1. Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease
- Author
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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, and Kathiresan, Sekar
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Heart Disease - Coronary Heart Disease ,Genetics ,Prevention ,Cardiovascular ,Atherosclerosis ,Heart Disease ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Humans ,Coronary Artery Disease ,Polymorphism ,Genetic ,Nitric Oxide ,Cholesterol ,Hypercholesterolemia ,atherosclerosis ,coronary artery disease ,genetic association studies ,nitric oxide synthase type III ,precision medicine ,Medical Biotechnology ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology - Abstract
BackgroundA 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.MethodsTo 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.ResultsRare 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.ConclusionsBeyond LDLR, we identified an additional nonlipid molecular subtype of CAD characterized by rare variants in the NOS3 gene.
- Published
- 2022