swaroop A: A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci USA 2007;104:16227–16232.
  98. Wang G, Spencer KL, Court BL, Olson LM, Scott WK, Haines JL, Pericak-Vance MA: Localization of age-related macular degeneration-associated ARMS2 in cytosol, not mitochondria. Invest Ophthalmol Vis Sci 2009;50:3084–3090.
  99. Kortvely E, Hauck SM, Duetsch G, Gloeckner CJ, Kremmer E, Alge-Priglinger CS, Deeg CA, Ueffing M: ARMS2 is a constituent of the extracellular matrix providing a link between familial and sporadic age-related macular degenerations. Invest Ophthalmol Vis Sci 2010;51:79–88.
  100. Friedrich U, Myers CA, Fritsche LG, Milenkovich A, Wolf A, Corbo JC, Weber BH: Risk- and non-risk-associated variants at the 10q26 AMD locus influence ARMS2 mRNA expression but exclude pathogenic effects due to protein deficiency. Hum Mol Genet 2011;20:1387–1399.
  101. Kanda A, Stambolian D, Chen W, Curcio CA, Abecasis GR, Swaroop A: Age-related macular degeneration-associated variants at chromosome 10q26 do not significantly alter ARMS2 and HTRA1 transcript levels in the human retina. Mol Vis 2010;16:1317–1323.
  102. An E, Sen S, Park SK, Gordish-Dressman H, Hathout Y: Identification of novel substrates for the serine protease HTRA1 in the human RPE secretome. Invest Ophthalmol Vis Sci 2010;51:3379–3386.
  103. Yang Z, Tong Z, Chen Y, Zeng J, Lu F, Sun X, Zhao C, Wang K, Davey L, Chen H, London N, Muramatsu D, Salasar F, Carmona R, Kasuga D, Wang X, Bedell M, Dixie M, Zhao P, Yang R, Gibbs D, Liu X, Li Y, Li C, Li Y, Campochiaro B, Constantine R, Zack DJ, Campochiaro P, Fu Y, Li DY, Katsanis N, Zhang K: Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. PLoS Genet 2010;6:e1000836.
  104. Ng TK, Yam GH, Chen WQ, Lee VY, Chen H, Chen LJ, Choy KW, Yang Z, Pang CP: Interactive expressions of HtrA1 and VEGF in human vitreous humors and fetal RPE cells. Invest Ophthalmol Vis Sci 2011, Epub ahead of print.
  105. Conley YP, Jakobsdottir J, Mah T, Weeks DE, Klein R, Kuller L, Ferrell RE, Gorin MB: CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Hum Mol Genet 2006;15:3206–3218.
  106. Curcio CA, Presley JB, Malek G, Medeiros NE, Avery DV, Kruth HS: Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy. Exp Eye Res 2005;81:731–741.
  107. Li CM, Chung BH, Presley JB, Malek G, Zhang X, Dashti N, Li L, Chen J, Bradley K, Kruth HS, Curcio CA: Lipoprotein-like particles and cholesteryl esters in human Bruch’s membrane: initial characterization. Invest Ophthalmol Vis Sci 2005;46:2576–2586.
  108. Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH: Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E (LDL) receptors in the brain. J Biol Chem 1987;262:14352–14360.
  109. Schneider WJ, Nimpf J: LDL receptor relatives at the crossroad of endocytosis and signaling. Cell Mol Life Sci 2003;60:892–903.
  110. Corbo RM, Scacchi R: Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele? Ann Hum Genet 1999;63:301–310.
  111. Klaver CC, Kliffen M, van Duijn CM, Hofman A, Cruts M, Grobbee DE, van Broeckhoven C, de Jong PT: Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 1998;63:200–206.
  112. Souied EH, Benlian P, Amouyel P, Feingold J, Lagarde JP, Munnich A, Kaplan J, Coscas G, Soubrane G: The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol 1998;125:353–359.
  113. Schmidt S, Saunders AM, De La Paz MA, Postel EA, Heinis RM, Agarwal A, Scott WK, Gilbert JR, McDowell JG, Bazyk A, Gass JD, Haines JL, Pericak-Vance MA: Association of the apolipoprotein E gene with age-related macular degeneration: possible effect modification by family history, age, and gender. Mol Vis 2000;6:287–293.
  114. Simonelli F, Margaglione M, Testa F, Cappucci G, Manitto MP, Brancato R, Rinaldi E: Apolipoprotein E polymorphisms in age-related macular degeneration in an Italian population. Ophthalmic Res 2001;33:325–328.
  115. Schmidt S, Klaver C, Saunders A, Postel E, De La Paz M, Agarwal A, Small K, Udar N, Ong J, Chalukya M, Nesburn A, Kenney C, Domurath R, Hogan M, Mah T, Conley Y, Ferrell R, Weeks D, de Jong PT, van Duijn C, Haines J, Pericak-Vance M, Gorin M: A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy. Ophthalmic Genet 2002;23:209–223.
  116. Zareparsi S, Reddick AC, Branham KE, Moore KB, Jessup L, Thoms S, Smith-Wheelock M, Yashar BM, Swaroop A: Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. Invest Ophthalmol Vis Sci 2004;45:1306–1310.
  117. Baird PN, Guida E, Chu DT, Vu HT, Guymer RH: The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 2004;45:1311–1315.
  118. Bojanowski CM, Shen D, Chew EY, Ning B, Csaky KG, Green WR, Chan CC, Tuo J: An apolipoprotein E variant may protect against age-related macular degeneration through cytokine regulation. Environ Mol Mutagen 2006;47:594–602.
  119. Kaur I, Hussain A, Hussain N, Das T, Pathangay A, Mathai A, Hussain A, Nutheti R, Nirmalan PK, Chakrabarti S: Analysis of CFH, TLR4, and APOE polymorphism in India suggests the Tyr402His variant of CFH to be a global marker for age-related macular degeneration. Invest Ophthalmol Vis Sci 2006;47:3729–3735.
  120. Tikellis G, Sun C, Gorin MB, Klein R, Klein BE, Larsen EK, Siscovick DS, Hubbard LD, Wong TY: Apolipoprotein E gene and age-related maculopathy in older individuals: the cardiovascular health study. Arch Ophthalmol 2007;125:68–73.
  121. Francis PJ, Hamon SC, Ott J, Weleber RG, Klein ML: Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J Med Genet 2009;46:300–307.
  122. Fritsche LG, Freitag-Wolf S, Bettecken T, Meitinger T, Keilhauer CN, Krawczak M, Weber BH: Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene. Hum Mutat 2009;30:1048–1053.
  123. Thakkinstian A, Bowe S, McEvoy M, Smith W, Attia J: Association between apolipoprotein E polymorphisms and age-related macular degeneration: A HuGE review and meta-analysis. Am J Epidemiol 2006;164:813–822.
  124. Pang CP, Baum L, Chan WM, Lau TC, Poon PM, Lam DS: The apolipoprotein E epsilon4 allele is unlikely to be a major risk factor of age-related macular degeneration in Chinese. Ophthalmologica 2000;214:289–291.
  125. Schultz DW, Klein ML, Humpert A, Majewski J, Schain M, Weleber RG, Ott J, Acott TS: Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration. Arch Ophthalmol 2003;121:679–683.
  126. Gotoh N, Kuroiwa S, Kikuchi T, Arai J, Arai S, Yoshida N, Yoshimura N: Apolipoprotein E polymorphisms in Japanese patients with polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Am J Ophthalmol 2004;138:567–573.
  127. DeAngelis MM, Ji F, Kim IK, Adams S, Capone A Jr, Ott J, Miller JW, Dryja TP: Cigarette smoking, CFH, APOE, ELOVL4, and risk of neovascular age-related macular degeneration. Arch Ophthalmol 2007;125:49–54.
  128. Utheim ØA, Ritland JS, Utheim TP, Espeseth T, Lydersen S, Rootwelt H, Semb SO, Elsås T: Apolipoprotein E genotype and risk for development of cataract and age-related macular degeneration. Acta Ophthalmol 2008;86:401–403.
  129. Losonczy G, Fekete A, Vokó Z, Takács L, Káldi I, Ajzner E, Kasza M, Vajas A, Berta A, Balogh I: Analysis of complement factor H Y402H, LOC387715, HTRA1 polymorphisms and ApoE alleles with susceptibility to age-related macular degeneration in Hungarian patients. Acta Ophthalmol 2011;89:255–262.
  130. Payami H, Zareparsi S, Montee KR, Sexton GJ, Kaye JA, Bird TD, Yu CE, Wijsman EM, Heston LL, Litt M, Schellenberg GD: Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet 1996;58:803–811.
  131. Wilson PW, Schaefer EJ, Larson MG, Ordovas JM: Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler Thromb Vasc Biol 1996;16:1250–1255.
  132. Vergeer M, Korporaal SJ, Franssen R, Meurs I, Out R, Hovingh GK, Hoekstra M, Sierts JA, Dallinga-Thie GM, Motazacker MM, Holleboom AG, Van Berkel TJ, Kastelein JJ, Van Eck M, Kuivenhoven JA: Genetic variant of the scavenger receptor BI in humans. N Engl J Med 2011;364:136–145.
  133. Reboul E, Abou L, Mikail C, Ghiringhelli O, André M, Portugal H, Jourdheuil-Rahmani D, Amiot MJ, Lairon D, Borel P: Lutein transport by Caco-2 TC-7 cells occurs partly by a facilitated process involving the scavenger receptor class B type I (SR-BI). Biochem J 2005;387:455–461.
  134. Zerbib J, Seddon JM, Richard F, Reynolds R, Leveziel N, Benlian P, Borel P, Feingold J, Munnich A, Soubrane G, Kaplan J, Rozet JM, Souied EH: rs5888 variant of SCARB1 gene is a possible susceptibility factor for age-related macular degeneration. PLoS One 2009;4:e7341.
  135. Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J, et al: Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci USA 2010;107:7401–7406.
  136. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, et al: Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161–169.
  137. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, et al: Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41:56–65.
  138. Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S, et al: Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci USA 2010;107:7395–7400.
  139. Reynolds R, Rosner B, Seddon JM: Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology 2010;117:1989–1995.
  140. Seddon JM, Reynolds R, Rosner B: Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration. Mol Vis 2010;16:2412–2424.
  141. Karunadharma PP, Nordgaard CL, Olsen TW, Ferrington DA: Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51:5470–5479.
  142. SanGiovanni JP, Arking DE, Iyengar SK, Elashoff M, Clemons TE, Reed GF, Henning AK, Sivakumaran TA, Xu X, DeWan A, Agrón E, Rochtchina E, Sue CM, Wang JJ, Mitchell P, Hoh J, Francis PJ, Klein ML, Chew EY, Chakravarti A: Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PLoS One 2009;4:e5508.
  143. Udar N, Atilano SR, Memarzadeh M, Boyer DS, Chwa M, Lu S, Maguen B, Langberg J, Coskun P, Wallace DC, Nesburn AB, Khatibi N, Hertzog D, Le K, Hwang D, Kenney MC: Mitochondrial DNA haplogroups associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50:2966–2974.
  144. Jones MM, Manwaring N, Wang JJ, Rochtchina E, Mitchell P, Sue CM: Mitochondrial DNA haplogroups and age-related maculopathy. Arch Ophthalmol 2007;125:1235–1240.
  145. Schmid-Kubista KE, Tosakulwong N, Wu Y, Ryu E, Hecker LA, Baratz KH, Brown WL, Edwards AO: Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50:5070–5079.
  146. Liu MM, Agrón E, Chew E, Meyerle C, Ferris FL 3rd, Chan CC, Tuo J: Copy number variations in candidate genes in neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 2011. Epub ahead of print.
  147. Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N, Redon R, Bird CP, de Grassi A, Lee C, Tyler-Smith C, Carter N, Scherer SW, Tavaré S, Deloukas P, Hurles ME, Dermitzakis ET: Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007;315:848–853.
  148. Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U: A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 2006;38:1173–1177.
  149. Hageman GS, Hancox LS, Taiber AJ, Gehrs KM, Anderson DH, Johnson LV, Radeke MJ, Kavanagh D, Richards A, Atkinson J, Meri S, Bergeron J, Zernant J, Merriam J, Gold B, Allikmets R, Dean M; AMD Clinical Study Group: Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 2006;38:592–604.
  150. Spencer KL, Hauser MA, Olson LM, Schmidt S, Scott WK, Gallins P, Agarwal A, Postel EA, Pericak-Vance MA, Haines JL: Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration. Hum Mol Genet 2008;17:971–977.
  151. Raychaudhuri S, Ripke S, Li M, Neale BM, Fagerness J, Reynolds R, Sobrin L, Swaroop A, Abecasis G, Seddon JM, Daly MJ: Associations of CFHR1-CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. Nat Genet 2010;42:553–555.
  152. Heinen S, Hartmann A, Lauer N, Wiehl U, Dahse HM, Schirmer S, Gropp K, Enghardt T, Wallich R, Hälbich S, Mihlan M, Schlötzer-Schrehardt U, Zipfel PF, Skerka C: Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood 2009;114:2439–2447.
  153. Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML: Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA 2007;297:1793–1800.
  154. Klein ML, Ferris FL 3rd, Francis PJ, Lindblad AS, Chew EY, Hamon SC, Ott J: Progression of geographic atrophy and genotype in age-related macular degeneration. Ophthalmology 2010;117:1554–1559.
  155. Brantley MA Jr, Fang AM, King JM, Tewari A, Kymes SM, Shiels A: Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology 2007;114:2168–2173.
  156. Leveziel N, Zerbib J, Richard F, Querques G, Morineau G, Fremeaux-Bacchi V, Coscas G, Soubrane G, Benlian P, Souied EH: Genotype-phenotype correlations for exudative age-related macular degeneration associated with homozygous HTRA1 and CFH genotypes. Invest Ophthalmol Vis Sci 2008;49:3090–3094.
  157. Shuler RK Jr, Schmidt S, Gallins P, Hauser MA, Scott WK, Caldwell J, Agarwal A, Haines JL, Pericak-Vance MA, Postel EA: Phenotype analysis of patients with the risk variant LOC387715 (A69S) in age-related macular degeneration. Am J Ophthalmol 2008;145:303–307.
  158. Brantley MA Jr, Edelstein SL, King JM, Plotzke MR, Apte RS, Kymes SM, Shiels A: Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to photodynamic therapy. Eye 2009;23:626–631.
  159. Andreoli MT, Morrison MA, Kim BJ, Chen L, Adams SM, Miller JW, DeAngelis MM, Kim IK: Comprehensive analysis of complement factor H and LOC387715/ARMS2/HTRA1 variants with respect to phenotype in advanced age-related macular degeneration. Am J Ophthalmol 2009;148:869–874.
  160. Gotoh N, Yamada R, Nakanishi H, et al: Correlation between CFH Y402H and HTRA1 rs11200638 genotype to typical exudative age-related macular degeneration and polypoidal choroidal vasculopathy phenotype in the Japanese population. Clin Experiment Ophthalmol 2008;36:437–442.
  161. Leveziel N, Puche N, Richard F, Somner JE, Zerbib J, Bastuji-Garin S, Cohen SY, Korobelnik JF, Sahel J, Soubrane G, Benlian P, Souied EH: Genotypic influences on severity of exudative age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51:2620–2625.
  162. Chen Y, Zeng J, Zhao C, Wang K, Trood E, Buehler J, Weed M, Kasuga D, Bernstein PS, Hughes G, Fu V, Chin J, Lee C, Crocker M, Bedell M, Salasar F, Yang Z, Goldbaum M, Ferreyra H, Freeman WR, Kozak I, Zhang K: Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors. Arch Ophthalmol 2011;129:344–351.
  163. Wegscheider BJ, Weger M, Renner W, Steinbrugger I, März W, Mossböck G, Temmel W, El-Shabrawi Y, Schmut O, Jahrbacher R, Haas A: Association of complement factor H Y402H gene polymorphism with different subtypes of exudative age-related macular degeneration. Ophthalmology 2007;114:738–742.
  164. Brantley MA Jr, Edelstein SL, King JM, Apte RS, Kymes SM, Shiels A: Clinical phenotypes associated with the complement factor H Y402H variant in age-related macular degeneration. Am J Ophthalmol 2007;144:404–408.
  165. Goverdhan SV, Hannan S, Newsom RB, Luff AJ, Griffiths H, Lotery AJ: An analysis of the CFH Y402H genotype in AMD patients and controls from the UK, and response to PDT treatment. Eye (Lond) 2008;22:849–854.
  166. Sobrin L, Reynolds R, Yu Y, Fagerness J, Leveziel N, Bernstein PS, Souied EH, Daly MJ, Seddon JM: ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related macular degeneration. Am J Ophthalmol 2011;151:345–352.
  167. Nakanishi H, Yamashiro K, Yamada R, Gotoh N, Hayashi H, Nakata I, Saito M, Iida T, Oishi A, Kurimoto Y, Matsuo K, Tajima K, Matsuda F, Yoshimura N: Joint effect of cigarette smoking and CFH and LOC387715/HTRA1 polymorphisms on polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2010;51:6183–6187.
  168. Seddon JM, Reynolds R, Rosner B: Peripheral retinal drusen and reticular pigment: association with CFHY402H and CFHrs1410996 genotypes in family and twin studies. Invest Ophthalmol Vis Sci 2009;50:586–591.
  169. Munch IC, Ek J, Kessel L, Sander B, Almind GJ, Brøndum-Nielsen K, Linneberg A, Larsen M: Small, hard macular drusen and peripheral drusen: associations with AMD genotypes in the Inter99 Eye Study. Invest Ophthalmol Vis Sci 2010;51:2317–2321.
  170. Grassi MA, Folk JC, Scheetz TE, Taylor CM, Sheffield VC, and Stone EM: Complement factor H polymorphism p.Tyr402His and cuticular drusen. Arch Ophthalmol 2007;125:93–97.
  171. Boon CJ, Klevering BJ, Hoyng CB, Zonneveld-Vrieling MN, Nabuurs SB, Blokland E, Cremers FP, den Hollander AI: Basal laminar drusen caused by compound heterozygous variants in the CFH gene. Am J Hum Genet 2008;82:516–523.
  172. Sepp T, Khan JC, Thurlby DA, Shahid H, Clayton DG, Moore AT, Bird AC, Yates JR: Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci 2006;47:536–540.
  173. Hughes AE, Orr N, Patterson C, Esfandiary H, Hogg R, McConnell V, Silvestri G, Chakravarthy U: Neovascular age-related macular degeneration risk based on CFH, LOC387715/HTRA1, and smoking. PLoS Med 2007;4:e355.
  174. Francis PJ, George S, Schultz DW, Rosner B, Hamon S, Ott J, Weleber RG, Klein ML, Seddon JM: The LOC387715 gene, smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 2007;63:212–218.
  175. Wang JJ, Ross RJ, Tuo J, Burlutsky G, Tan AG, Chan CC, Favaloro EJ, Williams A, Mitchell P: The LOC387715 polymorphism, inflammatory markers, smoking, and age-related macular degeneration. A population-based case-control study. Ophthalmology 2008;115:693–699.
  176. Lee SJ, Kim NR, Chin HS: LOC387715/HTRA1 polymorphisms, smoking and combined effects on exudative age-related macular degeneration in a Korean population. Clin Experiment Ophthalmol 2010;38:698–704.
  177. Age-related Eye Disease Study Report Number 3. Ophthalmology 2000;107:2224–2232.
  178. Delcourt C, Michel F, Colvez A, Lacroux A, Delage M, Vernet MH; POLA Study Group: Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study. Ophthalmic Epidemiol 2001;8:237–249.
  179. Seddon JM, Cote J, Davis N, Rosner B: Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio. Arch Ophthalmol 2003;121:785–792.
  180. Clemons TE, Milton RC, Klein R, Seddon JM, Ferris FL 3rd; Age-related Eye Disease Study Research Group: Risk factors for the incidence of Advanced Age-related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report No 19. Ophthalmology 2005;112:533–539.
  181. Seddon JM, George S, Rosner B, Klein ML: CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 2006;61:157–165.
  182. Lee SY, McLeod HL: Pharmacogenetic tests in cancer chemotherapy: what physicians should know for clinical application. J Pathol 2011;223:15–27.
  183. Ellsworth RE, Decewicz DJ, Shriver CD, Ellsworth DL: Breast cancer in the personal genomics era. Curr Genomics 2010;11:146–161.
  184. Age-Related Eye Disease Study Research Group: A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, β-carotene, and zinc for age-related macular degeneration and vision loss: AREDS report No 8. Arch Ophthalmol 2001;119:1417–1436.
  185. Klein ML, Francis PJ, Rosner B, Reynolds R, Hamon SC, Schultz DW, Ott J, Seddon JM: CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 2008;115:1019–1025.
  186. Tsuchihashi T, Mori K, Horie-Inoue K, Gehlbach PL, Kabasawa S, Takita H, Ueyama K, Okazaki Y, Inoue S, Awata T, Katayama S, Yoneya S: Complement factor H and high-temperature requirement A-1 genotypes and treatment response of age-related macular degeneration. Ophthalmology 2011;118:93–100.
  187. Kloeckener-Gruissem B, Barthelmes D, Labs S, Schindler C, Kurz-Levin M, Michels S, Fleischhauer J, Berger W, Sutter F, Menghini M: Genetic association with response to intravitreal ranibizumab (Lucentis®) in neovascular AMD patients. Invest Ophthalmol Vis Sci 2011. Epub ahead of print.
  188. Wickremasinghe SS, Xie J, Lim J, Chauhan DS, Robman L, Richardson AJ, Hageman G, Baird PN, Guymer R: Variants in the APOE Gene are Associated with Improved Treatment Outcome Following Anti-VEGF Therapy for Neovascular AMD. Invest Ophthalmol Vis Sci 2011. Epub ahead of print.
  189. McDermott U, Downing JR, Stratton MR: Genomics and the continuum of cancer care. N Engl J Med 2011;364:340–350.
  190. Janssens AC, Moonesinghe R, Yang Q, Steyerberg EW, van Duijn CM, Khoury MJ: The impact of genotype frequencies on the clinical validity of genomic profiling for predicting common chronic diseases. Genet Med 2007;9:528–535.
  191. Gu J, Pauer GJ, Yue X, Narendra U, Sturgill GM, Bena J, Gu X, Peachey NS, Salomon RG, Hagstrom SA, Crabb JW; Clinical Genomic and Proteomic AMD Study Group: Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers. Mol Cell Proteomics 2009;8:1338–1349.

Author Contacts

Dr. Nicolas Leveziel

Service d’Ophtalmologie, Hôpital Henri-Mondor

51, avenue du Maréchal-de-Lattre-de-Tassigny

FR–94010 Créteil Cedex (France)

Tel. +33 1 45 17 52 22, E-Mail nicolas.leveziel@chicreteil.fr


Article / Publication Details

First-Page Preview
Abstract of EURETINA &#x2013; Review

Received: April 27, 2011
Accepted: April 27, 2011
Published online: July 14, 2011
Issue release date: September 2011

Number of Print Pages: 16
Number of Figures: 0
Number of Tables: 0

ISSN: 0030-3755 (Print)
eISSN: 1423-0267 (Online)

For additional information: https://www.karger.com/OPH


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Chakravarthy U, Wong TY, Fletcher A, Piault E, Evans C, Zlateva G, Buggage R, Pleil A, Mitchell P: Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol 2010;10:31.
  2. Klein R, Cruickshanks KJ, Nash SD, Krantz EM, Javier Nieto F, Huang GH, Pankow JS, Klein BE: The prevalence of age-related macular degeneration and associated risk factors. Arch Ophthalmol 2010;128:750–758.
  3. Chong EW, Robman LD, Simpson JA, Hodge AM, Aung KZ, Dolphin TK, English DR, Giles GG, Guymer RH: Fat consumption and its association with age-related macular degeneration. Arch Ophthalmol 2009;127:674–680.
  4. Seddon JM, George S, Rosner B: Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-related Macular Degeneration. Arch Ophthalmol 2006;124:995–1001.
  5. Delcourt C, Carrière I, Delage M, Barberger-Gateau P, Schalch W; POLA Study Group: Plasma lutein and zeaxanthin and other carotenoids as modifiable risk factors for age-related maculopathy and cataract: the POLA Study. Invest Ophthalmol Vis Sci 2006;47:2329–2335.
  6. Age-Related Eye Disease Study Research Group, San Giovanni JP, Chew EY, Clemons TE, Ferris FL 3rd, Gensler G, Lindblad AS, Milton RC, Seddon JM, Sperduto RD: The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No 22. Arch Ophthalmol 2007;125:1225–1232.
  7. Despriet DD, Klaver CC, Witteman JC, Bergen AA, Kardys I, de Maat MP, Boekhoorn SS, Vingerling JR, Hofman A, Oostra BA, Uitterlinden AG, Stijnen T, van Duijn CM, de Jong PT: Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA 2006;296:301–309.
  8. Seitsonen SP, Onkamo P, Peng G, Xiong M, Tommila PV, Ranta PH, Holopainen JM, Moilanen JA, Palosaari T, Kaarniranta K, Meri S, Immonen IR, Järvelä IE: Multifactor effects and evidence of potential interaction between complement factor H Y402H and LOC387715 A69S in age-related macular degeneration. PLoS One 2008;3:e3833.
  9. Gibson J, Cree A, Collins A, Lotery A, Ennis S: Determination of a gene and environment risk model for age-related macular degeneration. Br J Ophthalmol 2010;94:1382–1387.
  10. Seddon JM, Reynolds R, Maller J, Fagerness JA, Daly MJ, Rosner B: Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci 2009;50:2044–2053.
  11. Wang JJ, Rochtchina E, Smith W, Klein R, Klein BE, Joshi T, Sivakumaran TA, Iyengar S, Mitchell P: Combined effects of complement factor H genotypes, fish consumption, and inflammatory markers on long-term risk for age-related macular degeneration in a cohort. Am J Epidemiol 2009;169:633–641.
  12. Schaumberg DA, Hankinson SE, Guo Q, Rimm E, Hunter DJ: A prospective study of 2 major age-related macular degeneration susceptibility alleles and interactions with modifiable risk factors. Arch Ophthalmol 2007;125:55–62.
  13. Schmidt S, Hauser MA, Scott WK, Postel EA, Agarwal A, Gallins P, Wong F, Chen YS, Spencer K, Schnetz-Boutaud N, Haines JL, Pericak-Vance MA: Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet 2006;78:852–864.
  14. Robman L, Baird PN, Dimitrov PN, Richardson AJ, Guymer RH: C-reactive protein levels and complement factor H polymorphism interaction in age-related macular degeneration and its progression. Ophthalmology 2010;117:1982–1988.
  15. Meyers SM: A twin study on age-related macular degeneration. Trans Am Ophthalmol Soc 1994;92:775–843.
  16. Meyers SM, Greene T, Gutman FA: A twin study of age-related macular degeneration. Am J Ophthalmol 1995;120:757–766.
  17. Gottfredsdottir MS, Sverrisson T, Musch DC, Stefánsson E: Age related macular degeneration in monozygotic twins and their spouses in Iceland. Acta Ophthalmol Scand 1999;77:422–425.
  18. Hammond CJ, Webster AR, Snieder H, Bird AC, Gilbert CE, Spector TD: Genetic influence on early age-related maculopathy: a twin study. Ophthalmology 2002;109:730–736.
  19. Grizzard SW, Arnett D, Haag SL: Twin study of age-related macular degeneration. Ophthalmic Epidemiol 2003;10:315–322.
  20. Seddon JM, Cote J, Page WF, Aggen SH, Neale MC: The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 2005;123:321–327.
  21. Bradley AE: Dystrophy of the macula. Am J Ophthalmol 1966;61:1–24.
  22. Gass JDM: Drusen and disciform macular detachment and degeneration. Arch Ophthalmol 1973;90:206–217.
  23. Hyman LG, Lilienfeld AM, Ferris FL 3rd, Fine SL: Senile macular degeneration: a case-control study. Am J Epidemiol 1983;118:213–227.
  24. Silvestri G, Johnston PB, Hughes AE: Is genetic predisposition an important risk factor for age-related macular degeneration? Eye 1995;8:564–568.
    External Resources
  25. Seddon JM, Ajani UA, Mitchell BD: Familial aggregation of age-related maculopathy. Am J Ophthalmol 1997;123:199–206.
  26. Klaver CC, Wolfs RC, Assink JJ, van Duijn CM, Hofman A, de Jong PT: Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophthalmol 1998;116:1646–1651.
  27. Heiba IM, Elston RC, Klein BE, Klein R: Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam Eye Study. Genet Epidemiol1994;11:51–67.
  28. Souied EH, Ducroq D, Rozet JM, Gerber S, Perrault I, Munnich A, Coscas G, Soubrane G, Kaplan J: ABCR gene analysis in familial exudative age-related macular degeneration. Invest Ophthalmol Vis Sci 2000;41:244–247.
  29. Guymer RH, Héon E, Lotery AJ, Munier FL, Schorderet DF, Baird PN, McNeil RJ, Haines H, Sheffield VC, Stone EM: Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration. Arch Ophthalmol 2001;119:745–751.
  30. Schultz DW, Klein ML, Humpert AJ, Luzier CW, Persun V, Schain M, Mahan A, Runckel C, Cassera M, Vittal V, Doyle TM, Martin TM, Weleber RG, Francis PJ, Acott TS: Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. Hum Mol Genet 2003;12:3315–3323.
  31. Abecasis GR, Yashar BM, Zhao Y, Ghiasvand NM, Zareparsi S, Branham KE, Reddick AC, Trager EH, Yoshida S, Bahling J, Filippova E, Elner S, Johnson MW, Vine AK, Sieving PA, Jacobson SG, Richards JE, Swaroop A: Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease. Am J Hum Genet 2004;74:482–494.
  32. Schick JH, Iyengar SK, Klein BE, Klein R, Reading K, Liptak R, Millard C, Lee KE, Tomany SC, Moore EL, Fijal BA, Elston RC: A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study. Am J Hum Genet 2003;72:1412–1424.
  33. Klein ML, Schultz DW, Edwards A, Matise TC, Rust K, Berselli CB, Trzupek K, Weleber RG, Ott J, Wirtz MK, Acott TS: Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Arch Ophthalmol 1998;116:1082–1088.
  34. Iyengar SK, Song D, Klein BE, Klein R, Schick JH, Humphrey J, Millard C, Liptak R, Russo K, Jun G, Lee KE, Fijal B, Elston RC: Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. Am J Hum Genet 2004;74:20–39.
  35. Majewski J, Schultz DW, Weleber RG, Schain MB, Edwards AO, Matise TC, Acott TS, Ott J, Klein ML: Age-related macular degeneration – a genome scan in extended families. Am J Hum Genet 2003;73:540–550.
  36. Seddon JM, Santangelo SL, Book K, Chong S, Cote J: A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions. Am J Hum Genet 2003;73:780–790.
  37. Weeks DE, Conley YP, Mah TS, Paul TO, Morse L, Ngo-Chang J, Dailey JP, Ferrell RE, Gorin MB: A full genome scan for age-related maculopathy. Hum Mol Genet 2000;9:1329–1349.
  38. Jorgensen TJ, Ruczinski I, Kessing B, Smith MW, Shugart YY, Alberg AJ: Hypothesis-driven candidate gene association studies: practical design and analytical considerations. Am J Epidemiol 2009;170:986–993.
  39. Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH: A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 2000;70:441–449.
  40. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF: An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705–732.
  41. Mullins RF, Aptsiauri N, Hageman GS: Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye (Lond) 2001;15:390–395.
  42. Umeda S, Suzuki MT, Okamoto H, Ono F, Mizota A, Terao K, Yoshikawa Y, Tanaka Y, Iwata T: Molecular composition of drusen and possible involvement of anti-retinal autoimmunity in two different forms of macular degeneration in cynomolgus monkey (Macaca fascicularis). FASEB J 2005;19:1683–1685.
  43. Anderson DH, Mullins RF, Hageman GS, Johnson LV: A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134:411–431.
  44. Bora PS, Sohn JH, Cruz JM, Jha P, Nishihori H, Wang Y, Kaliappan S, Kaplan HJ, Bora NS: Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization. J Immunol 2005;174:491–497.
  45. Kijlstra A, La Heij E, Hendrikse F: Immunological factors in the pathogenesis and treatment of age-related macular degeneration. Ocul Immunol Inflamm 2005;13:3–11.
  46. Swaroop A, Branham KE, Chen W, Abecasis G: Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Hum Mol Genet 2007;16:174–182.
    External Resources
  47. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R: A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.Proc Natl Acad Sci USA 2005;102:7227–7232.
  48. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA: Complement factor H polymorphism and age-related macular degeneration. Science 2005;308:421–424.
  49. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J: Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–389.
  50. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA: Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419–421.
  51. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM: Finding the missing heritability of complex diseases. Nature 2009;461:747–753.
  52. Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, Tam PO, Chan WM, Lam DS, Snyder M, Barnstable C, Pang CP, Hoh J: HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 2006;314:989–992.
  53. Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research, et al: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331–1336.
  54. Easton DF, Pooley KA, Dunning AM, et al: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007;447:1087–1093.
  55. Klein C, Ziegler A: From GWAS to clinical utility in Parkinson’s disease. Lancet 2011;377:613–614.
  56. Johnson LV, Leitner WP, Staples MK, Anderson DH: Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res 2001;73:887–896.
  57. Baudouin C, Peyman GA, Fredj-Reygrobellet D, Gordon WC, Lapalus P, Gastaud P, Bazan NG: Immunohistological study of subretinal membranes in age-related macular degeneration. Jpn J Ophthalmol 1992;36:443–451.
  58. Giannakis E, Jokiranta TS, Male DA, Ranganathan S, Ormsby RJ, Fischetti VA, Mold C, Gordon DL: A common site within factor H SCR 7 responsible for binding heparin, C-reactive protein and streptococcal M protein. Eur J Immunol 2003;33:962–969.
  59. Sjöberg AP, Trouw LA, Clark SJ, Sjölander J, Heinegård D, Sim RB, Day AJ, Blom AM: The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells. J Biol Chem 2007;282:10894–10900.
  60. Skerka C, Lauer N, Weinberger AA, Keilhauer CN, Sühnel J, Smith R, Schlötzer-Schrehardt U, Fritsche L, Heinen S, Hartmann A, Weber BH, Zipfel PF: Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol Immunol 2007;44:3398–3406.
  61. Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, Hancox LS, Hu J, Ebright JN, Malek G, Hauser MA, Rickman CB, Bok D, Hageman GS, Johnson LV: The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 2010;29:95–112.
  62. Hayashi H, Yamashiro K, Gotoh N, Nakanishi H, Nakata I, Tsujikawa A, Otani A, Saito M, Iida T, Matsuo K, Tajima K, Yamada R, Yoshimura N: CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 2010;51:5914–5919.
  63. Dong L, Qu Y, Jiang H, Dai H, Zhou F, Xu X, Bi H, Pan X, Dang G: Correlation of complement factor H gene polymorphisms with exudative age-related macular degeneration in a Chinese cohort. Neurosci Lett 2011;488:283–287.
  64. Xu Y, Guan N, Xu J, Yang X, Ma K, Zhou H, Zhang F, Snellingen T, Jiao Y, Liu X, Wang N, Liu N: Association of CFH, LOC387715, and HTRA1 polymorphisms with exudative age-related macular degeneration in a northern Chinese population. Mol Vis 2008;14:1373–1381.
  65. Fuse N, Miyazawa A, Mengkegale M, Yoshida M, Wakusawa R, Abe T, Tamai M: Polymorphisms in complement Factor H and hemicentin-1 genes in a Japanese population with dry-type age-related macular degeneration. Am J Ophthalmol 2006;142:1074–1076.
  66. Mori K, Gehlbach PL, Kabasawa S, Kawasaki I, Oosaki M, Iizuka H, Katayama S, Awata T, Yoneya S: Coding and noncoding variants in the CFH gene and cigarette smoking influence the risk of age-related macular degeneration in a Japanese population. Invest Ophthalmol Vis Sci 2007;48:5315–5319.
  67. Kim NR, Kang JH, Kwon OW, Lee SJ, Oh JH, Chin HS: Association between complement factor H gene polymorphisms and neovascular age-related macular degeneration in Koreans. Invest Ophthalmol Vis Sci 2008;49:2071–2076.
  68. Chen LJ, Liu DT, Tam PO, Chan WM, Liu K, Chong KK, Lam DS, Pang CP: Association of complement factor H polymorphisms with exudative age-related macular degeneration. Mol Vis 2006;12:1536–1542.
  69. Ng TK, Chen LJ, Liu DT, Tam PO, Chan WM, Liu K, Hu YJ, Chong KK, Lau CS, Chiang SW, Lam DS, Pang CP: Multiple gene polymorphisms in the complement factor H gene are associated with exudative age related macular degeneration in Chinese. Invest Ophthalmol Vis Sci 2008;49:3312–3317.
  70. Lau LI, Chen SJ, Cheng CY, et al: Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. Invest Ophthalmol Vis Sci 2006;47:3242–3246.
  71. Gotoh N, Yamada R, Hiratani H, Renault V, Kuroiwa S, Monet M, Toyoda S, Chida S, Mandai M, Otani A, Yoshimura N, Matsuda F: No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese. Hum Genet2006;120:139–143.
  72. Uka J, Tamura H, Kobayashi T, Yamane K, Kawakami H, Minamoto A, Mishima HK: No association of complement factor H gene polymorphism and age-related macular degeneration in the Japanese population. Retina 2006;26:985–987.
  73. Lee KY, Vithana EN, Mathur R, Yong VH, Yeo IY, Thalamuthu A, Lee MW, Koh AH, Lim MC, How AC, Wong DW, Aung T: Association analysis of CFH, C2, BF, and HTRA1 gene polymorphisms in Chinese patients with polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2008;49:2613–2619.
  74. Kondo N, Honda S, Kuno S, Negi A: Coding variant I62V in the complement factor H gene is strongly associated with polypoidal choroidal vasculopathy. Ophthalmology. 2009;116:304–310.
  75. Goto A, Akahori M, Okamoto H, Minami M, Terauchi N, Haruhata Y, Obazawa M, Noda T, Honda M, Mizota A, Tanaka M, Hayashi T, Tanito M, Ogata N, Iwata T: Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population. J Ocul Biol Dis Infor 2009;2:164–175.
  76. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT; AMD Genetics Clinical Study Group, Hageman GS, Dean M, Allikmets R: Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006;38:458–462.
  77. Spencer KL, Hauser MA, Olson LM, Schmidt S, Scott WK, Gallins P, Agarwal A, Postel EA, Pericak-Vance MA, Haines JL: Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Hum Mol Genet 2007;16:1986–1992.
  78. Jakobsdottir J, Conley YP, Weeks DE, Ferrell RE, Gorin MB: C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes. PLoS One 2008;3:e2199.
  79. Montes T, Tortajada A, Morgan BP, Rodríguez de Córdoba S, Harris CL: Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc Natl Acad Sci USA 2009;106:4366–4371.
  80. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT; Genetic Factors in AMD Study Group: Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 2007;357:553–561.
  81. Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM: Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 2007;39:1200–1201.
  82. Spencer KL, Olson LM, Anderson BM, Schnetz-Boutaud N, Scott WK, Gallins P, Agarwal A, Postel EA, Pericak-Vance MA, Haines JL: C3 R102G polymorphism increases risk of age-related macular degeneration. Hum Mol Genet 2008;17:1821–1824.
  83. Despriet DD, van Duijn CM, Oostra BA, Uitterlinden AG, Hofman A, Wright AF, ten Brink JB, Bakker A, de Jong PT, Vingerling JR, Bergen AA, Klaver CC: Complement component C3 and risk of age-related macular degeneration. Ophthalmology 2009;116:474–480.
  84. Park KH, Fridley BL, Ryu E, Tosakulwong N, Edwards AO: Complement component 3 (C3) haplotypes and risk of advanced age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50:3386–3393.
  85. Bergeron-Sawitzke J, Gold B, Olsh A, Schlotterbeck S, Lemon K, Visvanathan K, Allikmets R, Dean M: Multilocus analysis of age-related macular degeneration. Eur J Hum Genet 2009;17:1190–1199.
  86. Scholl HP, Fleckenstein M, Fritsche LG, Schmitz-Valckenberg S, Göbel A, Adrion C, Herold C, Keilhauer CN, Mackensen F, Mössner A, Pauleikhoff D, Weinberger AW, Mansmann U, Holz FG, Becker T, Weber BH: CFH, C3 and ARMS2 are significant risk loci for susceptibility but not for disease progression of geographic atrophy due to AMD. PLoS One 2009;4:e7418.
  87. Zerbib J, Richard F, Puche N, Leveziel N, Cohen SY, Korobelnik JF, Sahel J, Munnich A, Kaplan J, Rozet JM, Souied EH: R102G polymorphism of the C3 gene associated with exudative age-related macular degeneration in a French population. Mol Vis 2010;16:1324–1330.
  88. Pei XT, Li XX, Bao YZ, Yu WZ, Yan Z, Qi HJ, Qian T, Xiao HX: Association of C3 gene polymorphisms with neovascular age-related macular degeneration in a Chinese population. Curr Eye Res 2009;34:615–622.
  89. Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM: Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 2009;17:100–104.
  90. Ennis S, Gibson J, Cree AJ, Collins A, Lotery AJ: Support for the involvement of complement factor I in age-related macular degeneration. Eur J Hum Genet 2010;18:15–16.
  91. Kondo N, Bessho H, Honda S, Negi A: Additional evidence to support the role of a common variant near the complement factor I gene in susceptibility to age-related macular degeneration. Eur J Hum Genet 2010;18:634–635.
  92. Yu Y, Bhangale TR, Fagerness J, Ripke S, Thorleifsson G, Tan PL, Souied EH, Richardson AJ, Merriam JE, Buitendijk GH, Reynolds R, Raychaudhuri S, Chin KA, Sobrin L, Evangelou E, Lee PH, Lee AY, Leveziel N, Zack DJ, Campochiaro B, Campochiaro P, Smith RT, Barile GR, Guymer RH, Hogg R, Chakravarthy U, Robman LD, Gustafsson O, Sigurdsson H, Ortmann W, Behrens TW, Stefansson K, Uitterlinden AG, van Duijn CM, Vingerling JR, Klaver CC, Allikmets R, Brantley MA Jr, Baird PN, Katsanis N, Thorsteinsdottir U, Ioannidis JP, Daly MJ, Graham RR, Seddon JM: Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum Mol Genet 2011, Epub ahead of print.
  93. Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB: Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 2005;77:389–407.
  94. Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, Weber BH: Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 2005;14:3227–3236.
  95. Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K: A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006;314:992–993.
  96. Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, Weber BH: Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 2008;40:892–896.
  97. Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, He S, Lyons R, Abecasis GR, Swaroop A: A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci USA 2007;104:16227–16232.
  98. Wang G, Spencer KL, Court BL, Olson LM, Scott WK, Haines JL, Pericak-Vance MA: Localization of age-related macular degeneration-associated ARMS2 in cytosol, not mitochondria. Invest Ophthalmol Vis Sci 2009;50:3084–3090.
  99. Kortvely E, Hauck SM, Duetsch G, Gloeckner CJ, Kremmer E, Alge-Priglinger CS, Deeg CA, Ueffing M: ARMS2 is a constituent of the extracellular matrix providing a link between familial and sporadic age-related macular degenerations. Invest Ophthalmol Vis Sci 2010;51:79–88.
  100. Friedrich U, Myers CA, Fritsche LG, Milenkovich A, Wolf A, Corbo JC, Weber BH: Risk- and non-risk-associated variants at the 10q26 AMD locus influence ARMS2 mRNA expression but exclude pathogenic effects due to protein deficiency. Hum Mol Genet 2011;20:1387–1399.
  101. Kanda A, Stambolian D, Chen W, Curcio CA, Abecasis GR, Swaroop A: Age-related macular degeneration-associated variants at chromosome 10q26 do not significantly alter ARMS2 and HTRA1 transcript levels in the human retina. Mol Vis 2010;16:1317–1323.
  102. An E, Sen S, Park SK, Gordish-Dressman H, Hathout Y: Identification of novel substrates for the serine protease HTRA1 in the human RPE secretome. Invest Ophthalmol Vis Sci 2010;51:3379–3386.
  103. Yang Z, Tong Z, Chen Y, Zeng J, Lu F, Sun X, Zhao C, Wang K, Davey L, Chen H, London N, Muramatsu D, Salasar F, Carmona R, Kasuga D, Wang X, Bedell M, Dixie M, Zhao P, Yang R, Gibbs D, Liu X, Li Y, Li C, Li Y, Campochiaro B, Constantine R, Zack DJ, Campochiaro P, Fu Y, Li DY, Katsanis N, Zhang K: Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. PLoS Genet 2010;6:e1000836.
  104. Ng TK, Yam GH, Chen WQ, Lee VY, Chen H, Chen LJ, Choy KW, Yang Z, Pang CP: Interactive expressions of HtrA1 and VEGF in human vitreous humors and fetal RPE cells. Invest Ophthalmol Vis Sci 2011, Epub ahead of print.
  105. Conley YP, Jakobsdottir J, Mah T, Weeks DE, Klein R, Kuller L, Ferrell RE, Gorin MB: CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Hum Mol Genet 2006;15:3206–3218.
  106. Curcio CA, Presley JB, Malek G, Medeiros NE, Avery DV, Kruth HS: Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy. Exp Eye Res 2005;81:731–741.
  107. Li CM, Chung BH, Presley JB, Malek G, Zhang X, Dashti N, Li L, Chen J, Bradley K, Kruth HS, Curcio CA: Lipoprotein-like particles and cholesteryl esters in human Bruch’s membrane: initial characterization. Invest Ophthalmol Vis Sci 2005;46:2576–2586.
  108. Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH: Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E (LDL) receptors in the brain. J Biol Chem 1987;262:14352–14360.
  109. Schneider WJ, Nimpf J: LDL receptor relatives at the crossroad of endocytosis and signaling. Cell Mol Life Sci 2003;60:892–903.
  110. Corbo RM, Scacchi R: Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele? Ann Hum Genet 1999;63:301–310.
  111. Klaver CC, Kliffen M, van Duijn CM, Hofman A, Cruts M, Grobbee DE, van Broeckhoven C, de Jong PT: Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 1998;63:200–206.
  112. Souied EH, Benlian P, Amouyel P, Feingold J, Lagarde JP, Munnich A, Kaplan J, Coscas G, Soubrane G: The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol 1998;125:353–359.
  113. Schmidt S, Saunders AM, De La Paz MA, Postel EA, Heinis RM, Agarwal A, Scott WK, Gilbert JR, McDowell JG, Bazyk A, Gass JD, Haines JL, Pericak-Vance MA: Association of the apolipoprotein E gene with age-related macular degeneration: possible effect modification by family history, age, and gender. Mol Vis 2000;6:287–293.
  114. Simonelli F, Margaglione M, Testa F, Cappucci G, Manitto MP, Brancato R, Rinaldi E: Apolipoprotein E polymorphisms in age-related macular degeneration in an Italian population. Ophthalmic Res 2001;33:325–328.
  115. Schmidt S, Klaver C, Saunders A, Postel E, De La Paz M, Agarwal A, Small K, Udar N, Ong J, Chalukya M, Nesburn A, Kenney C, Domurath R, Hogan M, Mah T, Conley Y, Ferrell R, Weeks D, de Jong PT, van Duijn C, Haines J, Pericak-Vance M, Gorin M: A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy. Ophthalmic Genet 2002;23:209–223.
  116. Zareparsi S, Reddick AC, Branham KE, Moore KB, Jessup L, Thoms S, Smith-Wheelock M, Yashar BM, Swaroop A: Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. Invest Ophthalmol Vis Sci 2004;45:1306–1310.
  117. Baird PN, Guida E, Chu DT, Vu HT, Guymer RH: The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 2004;45:1311–1315.
  118. Bojanowski CM, Shen D, Chew EY, Ning B, Csaky KG, Green WR, Chan CC, Tuo J: An apolipoprotein E variant may protect against age-related macular degeneration through cytokine regulation. Environ Mol Mutagen 2006;47:594–602.
  119. Kaur I, Hussain A, Hussain N, Das T, Pathangay A, Mathai A, Hussain A, Nutheti R, Nirmalan PK, Chakrabarti S: Analysis of CFH, TLR4, and APOE polymorphism in India suggests the Tyr402His variant of CFH to be a global marker for age-related macular degeneration. Invest Ophthalmol Vis Sci 2006;47:3729–3735.
  120. Tikellis G, Sun C, Gorin MB, Klein R, Klein BE, Larsen EK, Siscovick DS, Hubbard LD, Wong TY: Apolipoprotein E gene and age-related maculopathy in older individuals: the cardiovascular health study. Arch Ophthalmol 2007;125:68–73.
  121. Francis PJ, Hamon SC, Ott J, Weleber RG, Klein ML: Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J Med Genet 2009;46:300–307.
  122. Fritsche LG, Freitag-Wolf S, Bettecken T, Meitinger T, Keilhauer CN, Krawczak M, Weber BH: Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene. Hum Mutat 2009;30:1048–1053.
  123. Thakkinstian A, Bowe S, McEvoy M, Smith W, Attia J: Association between apolipoprotein E polymorphisms and age-related macular degeneration: A HuGE review and meta-analysis. Am J Epidemiol 2006;164:813–822.
  124. Pang CP, Baum L, Chan WM, Lau TC, Poon PM, Lam DS: The apolipoprotein E epsilon4 allele is unlikely to be a major risk factor of age-related macular degeneration in Chinese. Ophthalmologica 2000;214:289–291.
  125. Schultz DW, Klein ML, Humpert A, Majewski J, Schain M, Weleber RG, Ott J, Acott TS: Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration. Arch Ophthalmol 2003;121:679–683.
  126. Gotoh N, Kuroiwa S, Kikuchi T, Arai J, Arai S, Yoshida N, Yoshimura N: Apolipoprotein E polymorphisms in Japanese patients with polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Am J Ophthalmol 2004;138:567–573.
  127. DeAngelis MM, Ji F, Kim IK, Adams S, Capone A Jr, Ott J, Miller JW, Dryja TP: Cigarette smoking, CFH, APOE, ELOVL4, and risk of neovascular age-related macular degeneration. Arch Ophthalmol 2007;125:49–54.
  128. Utheim ØA, Ritland JS, Utheim TP, Espeseth T, Lydersen S, Rootwelt H, Semb SO, Elsås T: Apolipoprotein E genotype and risk for development of cataract and age-related macular degeneration. Acta Ophthalmol 2008;86:401–403.
  129. Losonczy G, Fekete A, Vokó Z, Takács L, Káldi I, Ajzner E, Kasza M, Vajas A, Berta A, Balogh I: Analysis of complement factor H Y402H, LOC387715, HTRA1 polymorphisms and ApoE alleles with susceptibility to age-related macular degeneration in Hungarian patients. Acta Ophthalmol 2011;89:255–262.
  130. Payami H, Zareparsi S, Montee KR, Sexton GJ, Kaye JA, Bird TD, Yu CE, Wijsman EM, Heston LL, Litt M, Schellenberg GD: Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet 1996;58:803–811.
  131. Wilson PW, Schaefer EJ, Larson MG, Ordovas JM: Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler Thromb Vasc Biol 1996;16:1250–1255.
  132. Vergeer M, Korporaal SJ, Franssen R, Meurs I, Out R, Hovingh GK, Hoekstra M, Sierts JA, Dallinga-Thie GM, Motazacker MM, Holleboom AG, Van Berkel TJ, Kastelein JJ, Van Eck M, Kuivenhoven JA: Genetic variant of the scavenger receptor BI in humans. N Engl J Med 2011;364:136–145.
  133. Reboul E, Abou L, Mikail C, Ghiringhelli O, André M, Portugal H, Jourdheuil-Rahmani D, Amiot MJ, Lairon D, Borel P: Lutein transport by Caco-2 TC-7 cells occurs partly by a facilitated process involving the scavenger receptor class B type I (SR-BI). Biochem J 2005;387:455–461.
  134. Zerbib J, Seddon JM, Richard F, Reynolds R, Leveziel N, Benlian P, Borel P, Feingold J, Munnich A, Soubrane G, Kaplan J, Rozet JM, Souied EH: rs5888 variant of SCARB1 gene is a possible susceptibility factor for age-related macular degeneration. PLoS One 2009;4:e7341.
  135. Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J, et al: Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci USA 2010;107:7401–7406.
  136. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, et al: Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161–169.
  137. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, et al: Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41:56–65.
  138. Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S, et al: Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci USA 2010;107:7395–7400.
  139. Reynolds R, Rosner B, Seddon JM: Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology 2010;117:1989–1995.
  140. Seddon JM, Reynolds R, Rosner B: Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration. Mol Vis 2010;16:2412–2424.
  141. Karunadharma PP, Nordgaard CL, Olsen TW, Ferrington DA: Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51:5470–5479.
  142. SanGiovanni JP, Arking DE, Iyengar SK, Elashoff M, Clemons TE, Reed GF, Henning AK, Sivakumaran TA, Xu X, DeWan A, Agrón E, Rochtchina E, Sue CM, Wang JJ, Mitchell P, Hoh J, Francis PJ, Klein ML, Chew EY, Chakravarti A: Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PLoS One 2009;4:e5508.
  143. Udar N, Atilano SR, Memarzadeh M, Boyer DS, Chwa M, Lu S, Maguen B, Langberg J, Coskun P, Wallace DC, Nesburn AB, Khatibi N, Hertzog D, Le K, Hwang D, Kenney MC: Mitochondrial DNA haplogroups associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50:2966–2974.
  144. Jones MM, Manwaring N, Wang JJ, Rochtchina E, Mitchell P, Sue CM: Mitochondrial DNA haplogroups and age-related maculopathy. Arch Ophthalmol 2007;125:1235–1240.
  145. Schmid-Kubista KE, Tosakulwong N, Wu Y, Ryu E, Hecker LA, Baratz KH, Brown WL, Edwards AO: Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50:5070–5079.
  146. Liu MM, Agrón E, Chew E, Meyerle C, Ferris FL 3rd, Chan CC, Tuo J: Copy number variations in candidate genes in neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 2011. Epub ahead of print.
  147. Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N, Redon R, Bird CP, de Grassi A, Lee C, Tyler-Smith C, Carter N, Scherer SW, Tavaré S, Deloukas P, Hurles ME, Dermitzakis ET: Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007;315:848–853.
  148. Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U: A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 2006;38:1173–1177.
  149. Hageman GS, Hancox LS, Taiber AJ, Gehrs KM, Anderson DH, Johnson LV, Radeke MJ, Kavanagh D, Richards A, Atkinson J, Meri S, Bergeron J, Zernant J, Merriam J, Gold B, Allikmets R, Dean M; AMD Clinical Study Group: Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 2006;38:592–604.
  150. Spencer KL, Hauser MA, Olson LM, Schmidt S, Scott WK, Gallins P, Agarwal A, Postel EA, Pericak-Vance MA, Haines JL: Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration. Hum Mol Genet 2008;17:971–977.
  151. Raychaudhuri S, Ripke S, Li M, Neale BM, Fagerness J, Reynolds R, Sobrin L, Swaroop A, Abecasis G, Seddon JM, Daly MJ: Associations of CFHR1-CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. Nat Genet 2010;42:553–555.
  152. Heinen S, Hartmann A, Lauer N, Wiehl U, Dahse HM, Schirmer S, Gropp K, Enghardt T, Wallich R, Hälbich S, Mihlan M, Schlötzer-Schrehardt U, Zipfel PF, Skerka C: Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood 2009;114:2439–2447.
  153. Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML: Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA 2007;297:1793–1800.
  154. Klein ML, Ferris FL 3rd, Francis PJ, Lindblad AS, Chew EY, Hamon SC, Ott J: Progression of geographic atrophy and genotype in age-related macular degeneration. Ophthalmology 2010;117:1554–1559.
  155. Brantley MA Jr, Fang AM, King JM, Tewari A, Kymes SM, Shiels A: Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology 2007;114:2168–2173.
  156. Leveziel N, Zerbib J, Richard F, Querques G, Morineau G, Fremeaux-Bacchi V, Coscas G, Soubrane G, Benlian P, Souied EH: Genotype-phenotype correlations for exudative age-related macular degeneration associated with homozygous HTRA1 and CFH genotypes. Invest Ophthalmol Vis Sci 2008;49:3090–3094.
  157. Shuler RK Jr, Schmidt S, Gallins P, Hauser MA, Scott WK, Caldwell J, Agarwal A, Haines JL, Pericak-Vance MA, Postel EA: Phenotype analysis of patients with the risk variant LOC387715 (A69S) in age-related macular degeneration. Am J Ophthalmol 2008;145:303–307.
  158. Brantley MA Jr, Edelstein SL, King JM, Plotzke MR, Apte RS, Kymes SM, Shiels A: Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to photodynamic therapy. Eye 2009;23:626–631.
  159. Andreoli MT, Morrison MA, Kim BJ, Chen L, Adams SM, Miller JW, DeAngelis MM, Kim IK: Comprehensive analysis of complement factor H and LOC387715/ARMS2/HTRA1 variants with respect to phenotype in advanced age-related macular degeneration. Am J Ophthalmol 2009;148:869–874.
  160. Gotoh N, Yamada R, Nakanishi H, et al: Correlation between CFH Y402H and HTRA1 rs11200638 genotype to typical exudative age-related macular degeneration and polypoidal choroidal vasculopathy phenotype in the Japanese population. Clin Experiment Ophthalmol 2008;36:437–442.
  161. Leveziel N, Puche N, Richard F, Somner JE, Zerbib J, Bastuji-Garin S, Cohen SY, Korobelnik JF, Sahel J, Soubrane G, Benlian P, Souied EH: Genotypic influences on severity of exudative age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51:2620–2625.
  162. Chen Y, Zeng J, Zhao C, Wang K, Trood E, Buehler J, Weed M, Kasuga D, Bernstein PS, Hughes G, Fu V, Chin J, Lee C, Crocker M, Bedell M, Salasar F, Yang Z, Goldbaum M, Ferreyra H, Freeman WR, Kozak I, Zhang K: Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors. Arch Ophthalmol 2011;129:344–351.
  163. Wegscheider BJ, Weger M, Renner W, Steinbrugger I, März W, Mossböck G, Temmel W, El-Shabrawi Y, Schmut O, Jahrbacher R, Haas A: Association of complement factor H Y402H gene polymorphism with different subtypes of exudative age-related macular degeneration. Ophthalmology 2007;114:738–742.
  164. Brantley MA Jr, Edelstein SL, King JM, Apte RS, Kymes SM, Shiels A: Clinical phenotypes associated with the complement factor H Y402H variant in age-related macular degeneration. Am J Ophthalmol 2007;144:404–408.
  165. Goverdhan SV, Hannan S, Newsom RB, Luff AJ, Griffiths H, Lotery AJ: An analysis of the CFH Y402H genotype in AMD patients and controls from the UK, and response to PDT treatment. Eye (Lond) 2008;22:849–854.
  166. Sobrin L, Reynolds R, Yu Y, Fagerness J, Leveziel N, Bernstein PS, Souied EH, Daly MJ, Seddon JM: ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related macular degeneration. Am J Ophthalmol 2011;151:345–352.
  167. Nakanishi H, Yamashiro K, Yamada R, Gotoh N, Hayashi H, Nakata I, Saito M, Iida T, Oishi A, Kurimoto Y, Matsuo K, Tajima K, Matsuda F, Yoshimura N: Joint effect of cigarette smoking and CFH and LOC387715/HTRA1 polymorphisms on polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2010;51:6183–6187.
  168. Seddon JM, Reynolds R, Rosner B: Peripheral retinal drusen and reticular pigment: association with CFHY402H and CFHrs1410996 genotypes in family and twin studies. Invest Ophthalmol Vis Sci 2009;50:586–591.
  169. Munch IC, Ek J, Kessel L, Sander B, Almind GJ, Brøndum-Nielsen K, Linneberg A, Larsen M: Small, hard macular drusen and peripheral drusen: associations with AMD genotypes in the Inter99 Eye Study. Invest Ophthalmol Vis Sci 2010;51:2317–2321.
  170. Grassi MA, Folk JC, Scheetz TE, Taylor CM, Sheffield VC, and Stone EM: Complement factor H polymorphism p.Tyr402His and cuticular drusen. Arch Ophthalmol 2007;125:93–97.
  171. Boon CJ, Klevering BJ, Hoyng CB, Zonneveld-Vrieling MN, Nabuurs SB, Blokland E, Cremers FP, den Hollander AI: Basal laminar drusen caused by compound heterozygous variants in the CFH gene. Am J Hum Genet 2008;82:516–523.
  172. Sepp T, Khan JC, Thurlby DA, Shahid H, Clayton DG, Moore AT, Bird AC, Yates JR: Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci 2006;47:536–540.
  173. Hughes AE, Orr N, Patterson C, Esfandiary H, Hogg R, McConnell V, Silvestri G, Chakravarthy U: Neovascular age-related macular degeneration risk based on CFH, LOC387715/HTRA1, and smoking. PLoS Med 2007;4:e355.
  174. Francis PJ, George S, Schultz DW, Rosner B, Hamon S, Ott J, Weleber RG, Klein ML, Seddon JM: The LOC387715 gene, smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 2007;63:212–218.
  175. Wang JJ, Ross RJ, Tuo J, Burlutsky G, Tan AG, Chan CC, Favaloro EJ, Williams A, Mitchell P: The LOC387715 polymorphism, inflammatory markers, smoking, and age-related macular degeneration. A population-based case-control study. Ophthalmology 2008;115:693–699.
  176. Lee SJ, Kim NR, Chin HS: LOC387715/HTRA1 polymorphisms, smoking and combined effects on exudative age-related macular degeneration in a Korean population. Clin Experiment Ophthalmol 2010;38:698–704.
  177. Age-related Eye Disease Study Report Number 3. Ophthalmology 2000;107:2224–2232.
  178. Delcourt C, Michel F, Colvez A, Lacroux A, Delage M, Vernet MH; POLA Study Group: Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study. Ophthalmic Epidemiol 2001;8:237–249.
  179. Seddon JM, Cote J, Davis N, Rosner B: Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio. Arch Ophthalmol 2003;121:785–792.
  180. Clemons TE, Milton RC, Klein R, Seddon JM, Ferris FL 3rd; Age-related Eye Disease Study Research Group: Risk factors for the incidence of Advanced Age-related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report No 19. Ophthalmology 2005;112:533–539.
  181. Seddon JM, George S, Rosner B, Klein ML: CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 2006;61:157–165.
  182. Lee SY, McLeod HL: Pharmacogenetic tests in cancer chemotherapy: what physicians should know for clinical application. J Pathol 2011;223:15–27.
  183. Ellsworth RE, Decewicz DJ, Shriver CD, Ellsworth DL: Breast cancer in the personal genomics era. Curr Genomics 2010;11:146–161.
  184. Age-Related Eye Disease Study Research Group: A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, β-carotene, and zinc for age-related macular degeneration and vision loss: AREDS report No 8. Arch Ophthalmol 2001;119:1417–1436.
  185. Klein ML, Francis PJ, Rosner B, Reynolds R, Hamon SC, Schultz DW, Ott J, Seddon JM: CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 2008;115:1019–1025.
  186. Tsuchihashi T, Mori K, Horie-Inoue K, Gehlbach PL, Kabasawa S, Takita H, Ueyama K, Okazaki Y, Inoue S, Awata T, Katayama S, Yoneya S: Complement factor H and high-temperature requirement A-1 genotypes and treatment response of age-related macular degeneration. Ophthalmology 2011;118:93–100.
  187. Kloeckener-Gruissem B, Barthelmes D, Labs S, Schindler C, Kurz-Levin M, Michels S, Fleischhauer J, Berger W, Sutter F, Menghini M: Genetic association with response to intravitreal ranibizumab (Lucentis®) in neovascular AMD patients. Invest Ophthalmol Vis Sci 2011. Epub ahead of print.
  188. Wickremasinghe SS, Xie J, Lim J, Chauhan DS, Robman L, Richardson AJ, Hageman G, Baird PN, Guymer R: Variants in the APOE Gene are Associated with Improved Treatment Outcome Following Anti-VEGF Therapy for Neovascular AMD. Invest Ophthalmol Vis Sci 2011. Epub ahead of print.
  189. McDermott U, Downing JR, Stratton MR: Genomics and the continuum of cancer care. N Engl J Med 2011;364:340–350.
  190. Janssens AC, Moonesinghe R, Yang Q, Steyerberg EW, van Duijn CM, Khoury MJ: The impact of genotype frequencies on the clinical validity of genomic profiling for predicting common chronic diseases. Genet Med 2007;9:528–535.
  191. Gu J, Pauer GJ, Yue X, Narendra U, Sturgill GM, Bena J, Gu X, Peachey NS, Salomon RG, Hagstrom SA, Crabb JW; Clinical Genomic and Proteomic AMD Study Group: Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers. Mol Cell Proteomics 2009;8:1338–1349.
Figures

Tables