Endothelial Nitric Oxide Synthase Gene Variants and Primary Open-Angle Glaucoma Interactions With Hypertension, Alcohol Intake, and Cigarette Smoking

Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA.
Archives of ophthalmology (Impact Factor: 4.4). 06/2011; 129(6):773-80. DOI: 10.1001/archophthalmol.2011.118
Source: PubMed


To evaluate whether an association between risk of any of the factors of hypertension, alcohol intake, and cigarette smoking and the risk of primary open-angle glaucoma (POAG) depended on nitric oxide synthase 3 (NOS3) gene variants.
Two functional single-nucleotide polymorphisms (SNPs) (T-786C [rs2070744] and Glu298Asp [rs1799983]) and 2 tagging SNPs (rs7830 and rs3918188) were evaluated in nested case-control studies from the Nurses' Health Study (1980-2002) and the Health Professionals' Follow-up Study (1986-2002). Participants were 40 years of age or older and white, and were followed up biennially. We included 527 incident case patients with POAG and 1539 control participants, matched by cohort, age, and eye examination at the matched case patients' diagnosis dates. Cohort-specific relative risks were estimated using multivariable conditional logistic regression and were pooled using meta-analytic methods.
The association between hypertension and POAG depended on T-786C SNP variants. Compared with TT homozygotes without hypertension, the TT homozygotes with hypertension were at significantly higher risk of POAG (relative risk,1.45 [95% confidence interval, 1.01-2.08]); however, among carriers of the variant (C) allele, hypertension was not associated with POAG (P interaction = .007). Similarly, compared with CC homozygotes with the rs7830 tagging SNP who never smoked, CC homozygotes who were past or current smokers were at significantly higher risk of POAG (relative risk, 1.63 [95% confidence interval, 1.15-2.31]); however, among carriers of the variant allele (A), smoking was not associated with POAG (P interaction = .004). Interactions were not observed with alcohol intake.
The associations between hypertension and cigarette smoking in relation to POAG depended on NOS3 SNPs.

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Available from: Jonathan l. Haines, Apr 03, 2014
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    • "Recently in a cohort of African-American women, Wise L. A. et al. reported that smoking might be associated with increased risk of early-onset POAG [14]. Kang, J. H. et al. also reported cigarette smoking conferring risk to POAG [15]. Similar findings were also reported in other independent studies [16-18]. "
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    ABSTRACT: Background To date, studies on the role played by cigarette smoking in primary open-angle glaucoma (POAG) remains controversial. The current study evaluated cigarette smoking as a risk factor of POAG and its relationships with vertical cup-to-disc ratio (VCDR), central corneal thickness (CCT) and intraocular pressure (IOP) in a Chinese cohort. Methods In a total of 248 unrelated individuals including 30 juvenile-onset POAG (JOAG), 92 adult-onset POAG (AOAG) and 126 sex-matched senile cataract controls, underwent comprehensive ophthalmic examination. Their smoking was obtained and documented by questionnaire. Association of cigarette smoking with POAG was performed using logistic regression controlled for age and sex. Effects of cigarette smoking on VCDR, IOP and CCT were analyzed with multiple linear regression. Results In either JOAG or AOAG, no association of cigarette smoking was found with disease onset (P = 0.692 and 0.925 respectively). In controls and JOAG, no significant effects of smoking were found on VCDR, IOP or CCT (all P > 0.05). Smoking was found to be correlated with decreased CCT in AOAG and combined POAG (JOAG + AOAG) (P = 0.009 and 0.003), but no association with VCDR or IOP was observed (P > 0.05). Conclusions Although cigarette smoking was not found to be risk factor for onset of POAG, it was correlated with CCT in AOAG, and thus might still play a role in the disease course, especially for AOAG.
    Full-text · Article · Nov 2012 · BMC Ophthalmology
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    • "Perhaps in the latter instance lower circulating estrogen milieu in women with low parity may be more important than multiparity-induced endothelial dysfunction in dictating POAG risk. We have previously reported a “cross-over” type interaction for the functional T-786C SNP and hypertension and POAG [37]. It remains to be determined whether crossover interactions have real pathophysiological significance. "
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    ABSTRACT: 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. 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. 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. These data provide further support for the notion that NOS3 genotype - female reproductive health interactions are important in POAG pathogenesis.
    Full-text · Article · Sep 2011 · Molecular vision
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    ABSTRACT: Abstract Glaucoma is a leading cause of irreversible blindness. Intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, yet there is little known about the molecular events that regulate IOP. Genetic and genomic studies have helped identify genes that influence IOP and could lead to the identification of biological pathways that serve as targets for novel pressure-modifying therapies. Genetic linkage studies resulted in the identification of several genes that cause Mendelian (autosomal dominant or autosomal recessive) forms of high-pressure glaucoma, including MYOC. PITX2, FOXC1, and CYP1B1. Classical twin studies suggest that IOP is a heritable trait. More recently, genome-wide association studies (GWAS) have shown that common genetic variants in the GAS7 and TMCO1 genomic regions are associated with elevated IOP. TMCO1 has also been associated with primary open-angle glaucoma in patients with advanced disease. A further study identifying additional genes contributing to IOP will be necessary to fully define the underlying genetic architecture of IOP.
    No preview · Article · Oct 2013 · Seminars in ophthalmology
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