The impact of estrogen-related polymorphisms on risk of menopause symptoms in a large cohort of ethnically diverse, low income women

Abstract

Objective: This cross-sectional study examined the association between menopause symptoms and estrogen-related polymorphisms in a population of HIV+ and at-risk HIV- women and whether these associations were modified by HIV serostatus and menopause stage. Design: Participants included all perimenopausal and early postmenopausal women (age < 55) from the Women's Interagency HIV Study who had genetic testing and who completed the Study of Women's Health Across the Nation (SWAN) menopause symptom questionnaire, a 22-item checklist that is categorized into 4 symptom domains: (1) mood, (2) vasomotor, (3) somatic, and (4) sleep. Menopausal status was defined according to consensus guidelines from the Stages of Reproductive Aging Workshop. A persistent symptom was defined as occurring greater than 6 days within the last 2 weeks. We examined two single nucleotide polymorphisms (SNPs) in genes encoding the cytochrome 450 enzyme (rs2606345: CYP1A1 and rsl056836: CYP1B1) and two SNPs on the estrogen receptor a gene (rs9340799: Xbal, rs2234693: PvuII). Logistic regression was used to test the association between these SNPs and menopausal symptoms after adjusting for relevant sociodemographic, clinical and behavioral covariates. Results: The sample included 266 HIV+ and 96 at-risk, HIV- women (65% African-American) with a mean age of 43 years for perimenopausal women and 50 years for postmenopausal women. No associations were found between menopause symptoms and SNPs; however, important moderators where identified. We did not observe any significant interactions between serostatus and genotype group on any of the menopausal symptoms, but our power was limited to detect effect modification. The Xbal SNP interacted with menopause stage to influence risk of mood disturbance. Specifically, women that carried the Xbal minor allele were at increased risk of reporting persistent mood symptoms compared to those homozygous for the Xbal major allele (OR=2.51, 95% CI 1.16-5.42) among peri-, but not postmenopausal women. When examining individual symptoms within the mood domain, earners of the Xbal minor allele reported increased irritability (OR=2.46, 95%CI 1.185.16) and tension/nervousness (OR=1.80, 95% CI 0.99-3.24) but not to feeling blue/depressed or to frequent mood changes (all p's > 0.32). Conclusion: Previous clinical studies have shown that the Xbal SNP relates specifically to an increased risk of anxiety, but not depressive symptoms, among women but not men. Our results demonstrate that same SNP relates to anxiety symptoms during the menopausal transition in women with and without HIV. Basic science studies show that agonists at estrogen receptor a produce anxiety whereas agonists at estrogen receptor beta decrease anxiety. If our results are replicated by other investigators, treatments for anxiety symptoms during perimenopause should target estrogen receptor beta.