Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
May 2014

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

Sarah C. Janicki, M.D., M.P.H., Naeun Park, M.S., Rong Cheng, Ph.D., Lorraine N. Clark, Ph.D., Joseph H. Lee, Dr. PH, Nicole Schupf, Ph.D, Dr.PH

Sarah C. Janicki, MD, MPH Nicole Schupf, PhD, DrPH

Our group studied the relation between estrogen-related variants and risk for Alzheimer's disease (AD) in a multiethnic group of women participating in the Washington Heights-Inwood Community Aging Project (WHICAP). Our overall aim was to identify modifiable risk factors for AD for the development of interventions to delay or prevent onset. Estrogen is important in the normal maintenance of brain function in regions typically affected by AD, and may play a role in the cognitive decline associated with AD. In the brain, two estrogen receptors, ER-α, encoded by ESR1, and ER-β, encoded by ESR2, have been identified and have been found in regions affected in AD, including the hippocampus, basal forebrain and amygdala. Both ER-α and ER-β appear to have a role in the preservation of cholinergic activity and ER-α plays a role in the neuroprotective effects of estrogen against β-amyloid induced toxicity. Two closely linked restriction fragment length polymorphisms in the first intron of ESR1, PvuII and XbaI, have been reported to influence ER-&alpha expression and risk for AD Previous studies investigating the association of ESR1 polymorphisms to AD risk or age at onset have been conducted in homogeneous ethnic groups, and few polymorphisms have been assessed in a multiethnic cohort. Examination of SNPs in multiracial groups which are evaluated without taking ethnicity into account may have several limitations, including different linkage disequilibrium patterns between ethnicities, or differences in the distribution of comorbid conditions and risk factors for AD by ethnic group.

Recently published in the Journal of Alzheimer's Disease, our study had several aims: to confirm previous studies' results of ESR1 polymorphisms associated with AD; to identify additional SNPs which confer risk for AD using a denser set of SNPs than in previous studies; and to examine whether ESR1 variants would affect risk for AD differently in groups of women with different self-identified or genetically defined ethnicity. We examined 41 ESR1 SNPS in 1,436 women of non-Hispanic White, African-American and Hispanic ancestry, first stratifying by self-reported ethnicity and then by the predominant genetically defined ancestry.

In self-identified White women, six SNPs in ESR1 were associated with delayed age of AD onset, including the two restriction fragment length polymorphisms PvuII (rs2234693) and XbaI (rs9340799) (HR range = 0.420–0.483) previously identified. In self-identified African-American women one SNP (rs2982684) was associated with an earlier onset of AD and one SNP (rs2077647) with a delayed onset. No SNPS were significantly related to AD risk among self-identified Hispanic women. When women were recategorized according to their predominant genetically defined ancestry, one SNP, rs6909023, was associated with an earlier onset of AD in White women, and one SNP, rs2982684, was still associated with an earlier onset of AD in African-American women.

Overall, our findings confirm the importance of variation in estrogen receptor activity in modifying age at onset and risk for AD among elderly women. The discrepancy between SNPs found to be significant by self-defined ethnicity versus predominant genetic ancestry confirms our hypothesis that risk for AD onset may be affected by environmental and/or cultural factors as well as by genetic factors. Future studies with denser genotyping to achieve high resolution in all ethnic groups, along with gene expression studies, may further provide biological insights. Our group is currently conducting similar analyses in men.

Sarah Janicki, MD, MPH

Nicole Schupf, PhD

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