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.