Reproductive factors and NOS3 variant interactions in primary open-angle glaucoma

PURPOSE To investigate whether associations with the nitric oxide synthase gene (NOS3) variants and risk of primary open-angle glaucoma (POAG) depend on female reproductive factors. METHODS Two functional and two tagging single nucleotide polymorphisms (SNPs; T-786C: rs2070744, Glu298Asp: rs1799983, rs7830, and rs3918188) were evaluated in a nested case-control study from the Nurses' Health Study (women followed 1980 - 2002). Participants were aged ≥40 years and Caucasian, who were followed biennially with update information on reproductive factors. We included 374 Nurses' Health Study (NHS) cases and 1,085 controls, matched on age and eye exam at the matched cases' diagnosis dates. Relative risks (RRs) were estimated using multivariable conditional logistic regression. RESULTS Among women with age at menarche <13 years, compared with the CC homozygotes of the rs3918188 tagging SNP, the wild-type AA homozygotes were at significantly reduced risk of POAG (RR=0.31, 95% CI=0.16, 0.59); however, for women with age at menarche ≥13 years, the SNP was not associated with POAG (p-interaction=0.0007). Among parous women with 3+ children, carriers of the minor variant (T) allele of the functional Glu298Asp SNP were at increased risk, while among parous women with 1-2 children, they were not (p-interaction=0.003). No significant interactions between NOS3 SNPs and oral contraceptive use in POAG were detected. CONCLUSIONS These data provide further support for the notion that NOS3 genotype - female reproductive health interactions are important in POAG pathogenesis.