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

Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham & Women's Hospital, Boston, Massachusetts, USA.
Investigative ophthalmology & visual science (Impact Factor: 3.4). 10/2009; 51(2):971-9. DOI: 10.1167/iovs.09-4266
Source: PubMed


To evaluate the association between the nitric oxide synthase gene (NOS3) variants and primary open-angle glaucoma (POAG).
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 >or=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.
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.
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.

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Available from: Jonathan l. Haines, Apr 03, 2014
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    • "In this study, after stratification by sex, we found the CC genotype and the C allele of the T-786C NOS3 gene were associated with high-tension POAG in women but not in men. The CC genotype has been previously found to be linked with women in the United States [23], and TC+CC genotypes have been found to be linked with women in Brazil [19]. This might suggest that female sex hormones may interact with these genotypes resulting in the development of POAG. "
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    ABSTRACT: Purpose To analyze the association of polymorphisms of the endothelial nitric oxide synthase (NOS3) gene and nitric oxide (NO) levels with high-tension primary open-angle glaucoma (POAG) in an Egyptian population. Methods This case-control study included 160 patients who had high-tension POAG (76 men and 84 women; age range 41–75 years) and 110 controls (56 men and 54 women; age range 55–78 years). Genotyping of T-786C (rs2070744), Glu298Asp (rs1799983), and the 27-bp insertional variable number tandem repeat (VNTR) in intron 4 of the NOS3 gene was performed with an amplification refractory mutation system PCR assay. The NO level was determined by measuring the total nitrate/nitrite (NOX) plasma level. Results The CC genotype of the T-786C polymorphism was significantly associated with POAG (odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.26–5.13, p = 0.007). The C allele was significantly associated with POAG (OR = 1.86, 95% CI = 1.29–2.69, p<0.001). After stratification by sex, the CC genotype and the C allele were significantly associated with POAG in women only (OR = 3.06, 95% CI = 1.07–8.74, p = 0.03 for the CC genotype, and OR = 2.09, 95% CI = 1.24–3.53, p = 0.005 for the C allele). The genotype and allele frequencies of Glu298Asp and intron 4 were not significant between the patients with POAG and the controls, and after stratification by sex. The mean NOX plasma level was significantly lower in patients with POAG than in the controls (p = 0.01) and low in the (TC+CC) genotype compared to the TT genotype of T-786C in the patients and controls (p<0.001). Conclusions The results suggest that the CC genotype of T-786C NOS3 may be associated with an increased risk of developing high-tension POAG in Egyptians, particularly women. In addition, decreased NO levels may play a role in the development of POAG.
    Full-text · Article · Jun 2014 · Molecular vision
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    • "In humans, several mechanisms have been identified that can impair NO-cGMP signaling, potentially contributing to the development of POAG. For example, a candidate gene association study in 527 incident cases and 1543 controls revealed interactions between NOS3 gene variants, potentially affecting expression and/or activity of NOS3 (and, ultimately, sGC enzyme activity), and high tension POAG in females [26]. Alternatively, the mechanism by which increased oxidative stress results in POAG [77] may involve direct oxidation and inactivation of sGC [78]. "
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    ABSTRACT: Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α1 subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α1-deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α1 and β1 subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.
    Full-text · Article · Mar 2013 · PLoS ONE
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    • "To date, the polymorphisms addressed in this study all associated with vascular disease, have either not been thoroughly investigated in Caucasian glaucoma populations, or often in smaller groups, and only rarely in NTG [33]. In agreement with our findings, a recent study in Caucasians found no difference in the distribution of several NOS3 polymorphism (including G894T and T-786C) when POAG patients were compared with controls [34]. What our study further suggests is that also NTG patients and particularly those with clinically evident vascular dysfunction do not more likely carry these polymorphisms. "
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    ABSTRACT: Substantial evidence suggests that ocular perfusion is regulated by nitric oxide (NO), and polymorphisms in genes encoding for enzymes involved in NO formation and degradation (endothelial nitric oxide synthase [NOS3] and cytochrome b-235 alpha polypeptide gene [CYBA]) might contribute to vascular dysregulation observed in glaucoma. We therefore assessed the association of glaucoma with polymorphisms of NOS3 and CYBA previously associated with cardiovascular disease. We also compared the distribution of these polymorphisms in patients with high tension glaucoma (HTG) and normal tension glaucoma (NTG) and evaluated its association with vascular dysregulation in a subset of glaucoma patients. Three hundred Caucasian patients with HTG and 127 with NTG were enrolled in the study and genotyped for G894T (rs1799983) and T-786C (rs2070744) in NOS3 and C242T (rs4673) in CYBA. None of these polymorphisms had a different allele or genotype distribution between HTG and NTG patients nor had the presence of vasospasms any impact. We studied the frequencies of a set of relevant polymorphisms of the NO system in a large cohort of glaucoma patients and found no association. These results therefore suggest the absence of a relevant relationship with different glaucoma forms in Caucasians.
    Full-text · Article · Aug 2012 · Molecular vision
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