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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 =5.5×10 −9 ). These variants were associated with higher systolic blood pressure (+3.25 mm Hg; [95% CI, 1.86–4.65]; P =5.0×10 −6 ) and increased risk of hypertension (adjusted odds ratio 1.31; [95% CI, 1.14–1.51]; P =0.0002) 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.

Original publication




Journal article


Circulation: Genomic and Precision Medicine


Ovid Technologies (Wolters Kluwer Health)

Publication Date