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L. R. Pasquale, J. L. Wiggs, J. Haines, S. E. Hankinson, B. A. Rosner, J. H. Kang; The Interaction Between Attributes of Female Reproductive Aging and Nitric Oxide Synthase 3 Gene Variants in Primary Open-Angle Glaucoma: A Prospective Study. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1720.
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Declining estrogen levels may reduce endogenous nitric oxide production, altering the ophthalmic hemodynamic profile and making the optic nerve vulnerable to glaucomatous optic neuropathy. In a previous published cohort analysis, we reported that among women aged ≥ 65 years, later onset of menopause was associated with a reduced risk of primary open-angle glaucoma (POAG). We assessed whether age at menopause or postmenopausal hormone (PMH) use interacted with selected NOS3 genotypes to alter the risk of POAG.
We prospectively assessed the association between functional polymorphisms and haplotypes in NOS3 and POAG risk in a nested case-control study within the Nurses’ Health Study. We included 365 incident cases and 1062 matched controls. We genotyped 2 functional single nucleotide polymorphisms (T-786C: rs 2070744 and Glu(298)Asp: rs1799983) in the NOS3 gene. We further investigated gene-environment interactions between attributes of female reproductive aging (age at menopause and PMH use) and NOS3 gene variants in POAG using logistic regression analysis to control for several environmental exposures.
T -786C polymorphisms and NOS3 haplotypes were generally not related to POAG in multivariable analysis. However, we observed a 1.71-fold (95% CI: 1.12-2.61) increased risk of POAG among those who were homozygous for the Asp allele at Glu(298)Asp but a dose response effect for the Asp allele was of borderline significance (RR =1.21; 95% CI: 0.99-1.48; p = 0.06). Age at menopause did not modify the association with NOS3 gene variants (p > 0.25). There was a suggestion that PMH use modified risk associated with Glu(298)Asp (p interaction = 0.08). Among never- or past-users of PMH, the RR of POAG associated with the Asp/Asp variant was 2.39 (95%: 1.20-4.76) compared with those with other genotypes at this locus. In contrast, the RR associated with the Asp/Asp variant for current PMH users was not significant (RR=1.36; 95% CI: 0.56-3.32) compared with those with other genotypes at this locus.
This preliminary study suggests that PMH use may ameliorate the risk of POAG associated with the NOS3 Asp(298)Asp variant. We will perform additional genotyping and use a larger sample size to confirm this interaction.
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