Person:

Lee, I-Min

Introduction: Rheumatoid arthritis (RA) is more common in females than males and sex steroid hormones may in part explain this difference. We conducted a case–control study nested within two prospective studies to determine the associations between plasma steroid hormones measured prior to RA onset and polymorphisms in the androgen receptor (AR), estrogen receptor 2 (ESR2), aromatase (CYP19) and progesterone receptor (PGR) genes and RA risk. Methods: We genotyped AR, ESR2, CYP19, PGR SNPs and the AR CAG repeat in RA case–control studies nested within the Nurses' Health Study (NHS), NHS II (449 RA cases, 449 controls) and the Women's Health Study (72 cases, and 202 controls). All controls were matched on cohort, age, Caucasian race, menopausal status, and postmenopausal hormone use. We measured plasma dehydroepiandrosterone sulfate (DHEAS), testosterone, and sex hormone binding globulin in 132 pre-RA samples and 396 matched controls in the NHS cohorts. We used conditional logistic regression models adjusted for potential confounders to assess RA risk. Results: Mean age of RA diagnosis was 55 years in both cohorts; 58% of cases were rheumatoid factor positive at diagnosis. There was no significant association between plasma DHEAS, total testosterone, or calculated free testosterone and risk of future RA. There was no association between individual variants or haplotypes in any of the genes and RA or seropositive RA, nor any association for the AR CAG repeat. Conclusions: Steroid hormone levels measured at a single time point prior to RA onset were not associated with RA risk in this study. Our findings do not suggest that androgens or the AR, ESR2, PGR, and CYP19 genes are important to RA risk in women.

Prior studies have suggested that vitamin D may reduce ovarian cancer risk. Thus, we examined whether three single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene (Fok1, Bsm1, Cdx2) were associated with risk of epithelial ovarian cancer in a retrospective case-control study (New England Case-Control study, NECC) and a nested-case control study of three prospective cohort studies: the Nurses’ Health Study (NHS), NHSII, and the Women’s Health Study (WHS). Data from the cohort studies were combined and analyzed using conditional logistic regression and pooled with the results from the NECC, which were analyzed using unconditional logistic regression, using a random effects model. We obtained genotype data for 1,473 cases and 2,006 controls. We observed a significant positive association between the number of Fok1 f alleles and ovarian cancer risk in the pooled analysis (p-trend=0.03). The odds ratio (OR) for the ff versus FF genotype was 1.26 (95% confidence interval (CI)=1.01-1.57). Neither the Bsm1 (p-trend=0.96) or Cdx2 (p-trend=0.13) SNPs were significantly associated with ovarian cancer risk. Among the prospective studies, the risk of ovarian cancer by plasma vitamin D levels did not clearly vary by any of the genotypes. For example among women with the Fok1 FF genotype, the OR comparing plasma 25-hydroxyvitamin D ≥32 ng/mL versus <32 ng/mL was 0.66 (95%CI=0.34-1.28), and among women with the Ff or ff genotype the OR was 0.71 (95%CI=0.43-1.18). Our results of an association with the Fok1 VDR polymorphism further support a role of the vitamin D pathway in ovarian carcinogenesis.