Dataset Information

Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease.

ABSTRACT:

Background

A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene (LDLR) are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia.

Methods

To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls.

Results

Rare variants in LDLR were most strongly associated with CAD, present in 1% of cases and associated with 4.4-fold increased CAD risk. A second subtype was characterized by variants in endothelial nitric oxide synthase gene (NOS3), a key enzyme regulating vascular tone, endothelial function, and platelet aggregation. A rare predicted loss-of-function or damaging missense variants in NOS3 was present in 0.6% of cases and associated with 2.42-fold increased risk of CAD (95% CI, 1.80-3.26; P=5.50×10^-9). These variants were associated with higher systolic blood pressure (+3.25 mm Hg; [95% CI, 1.86-4.65]; P=5.00×10^-6) and increased risk of hypertension (adjusted odds ratio 1.31; [95% CI, 1.14-1.51]; P=2.00×10^-4) but not circulating cholesterol concentrations, suggesting that, beyond lipid pathways, nitric oxide synthesis is a key nonlipid driver of CAD risk.

Conclusions

Beyond LDLR, we identified an additional nonlipid molecular subtype of CAD characterized by rare variants in the NOS3 gene.

SUBMITTER: Khera AV

PROVIDER: S-EPMC9771961 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease.

Khera Amit V AV Wang Minxian M Chaffin Mark M Emdin Connor A CA Samani Nilesh J NJ Schunkert Heribert H Watkins Hugh H McPherson Ruth R Erdmann Jeanette J Elosua Roberto R Boerwinkle Eric E Ardissino Diego D Butterworth Adam S AS Di Angelantonio Emanuele E Naheed Aliya A Danesh John J Chowdhury Rajiv R Krumholz Harlan M HM Sheu Wayne H-H WH Rich Stephen S SS Rotter Jerome I JI Chen Yii-der Ida YI Gabriel Stacey S Lander Eric S ES Saleheen Danish D Kathiresan Sekar S

Circulation. Genomic and precision medicine 20221010 6

<h4>Background</h4>A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene (<i>LDLR</i>) are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia.<h4>Methods</h4>To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggreg ...[more]

PMID: 36215124

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Project description:ObjectiveBy releasing mediators, like nitric oxide (NO), vascular endothelium is considered so significant in the process of atherosclerotic . In fact, the major functions of NO consist in inhibiting the activation of platelet, relaxing the muscles (vascular and smooth ones), and modulating the growth and the migration of cells (vascular and smooth ones). Therefore, this process makes the endothelial nitric oxide synthase (NOS3) considerably important because it possesses atheroprotective activity. Polymophisms, rs1808593 (10G/T) as well as rs891512 (G24943A) within NOS3 gene, play major role in the coronary artery disease (CAD) development. The aim of the study is to evaluate the relationship between the 10G/T and G24943A polymorphisms and the CAD among Tunisian individuals.MethodsWe included, in this survey, a set of 274 patients suffering from CAD together with 162 normotensive subjects. The PCR-RFLP was applied to analyze the polymorphism of intron 23 (10G/T) gene, while the ASA-PCR was used to analyze the intronic G24943A gene polymorphism. Overall and subgroup analyses were performed. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the association between NOS3 10G/T and G24943A polymorphisms as well as CAD risk. Statistical analysis was performed with SPSS V.10.ResultsThe genotype frequencies for G24943A polymorphism differed significantly between the CAD patients and the controls. The former had a frequency of 11.4% for the AA genotype, 34.7% for the GA genotype and 53.9% for the GG genotype. The latter had a frequency of only 2.5% for the AA genotype, 29.7% for the GA genotype and 67.7% for the GG genotype (χ2=7.62; OR=1.79; p=0.006). The CAD patient group showed a significantly-higher frequency of the A allele compared to the controls (0.28 vs. 0.16; χ2=15.20; p<0.001). The odds ratio of CAD for A vs. G allele frequency was statistically significant 1.99 (1.4-2.82) at 95% CI. The genotype distribution for the 3 investigated variants of 10G/T were not significantly different between CAD and control subjects (χ2=1.46; OR=1.72; p=0.22). Whereas, 10G/T has revealed barely allelic (χ2=4.45; OR=2.3; p=0.034) correlation with coronary artery disease Conclusion: The present study was designed so that there would be an association between the CAD and NOS3 polymorphism (G24943A). However, these results have proven that the polymorphism of 10G/T is not associated with CAD in the Tunisian population.

Project description:BACKGROUND AND PURPOSE: Raloxifene improves cardiovascular function. This study examines the hypothesis that therapeutic concentrations of raloxifene augment endothelium-dependent relaxation via up-regulation of eNOS expression and activity in porcine coronary arteries. EXPERIMENTAL APPROACH: Isometric tension was measured in rings from isolated arteries. Intracellular Ca(2+) concentrations ([Ca(2+)](i)) in arterial endothelial cells were detected by Ca(2+) fluorescence imaging. Phosphorylation of eNOS at Ser-1177 was assayed by Western blot analysis. KEY RESULTS: In arterial rings pre-contracted with 9,11-dideoxy-11alpha,9alpha-epoxy-methano-prostaglandin F(2alpha) (U46619), treatment with raloxifene (1-3 nM) augmented bradykinin- or substance P-induced relaxation and this effect was antagonized by ICI 182,780, an estrogen receptor antagonist. The enhanced relaxation was abolished in rings treated with inhibitors of nitric oxide/cyclic GMP-dependent dilation, N(G)-nitro-L-arginine methyl ester (L-NAME) plus 1H-[1,2,4]oxadizolo[4,3-a]quinoxalin-1-one (ODQ). In contrast, effects of raloxifene were unaffected after inhibition of endothelium-derived hyperpolarizing factors by charybdotoxin plus apamin. Raloxifene (3 nM) did not influence endothelium-independent relaxation to sodium nitroprusside. 17beta-Estradiol (3-10 nM) also enhanced bradykinin-induced relaxation, which was inhibited by ICI 182,780. Treatment with raloxifene (3 nM) did not affect bradykinin-stimulated rise in endothelial cell [Ca(2+)](i). Raloxifene, 17beta-estradiol, and bradykinin increased eNOS phosphorylation at Ser-1177 and ICI 182,780 prevented effects of raloxifene or 17beta-estradiol but not that of bradykinin. Raloxifene had neither additive nor antagonistic effects on 17beta-estradiol-induced eNOS phosphorylation. CONCLUSIONS AND IMPLICATIONS: Raloxifene in therapeutically relevant concentrations augmented endothelial function in porcine coronary arteries in vitro through ICI 182,780-sensitive mechanisms that were associated with increased phosphorylation of eNOS but independent of changes in endothelial cell [Ca(2+)](i).

Dataset Information

Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease.

Background

Methods

Results

Conclusions

Publications

Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease.

Similar Datasets

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