Journal
CIRCULATION
Volume 137, Issue 3, Pages 222-232Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.117.028021
Keywords
cardiovascular disease; genetics; nitric oxide; nitric oxide synthase
Funding
- National Institutes of Health [R01 HL127564]
- UK Biobank resource [7089]
- Accelerating Medicines Partnership
- Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigacion Cardiovascular) [RD12/0042, PI09/90506]
- European Funds for Development (ERDF-FEDER)
- Catalan Research and Technology Innovation Interdepartmental Commission [2014SGR240]
- British Heart Foundation (British Heart Foundation Family Heart Study) [RG2000010]
- National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Center for Cardiovascular Science) [IS_BRU_0211_20033]
- British Heart Foundation
- German Federal Ministry of Education and Research (BMBF)
- FP7 European Union project CVgenes@target [261123]
- Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes) [12CVD02]
- Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces
- Programma di ricerca Regione-Universita Area 1-Strategic Programmes-Regione Emilia-Romagna
- National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]
- National Institute on Minority Health and Health Disparities
- National Institute of General Medical Sciences [U54GM115428]
- British Heart Foundation (UK Aneurysm Growth Study) [CS/14/2/30841]
- [SFB 1123]
- [RFPS-2007-3-644382]
- [RC2 HL103010]
- [RC2 HL102923]
- [RC2 HL102924]
- [5U54HG003067]
- British Heart Foundation [CS/14/2/30841] Funding Source: researchfish
- Medical Research Council [MC_qA137853] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10170] Funding Source: researchfish
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [KL2TR001100] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL127564, RC2HL102925, K08HL114642, RC2HL102924, RC2HL102923, R01HL131961, RC2HL103010, RC2HL102926] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U54HG003067] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U54GM115428] Funding Source: NIH RePORTER
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BACKGROUND: Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy. METHODS: We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [NOS3] and Guanylate Cyclase 1, Soluble, Alpha 3 [GUCY1A3]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815). RESULTS: A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31. 0.45; P= 5.5* 10(-26)], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P= 0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P= 0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; P= 5.6* 10(-5)) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; P=0.01). CONCLUSIONS: A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.
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