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Vol. 35, No. 5-6, 2013
Issue release date: May 2013

Aromatase Variants Modify Risk for Alzheimer's Disease in a Multiethnic Female Cohort

Janicki S.C. · Park N. · Cheng R. · Schupf N. · Clark L.N. · Lee J.H.
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Abstract

Background/Aims: Few studies of gene variants that affect estrogen activity investigate their association with risk for Alzheimer's disease (AD) in women of different ethnicities. We investigated the influence of CYP19 polymorphisms on risk for AD in a multiethnic cohort of women, with individual ethnicity assessed by genetic population ancestry informative markers (AIMs) as well as by self-identified ethnicity. Methods: Among 1,686 women participating in the Washington Heights Inwood Columbia Aging Project, association with risk for AD was assessed for 41 single nucleotide polymorphisms (SNPs) on the CYP19 gene using multivariable logistic regression, adjusting for age, presence of an APOE ε4 allele, years of education, and body mass index. Results: Risk for AD was associated with 6 SNPs in women of predominantly Caucasian AIMs-defined ancestry. Of these, 2 were also associated with decreased risk of AD in women of admixed/Hispanic AIMs ancestry. Two separate SNPs were found to be protective in women of predominantly African AIMs-based ancestry. Conclusions:CYP19 polymorphisms affect risk for AD in women, and risk alleles vary by AIMs-defined ancestry. These effects are possibly due to linkage disequilibrium patterns or differences in the prevalence of comorbid risk factors mediating the SNP effect on risk for AD by group.



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References

  1. Shughrue PJ, Lane MV, Merchenthaler I: Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol 1997;388:507-525.
  2. McEwen BS: Invited review: estrogen effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol 2001;91:2785-2801.
  3. Stoffel-Wagner B, Watzka M, Schramm J, Bidlingmaier F, Klingmuller D: Expression of CYP19 (aromatase) mRNA in different areas of the human brain. J Steroid Biochem Mol Biol 1999;70:237-241.
  4. Huang R, Poduslo SE: CYP19 haplotypes increase risk for Alzheimer's disease. J Med Genet 2006;43:e42.
  5. Iivonen S, Corder E, Lehtovirta M, Helisalmi S, Mannermaa A, Vepsalainen S, Hanninen T, Soininen H, Hiltunen M: Polymorphisms in the CYP19 gene confer increased risk for Alzheimer disease. Neurology 2004;62:1170-1176.
  6. Butler HT, Warden DR, Hogervorst E, Ragoussis J, Smith AD, Lehmann DJ: Association of the aromatase gene with Alzheimer's disease in women. Neurosci Lett 2010;468:202-206.
  7. Corbo RM, Gambina G, Ulizzi L, Moretto G, Scacchi R: Genetic variation of CYP19 (aromatase) gene influences age at onset of Alzheimer's disease in women. Dement Geriatr Cogn Disord 2009;27:513-518.
  8. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE: Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 2007;39:17-23.
  9. Tang MX, Cross P, Andrews H, Jacobs DM, Small S, Bell K, Merchant C, Lantigua R, Costa R, Stern Y, Mayeux R: Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan. Neurology 2001;56:49-56.
  10. Stern Y, Andrews H, Pittman J, Sano M, Tatemichi T, Lantigua R, Mayeux R: Diagnosis of dementia in a heterogeneous population. Development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. Arch Neurol 1992;49:453-460.
  11. Pritchard JK, Stephens M, Donnelly P: Inference of population structure using multilocus genotype data. Genetics 2000;155:945-959.
  12. Falush D, Stephens M, Pritchard JK: Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 2003;164:1567-1587.
  13. Hixson JE, Vernier DT: Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hhai. J Lipid Res 1990;31:545-548.
  14. Goodman Y, Bruce AJ, Cheng B, Mattson MP: Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem 1996;66:1836-1844.
  15. Toran-Allerand CD, Miranda RC, Bentham WD, Sohrabji F, Brown TJ, Hochberg RB, MacLusky NJ: Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proc Natl Acad Sci USA 1992;89:4668-4672.
  16. Luine VN: Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp Neurol 1985;89:484-490.
  17. Behl C, Widmann M, Trapp T, Holsboer F: 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun 1995;216:473-482.
  18. Jaffe AB, Toran-Allerand CD, Greengard P, Gandy SE: Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J Biol Chem 1994;269:13065-13068.
  19. Gerhard M, Ganz P: How do we explain the clinical benefits of estrogen? From bedside to bench. Circulation 1995;92:5-8.
  20. Simoncini T, Mannella P, Genazzani AR: Rapid estrogen actions in the cardiovascular system. Ann NY Acad Sci 2006;1089:424-430.
  21. Ishunina TA, Fischer DF, Swaab DF: Estrogen receptor alpha and its splice variants in the hippocampus in aging and Alzheimer's disease. Neurobiol Aging 2007;28:1670-1681.
  22. Ishunina TA, van Beurden D, van der Meulen G, Unmehopa UA, Hol EM, Huitinga I, Swaab DF: Diminished aromatase immunoreactivity in the hypothalamus, but not in the basal forebrain nuclei in Alzheimer's disease. Neurobiol Aging 2005;26:173-194.
  23. Stoffel-Wagner B, Watzka M, Steckelbroeck S, Schwaab R, Schramm J, Bidlingmaier F, Klingmuller D: Expression of CYP19 (aromatase) mRNA in the human temporal lobe. Biochem Biophys Res Commun 1998;244:768-771.
  24. Yague JG, Munoz A, de Monasterio-Schrader P, Defelipe J, Garcia-Segura LM, Azcoitia I: Aromatase expression in the human temporal cortex. Neuroscience 2006;138:389-401.
  25. Tworoger SS, Chubak J, Aiello EJ, Ulrich CM, Atkinson C, Potter JD, Yasui Y, Stapleton PL, Lampe JW, Farin FM, Stanczyk FZ, McTiernan A: Association of CYP17, CYP19,CYP1b1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2004;13:94-101.
  26. Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E, Novik KL, Kelemen L, Ogata S, Pharoah PD, Easton DF, Day NE, Ponder BA: Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 2004;96:936-945.
  27. De Castro F, Moron FJ, Montoro L, Galan JJ, Real LM, Ruiz A: Re: Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 2005;97:152-153; author reply 153-154.
  28. Baghaei F, Rosmond R, Westberg L, Hellstrand M, Eriksson E, Holm G, Bjorntorp P: The CYP19 gene and associations with androgens and abdominal obesity in premenopausal women. Obes Res 2003;11:578-585.
  29. Combarros O, Riancho JA, Infante J, Sanudo C, Llorca J, Zarrabeitia MT, Berciano J: Interaction between CYP19 aromatase and butyrylcholinesterase genes increases Alzheimer's disease risk. Dement Geriatr Cogn Disord 2005;20:153-157.
  30. Combarros O, Sanchez-Juan P, Riancho JA, Mateo I, Rodriguez-Rodriguez E, Infante J, Garcia-Gorostiaga I, Vazquez-Higuera JL, Berciano J: Aromatase and interleukin-10 genetic variants interactively modulate Alzheimer's disease risk. J Neural Transm 2008;115:863-867.
  31. Han MR, Schellenberg GD, Wang LS: Genome-wide association reveals genetic effects on human Aβ42 and tau protein levels in cerebrospinal fluids: a case control study. BMC Neurol 2010;10:90.


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