Meta-Analysis of Homogeneous Subgroups Reveals Association between PDE4D Gene Variants and Ischemic StrokeYoon D.a · Park S.K.c–e · Kang D.c–e · Park T.b · Park J.W.f
aInterdisciplinary Program in Bioinformatics, and bDepartment of Statistics, College of Natural Science, Seoul National University, cDepartment of Preventive Medicine, Seoul National University College of Medicine, dCancer Research Institute, Seoul National University, and eDepartment of Biomedical Science, Seoul National University Graduate School, Seoul, and fDepartment of Medical Genetics, Hallym University College of Medicine, Chuncheon, Republic of Korea
Dr. Ji Wan Park
Department of Medical Genetics
Hallym University College of Medicine, 39 Hallymdaehak-gil
Chuncheon, Gangwon-do 200-702 (Republic of Korea)
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Background: An Icelandic study showed a significant positive association between phosphodiesterase 4D (PDE4D) gene variants and stroke. However, subsequent studies reported conflicting results, possibly due to small sample sizes and the heterogeneity of the studies. Method: We performed a meta-analysis on 6 SNPs of the PDE4D gene to investigate the association between this gene and ischemic stroke by integrating the results of previous studies, comprising 11,834 cases and 15,233 controls. A pooled genotypic odds ratio (OR) for each SNP was determined under 3 genetic models (i.e. dominant, recessive, and codominant) using both fixed- and random-effects models with consideration for heterogeneity and publication bias across studies. Results: Among the SNPs included in this study, SNP56 (rs702553) showed the most significant association with ischemic stroke in a meta-analysis comprised of 7 homogenous studies. The overall OR of the TT genotype compared to the AA genotype was 1.29 (95% CI 1.03–1.61; p = 0.022). For SNP83 (rs966221), a protective effect of the ancestral allele T was observed only in Asian populations (ORTT 0.79, 95% CI 0.69–0.90; p = 0.0005). This meta-analysis revealed a significant association of PDE4D gene variants with the risk of ischemic stroke, and further investigations are warranted to evaluate possible ethnic-specific effects.
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- Strong K, Mathers C, Bonita R: Preventing stroke: saving lives around the world. Lancet Neurol 2007;6:182–187.
- Rosand J, Bayley N, Rost N, de Bakker PI: Many hypotheses but no replication for the association between PDE4D and stroke. Nat Genet 2006;38:1091–1092; author reply 1092–1093.
- Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, Culebras A, DeGraba TJ, Gorelick PB, Guyton JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, Sacco RL: Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council – cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Stroke 2006;37:1583–1633.
- Meschia JF: Subtyping in ischemic stroke genetic research. J Stroke Cerebrovasc Dis 2002;11:208–219.
- Dichgans M, Markus HS: Genetic association studies in stroke: methodological issues and proposed standard criteria. Stroke 2005;36:2027–2031.
- Touze E, Rothwell PM: Sex differences in heritability of ischemic stroke: a systematic review and meta-analysis. Stroke 2008;39:16–23.
- Schulz UG, Flossmann E, Rothwell PM: Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies. Stroke 2004;35:819–824.
- Moskau S, Golla A, Grothe C, Boes M, Pohl C, Klockgether T: Heritability of carotid artery atherosclerotic lesions: an ultrasound study in 154 families. Stroke 2005;36:5–8.
- Bolger GB, Erdogan S, Jones RE, Loughney K, Scotland G, Hoffmann R, Wilkinson I, Farrell C, Houslay MD: Characterization of five different proteins produced by alternatively spliced mRNAs from the human camp-specific phosphodiesterase PDE4D gene. Biochem J 1997;328:539–548.
- Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, Gudmundsdottir T, Bjarnadottir SM, Einarsson OB, Gudjonsdottir HM: The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 2003;35:131–138.
- Bevan S, Porteous L, Sitzer M, Markus HS: Phosphodiesterase 4D gene, ischemic stroke, and asymptomatic carotid atherosclerosis. Stroke 2005;36:949–953.
- Lohmussaar E, Gschwendtner A, Mueller JC, Org T, Wichmann E, Hamann G, Meitinger T, Dichgans M: ALOX5AP gene and the PDE4D gene in a central European population of stroke patients. Stroke 2005;36:731–736.
- Staton JM, Sayer MS, Hankey GJ, Attia J, Thakkinstian A, Yi Q, Cole VJ, Baker R, Eikelboom JW: Association between phosphodiesterase 4D gene and ischaemic stroke. J Neurol Neurosurg Psychiatry 2006;77:1067–1069.
- Worrall BB, Mychaleckyj JC: PDE4D and stroke: a real advance or a case of the emperor’s new clothes? Stroke 2006;37:1955–1957.
Berlin JA, Kim CJ: The use of meta-analysis in pharmacoepidemiology; in Strom BL (ed): Pharmacoepidemiology, ed 4. New York, Wiley, 2007, pp 681–707.
- Lövkvist H, Smith JG, Luthman H, Hoglund P, Norrving B, Kristoffersson U, Jonsson A-C, Lindgren AG: Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region. Eur J Hum Genet 2008;16:1117–1125.
- Bevan S, Dichgans M, Gschwendtner A, Kuhlenbaumer G, Ringelstein EB, Markus HS: Variation in the PDE4D gene and ischemic stroke risk: a systematic review and meta-analysis on 5,200 cases and 6,600 controls. Stroke 2008;39:1966–1971.
- Domingues-Montanari S, Fernández-Cadenas I, del Rio-Espinola A, Corbeto N, Krug T, Manso H, Gouveia L, Sobral J, Mendioroz M, Fernández-Morales J, Alvarez-Sabin J, Ribó M, Rubiera M, Obach V, Martí-Fàbregas J, Freijo M, Serena J, Ferro JM, Vicente AM, Oliveira SA, Montaner J: Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: a case-control, meta-analysis and functional study. Cerebrovasc Dis 2010;29:528–537.
- Xu X, Li X, Li J, Ou R, Sheng W: Meta-analysis of association between variation in the PDE4D gene and ischemic cerebral infarction risk in Asian populations. Neurogenetics 2010;11:327–333.
- Conti M, Richter W, Mehats C, Livera G, Park JY, Jin C: Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 2003;278:5493–5496.
- Hakonarson H: Role of FLAP and PDE4D in myocardial infarction and stroke: target discovery and future treatment options. Curr Treat Options Cardiovasc Med 2006;8:183–192.
- DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–188.
Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F: Methods for meta-analysis in medical research. New York, Wiley, 2000.
- Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analysis. BMJ 2003;327:557–560.
- Higgins JP, Thompson SG: Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–1558.
- Patsopoulos NA, Evangelou E, Ioannidis JP: Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation. Int J Epidemiol 2008;37:1148–1157.
- Egger M, Smith GD, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–634.
- Nakayama T, Asai S, Sato N, Soma M: Genotype and haplotype association study of the STRK1 region on 5q12 among Japanese: a case-control study. Stroke 2006;37:69–76.
- Matsushita T, Kubo M, Yonemoto K, Ninomiya T, Ashikawa K, Liang B, Hata J, Doi Y, Kitazono T, Ibayashi S, Iida M, Kiyohara Y, Nakamura Y: Lack of association between variations of PDE4D and ischemic stroke in the Japanese population. Stroke 2009;40:1245–1251.
- Saleheen D, Bukhari S, Haider SR, Nazir A, Khanum S, Shafqat S, Anis MK, Frossard P: Association of phosphodiesterase 4D gene with ischemic stroke in a Pakistani population. Stroke 2005;36:2275–2277.
- Lin HF, Liao YC, Liou CW, Liu CK, Juo SH: The phosphodiesterase 4D gene for early onset ischemic stroke among normotensive patients. J Thromb Haemost 2007;5:436–438.
- Banerjee I, Gupta V, Ahmed T, Faizaan M, Agarwal P, Ganesh S: Inflammatory system gene polymorphism and the risk of stroke: a case-control study in an Indian population. Brain Res Bull 2008;75:158–165.
- Munshi A, Babu MS, Kaul S, Shafi G, Anila AN, Alladi S, Jyothy A: Phosphodiesterase 4D (PDE4D) gene variants and the risk of ischemic stroke in a South Indian population. J Neurol Sci 2009;285:142–145.
- Xue H, Wang H, Song X, Li W, Sun K, Zhang W, Wang X, Wang Y, Hui R: Phosphodiesterase 4D gene polymorphism is associated with ischaemic and haemorrhagic stroke. Clin Sci (Lond) 2009;116:335–340.
- Sun Y, Huang Y, Chen X, Liu Y, Lu X, Shi Y, Tang W, Yang J, Chen W, Zhao X, Gao L, Li S, Feng G, He L: Association between the PDE4D gene and ischaemic stroke in the Chinese Han population. Clin Sci (Lond) 2009;117:265–272.
- Song Q, Cole JW, O’Connell JR, Stine OC, Gallagher M, Giles WH, Mitchell BD, Wozniak MA, Stern BJ, Sorkin JD, McArdle PF, Naj AC, Xu Q, Gibbons GH, Kittner SJ: Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study. Hum Mol Genet 2006;15:2468–2478.
- Brophy VH, Ro SK, Rhees BK, Lui LY, Lee JM, Umblas N, Bentley LG, Li J, Cheng S, Browner WS, Erlich HA: Association of phosphodiesterase 4D polymorphisms with ischemic stroke in a US population stratified by hypertension status. Stroke 2006;37:1385–1390.
- Zee RY, Brophy VH, Cheng S, Hegener HH, Erlich HA, Ridker PM: Polymorphisms of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene and risk of ischemic stroke: a prospective, nested case-control evaluation. Stroke 2006;37:2012–2017.
- Meschia JF, Brott TG, Brown RD Jr, Crook R, Worrall BB, Kissela B, Brown WM, Rich SS, Case LD, Evans EW, Hague S, Singleton A, Hardy J: Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Ann Neurol 2005;58:351–361.
- Woo D, Kaushal R, Kissela B, Sekar P, Wolujewicz M, Pal P, Alwell K, Haverbusch M, Ewing I, Miller R, Kleindorfer D, Flaherty M, Chakraborty R, Deka R, Broderick J: Association of phosphodiesterase 4D with ischemic stroke: a population-based case-control study. Stroke 2006;37:371–376.
- Kuhlenbaumer G, Berger K, Huge A, Lange E, Kessler C, John U, Funke H, Nabavi DG, Stogbauer F, Ringelstein EB, Stoll M: Evaluation of single nucleotide polymorphisms in the phosphodiesterase 4D gene (PDE4D) and their association with ischaemic stroke in a large German cohort. J Neurol Neurosurg Psychiatry 2006;77:521–524.
- van Rijn MJ, Slooter AJ, Schut AF, Isaacs A, Aulchenko YS, Snijders PJ, Kappelle LJ, van Swieten JC, Oostra BA, van Duijn CM: Familial aggregation, the PDE4D gene, and ischemic stroke in a genetically isolated population. Neurology 2005;65:1203–1209.
- Nilsson-Ardnor S, Wiklund PG, Lindgren P, Nilsson AK, Janunger T, Escher SA, Hallbeck B, Stegmayr B, Asplund K, Holmberg D: Linkage of ischemic stroke to the pde4d region on 5q in a Swedish population. Stroke 2005;36:1666–1671.
- Kostulas K, Gretarsdottir S, Kostulas V, Manolescu A, Helgadottir A, Thorleifsson G, Gudmundsson LJ, Thorsteinsdottir U, Gulcher JR, Stefansson K, Hillert J: PDE4D and ALOX5AP genetic variants and risk for ischemic cerebrovascular disease in Sweden. J Neurol Sci 2007;263:113–117.
- Fidani L, Clarimon J, Goulas A, Hatzitolios AI, Evans W, Tsirogianni E, Hardy J, Kotsis A: Association of phosphodiesterase 4D gene G0 haplotype and ischaemic stroke in a Greek population. Eur J Neurol 2007;14:745–749.
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