Endothelial Nitric Oxide Synthase Gene Variants and Primary Open-Angle Glaucoma: Interactions with Sex and Postmenopausal Hormone Use

PURPOSE. To evaluate the association between the nitric oxide synthase gene (NOS3) variants and primary open-angle glaucoma (POAG). METHODS. Two functional single-nucleotide polymorphisms (SNPs) (T - 786C: rs2070744; Glu298Asp: rs1799983) and three tagging SNPs (rs7830, rs3918188, and rs1800779) were evaluated in a nested case-control study from the Nurses' Health Study (1980-2002) and the Health Professionals' Follow-up Study (1986-2002). Participants were aged >= 40 years and Caucasian. Included were 527 incident cases and 1543 controls, matched by cohort, age, and eye examination at the matched cases' diagnosis dates. Cohort-specific relative risks (RR) were estimated by using multivariable conditional logistic regression and were pooled with meta-analysis. RESULTS. No NOS3 polymorphism was significantly associated with overall POAG. For high-tension POAG (HTPOAG), rs3918188 was significantly inversely associated among the women (AA versus CC genotype: RR = 0.48; 95% CI, 0.28-0.82) but not among the men (P-heterogeneity by sex = 0.02). The minor alleles of T - 786C and rs1800779 showed positive association with high-tension POAG (P-trend < 0.02) in the women only, but P-heterogeneity was not significant. In the women, four of the five NOS3 SNPs showed significant interactions with postmenopausal hormone (PMH) use in relation to HTPOAG: for example, among the women with the TT genotype in T - 786C, PMH use was inversely associated (RR = 0.41; 95% CI, 0.22-0.76), but among carriers of the minor allele, use of PMH was not associated. CONCLUSIONS. Interactions were observed between NOS3 SNPs and female sex and postmenopausal hormone use in the women in relation to HTPOAG. These findings should be confirmed in different racial/ethnic groups. (Invest Ophthalmol Vis Sci. 2010; 51: 971-979) DOI:10.1167/iovs.09-4266