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

Article (PDF Available)inInvestigative ophthalmology & visual science 51(2):971-9 · October 2009with28 Reads
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.
    • Whilst others have found no increase in risk of POAG due to smoking, findings from the Blue Mountain Eye Study suggest a moderate positive association between smoking and increased IOP (a significant risk factor for glaucoma) [14] . Additionally , Kang et al. [15] recently found that the associations with cigarette smoking status differed significantly depending on gene variants (p = 0.004). Compared with CC homozygotes who never smoked, CC homozygotes who were past or current smokers were at significantly higher risk of POAG (RR, 1.63 [95 % CI 1.15–2.31]).
    [Show abstract] [Hide abstract] ABSTRACT: Glaucoma is one of the most common causes of irreversible blindness, globally. Findings from the Blue Mountain Eye Study suggest a moderate positive association between smoking and increased IOP (a significant risk factor for glaucoma). The previous two reviews investigating the association between smoking and primary open-angle glaucoma (POAG) show inconsistent findings and do not include recent studies investigating the dose–response effect of smoking. The current study aims to conduct an up-to-date, comprehensive evaluation of the existing literature. Identification of relevant existing literature was performed by an online search in MEDLINE for studies published from 1st January 1946 to 5th February 2015. The MESH headings (keywords) included “open-angle glaucoma” and “cigarette” or “smoking” or “tobacco”. Two independent reviewers assessed the eligibility of each report based on predefined inclusion criteria. Odds ratios and 95 % confidence intervals (95 % CIs) were obtained from studies, for the change in risk of glaucoma due to both past and current smoking. Of the 26 abstracts reviewed, 17 papers were included in the final analysis. Nine of these were case–control studies, five cohort studies and three cross-sectional in design. Six of the case–control studies found a positive association between smoking and POAG, unlike the remaining studies. However, two relatively recent, large studies (including one prospective cohort study) investigating the effect of smoking dose have found a significant increase in risk of POAG in very heavy smokers. There is limited evidence for a causal association between tobacco smoking and POAG. The evidence for a link between current smoking and POAG appears stronger than that of past smoking, but recent studies suggest that heavy smoking may increase the risk of POAG. Future studies must further investigate the possible positive association between heavy smoking and POAG by stratifying participants by pack years and age.
    Full-text · Article · May 2016
    • Similarly , changes in the capillaries of fingers observed in NTG patients were not associated with allelic variants. Some studies [23,24] have shown that genetic variants of the T-786C polymorphism constitute a risk factor for high tension glaucoma only in women. Logan found an association between promoter region polymorphism and POAG in patients with the history of migraine [20], a disease more prevalent in woman and in patients with normal tension glaucoma.
    [Show abstract] [Hide abstract] ABSTRACT: Aim: The purpose of this study was to evaluate the influence of polymorphisms of the eNOS gene on the clinical status of patients with normal and high tension glaucoma. Methods: 266 Polish Caucasian patients with primary open angle glaucoma were studied. Of the 266, 156 had normal tension glaucoma (NTG) and 110 high tension glaucoma (HTG). DNA material was isolated from peripheral venous blood using commercial kits. Real-time PCR reaction was used to amplify the promoter site of the endothelial nitric oxide synthase (eNOS) gene, including the single nucleotide polymorphism (SNP) site T-786C and part of the 7th exon of eNOS, including G894T SNP. Genotypes were determined with TaqMan SNP Genotyping Assays. Results: There were no significant differences in frequencies of the allelic variants of both polymorphisms. In G894T SNP, however, the wild GG form was more common in the HTG group. The SNP of the eNOS gene did not significantly influence the progression rate in either of the groups studied. There were no differences in variants of the eNOS gene regarding the necessity for and success of surgery and the progression of the disease. In the NTG group, no statistical correlation was observed between G894T, T786C polymorphism variants, and risk factors such as optic disc haemorrhages, optic disc notches, and peripapillary atrophy. Mean diastolic and systolic pressure during the day and night were lowest in NTG patients with the CC variant of the T786C polymorphism. No statistical correlation was observed between the G894T and T786C polymorphisms and capillaroscopic examination results. Conclusions: Genotype frequencies are similar for both the eNOS G894T and T-786C polymorphisms in NTG and HTG patients. These polymorphisms do not correlate with risk factors and do not influence the state of the capillary system in NTG patients. Systolic blood pressure is lower in NTG patients with mutated alleles of both polymorphisms.
    Full-text · Article · Jan 2016
    • Cite this article as Cold Spring Harb Perspect Med 2014;4:a017244 factor for POAG (Kang et al. 2010 ). The estrogen metabolism pathway is also associated with POAG in women (Pasquale et al. 2013).
    [Show abstract] [Hide abstract] ABSTRACT: The characterization of genes responsible for glaucoma is the critical first step toward the development of gene-based diagnostic and screening tests, which could identify individuals at risk for disease before irreversible optic nerve damage occurs. Early-onset forms of glaucoma affecting children and young adults are typically inherited as Mendelian autosomal dominant or recessive traits whereas glaucoma affecting older adults has complex inheritance. In this report, we present a comprehensive overview of the genes and genomic regions contributing to inherited glaucoma.
    Article · Sep 2014
    • 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.
    [Show abstract] [Hide abstract] 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
    • At least one variant in the CAV1/CAV2 locus was subsequently found to be associated with increased IOP (Van Koolwijk et al., 2012; Ozel et al., 2014 ). Second, 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 high tension POAG in females (Kang et al., 2010 ). In addition, a functional NOS3 polymorphism (T-786C) was associated with POAG and appears to interact with gender and age in modulating the risk of POAG (Magalhaes Da Silva et al., 2012).
    [Show abstract] [Hide abstract] ABSTRACT: Glaucoma is a progressive optic neuropathy characterized by visual field defects that ultimately lead to irreversible blindness (Alward, 2000; Anderson et al., 2006). By the year 2020, an estimated 80 million people will have glaucoma, 11 million of which will be bilaterally blind. Primary open-angle glaucoma (POAG) is the most common type of glaucoma. Elevated intraocular pressure (IOP) is currently the only risk factor amenable to treatment. How IOP is regulated and can be modulated remains a topic of active investigation. Available therapies, mostly geared toward lowering IOP, offer incomplete protection, and POAG often goes undetected until irreparable damage has been done, highlighting the need for novel therapeutic approaches, drug targets, and biomarkers (Heijl et al., 2002; Quigley, 2011). In this review, the role of soluble (nitric oxide (NO)-activated) and membrane-bound, natriuretic peptide (NP)-activated guanylate cyclases that generate the secondary signaling molecule cyclic guanosine monophosphate (cGMP) in the regulation of IOP and in the pathophysiology of POAG will be discussed.
    Full-text · Article · May 2014
    • Although we observed a significant association with rs1800779 in NOS3 with baseline lung function in the derivation cohort we were unable to replicate the association in additional patient groups. Nevertheless, we were able to demonstrate that the rs1800779 SNP has a functional effect on the expression of the NOS3 gene and this has implications for the numerous disease states that have been associated with this polymorphism24252627. The NOS gene variants that we investigated were limited to those that had strong a priori evidence for involvement in regulation of gene expression or in a trait related to COPD.
    [Show abstract] [Hide abstract] ABSTRACT: Due to the pleiotropic effects of nitric oxide (NO) within the lungs, it is likely that NO is a significant factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to test for association between single nucleotide polymorphisms (SNPs) in three NO synthase (NOS) genes and lung function, as well as to examine gene expression and protein levels in relation to the genetic variation. One SNP in each NOS gene (neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3)) was genotyped in the Lung Health Study (LHS) and correlated with lung function. One SNP (rs1800779) was also analyzed for association with COPD and lung function in four COPD case--control populations. Lung tissue expression of NOS3 mRNA and protein was tested in individuals of known genotype for rs1800779. Immunohistochemistry of lung tissue was used to localize NOS3 expression. For the NOS3 rs1800779 SNP, the baseline forced expiratory volume in one second in the LHS was significantly higher in the combined AG + GG genotypic groups compared with the AA genotypic group. Gene expression and protein levels in lung tissue were significantly lower in subjects with the AG + GG genotypes than in AA subjects. NOS3 protein was expressed in the airway epithelium and subjects with the AA genotype demonstrated higher NOS3 expression compared with AG and GG individuals. However, we were not able to replicate the associations with COPD or lung function in the other COPD study groups. Variants in the NOS genes were not associated with lung function or COPD status. However, the G allele of rs1800779 resulted in a decrease of NOS3 gene expression and protein levels and this has implications for the numerous disease states that have been associated with this polymorphism.
    Full-text · Article · Nov 2013
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