Abstract
Purpose: :
The endothelial nitric oxide synthase gene (NOS3) is constitutively expressed in trabecular meshwork cells, ciliary body muscle cells and ocular vascular endothelia. Altered NOS3 activity may contribute to the glaucomatous process by influencing aqueous humor dynamics and ocular blood flow, prompting us to perform a gene association study of NOS3 variants and POAG.
Methods: :
We prospectively assessed the association between 2 functional single nucleotide polymorphisms (-786T>C: rs2070744 andGlu298Asp: rs1799983) and 3 tagging SNPs (rs7830; rs3918188; rs1800779) in NOS3 and POAG risk in a nested case-control study consisting of women in the Nurses’ Health Study (NHS) and men in the Health Professionals Follow-up Study (HPFS) (510 incident cases and 1444 matched controls). We formed cohort-specific models of the relative risk (RR) for the association between NOS3 variants and POAG using logistic regression to control for several environmental exposures. We pooled cohort-specific results using meta-analytical techniques, incorporating random effects. We also evaluated associations between NOS3 haplotypes and POAG using haplotypes with pooled frequency of >5%.
Results: :
None of the NOS3 polymorphisms or haplotypes were significantly associated with POAG overall. We did observe a borderline positive association between the TT genotype at Glu(298)Asp and POAG among women [RR=1.45 (0.98-2.13); p trend=0.15] but not men [RR=1.00 (0.50-2.01); p trend =0.70] compared to the reference GG genotype. In secondary analysis, the AA genotype of the tagging SNP rs3918188 was inversely associated with high tension POAG (defined by IOP > 21 mm Hg at visual field loss) among women (RR=0.48 [0.28-0.82]; p-trend=0.0008) but not men (RR=1.48 [0.77-2.84]) compared to the reference CC genotype (based on a total of 250 NHS cases and 112 HPFS cases). Also, the CC genotype of the promoter SNP T -786C was positively associated with high tension POAG among women (RR=1.80 [1.14-2.85]; p-trend=0.02) but not men (RR=1.02 [0.48-2.17]). Finally, there were haplotype associations in relation to high tension POAG, among women (for example, RR=1.70 [1.16-2.43] for haplotype C-G-C-A-G vs. the most highly prevalent haplotype, T-G-A-C-A for the following SNP series: rs2070744 - rs1799983 - rs3918188 - rs7830 - rs1800779) but not among men.
Conclusions: :
The associations between NOS3 gene variants and high-tension POAG only among women suggest that gender biology may modify the relation between NOS3 activity and POAG.
Keywords: clinical (human) or epidemiologic studies: natural history • genetics • nitric oxide