Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease. (10th October 2022)

• Record Type: Journal Article
• Authors: Khera, Amit V.; Wang, Minxian; Chaffin, Mark; Emdin, Connor A.; Samani, Nilesh J.; Schunkert, Heribert; Watkins, Hugh; McPherson, Ruth; Erdmann, Jeanette; Elosua, Roberto; Boerwinkle, Eric; Ardissino, Diego; Butterworth, Adam S.; Di Angelantonio, Emanuele; Naheed, Aliya; Danesh, John; Chowdhury, Rajiv; Krumholz, Harlan M.; Sheu, Wayne H.-H.; Rich, Stephen S.; Rotter, Jerome I.; Chen, Yii-der Ida; Gabriel, Stacey; Lander, Eric S.; Saleheen, Danish; Kathiresan, Sekar
• Is Part Of: Circulation. Volume 15:Number 6(2022)
• Page Start: e003598
• Publication Date: 2022-10-10
• Subjects: atherosclerosis -- coronary artery disease -- genetic association studies -- nitric oxide synthase type III -- precision medicine; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.121.003598
• Languages: English
• ISSNs: 2574-8300

Abstract

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.