Estrogen Receptor β Variants Modify Risk for Alzheimer's Disease in a Multiethnic Female Cohort

Article type: Research Article

Authors: Janicki, Sarah C.^{a; b; c; *} | Park, Naeun^{a; b} | Cheng, Rong^{a; b} | Lee, Joseph H.^{a; b; d; e} | Schupf, Nicole^{a; b; e} | Clark, Lorraine N.^{a; d; f}

Affiliations: [a] Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA | [b] Gertrude H. Sergievsky Center, College of Physicians & Surgeons, Columbia University, New York, NY, USA | [c] Department of Neurology, College of Physicians & Surgeons, Columbia University, New York, NY, USA | [d] Center for Human Genetics, College of Physicians & Surgeons, Columbia University, New York, NY, USA | [e] Departments of Epidemiology and Psychiatry, Columbia University Medical Center, New York, NY, USA | [f] Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA

Correspondence: [*] Correspondence to: Sarah C. Janicki, MD, MPH; Gertrude H. Sergievsky Center, Columbia University Medical Center, P&S Box 16, 630 West 168th Street, New York, NY 10032, USA. Tel.: +1 212 305 9194; Fax: +1 212 305 2526; E-mail: [email protected].

Abstract: Background:Few studies of gene variants that affect estrogen activity investigate their association with age at onset of Alzheimer’s disease (AD) in women of different ethnicities. We investigated the influence of ESR2 polymorphisms on age at onset of AD in a multiethnic cohort of women. Objectives:To determine whether gene variants would affect risk for AD differently in women of different population ancestries. Methods:Among 1,686 women participating in the Washington Heights Inwood Columbia Aging Project (WHICAP), association with risk for AD was assessed for 20 ESR2 single-nucleotide polymorphisms (SNPs) using multivariate logistic regression, adjusting for age at time of study enrollment, presence of an APOE 𝜀4 allele, years of education, and body mass index. Results:Increased risk for AD was associated with four ESR2 SNPs in women of predominantly Caucasian AIMS-defined ancestry: rs944045, rs1256062, rs10144225, and rs2274705 (OR range 1.6–1.9, empiric p-value range 0.002–0.004). A separate SNP (rs10137185) was associated with decreased risk for AD in women who identified themselves as Black (OR 0.6, 95% CI = 0.4–0.9). When vascular risk factors were included in the model, a separate SNP (rs1256059) was associated with increased risk for AD in women of admixed/Hispanic ancestry (OR 1.5, 95% CI = 1.1–2.4). Conclusions:ESR2 polymorphisms affect risk for AD in women, and risk alleles vary by AIMs-defined ancestry and self-identified ethnicity. These effects are possibly due to different linkage disequilibrium patterns or differences in comorbid risk factors mediating SNP effect on risk for AD by group.

Keywords: Alzheimer's disease, estrogen receptor 2, estrogen receptors beta, genetic association studies, Hispanic, women

DOI: 10.3233/JAD-130551

Journal: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 83-93, 2014