Connor A Emdin1,2,3, Amit V Khera1,2,3, Derek Klarin1,3,4, Pradeep Natarajan1,2,3, Seyedeh M Zekavat1,2,3, Akihiro Nomura1,2,3, Mary Haas1,2,3, Krishna Aragam1,2,3, Diego Ardissino5,6, James G Wilson7, Heribert Schunkert8, Ruth McPherson9, Hugh Watkins10,11, Roberto Elosua12,13,14, Matthew J Bown15, Nilesh J Samani15, Usman Baber16, Jeanette Erdmann17, Padhraig Gormley2,3, Aarno Palotie1,2,3, Nathan O Stitziel18, Namrata Gupta1, John Danesh19,20,21, Danish Saleheen22,23, Stacey Gabriel1, Sekar Kathiresan24,2,3. 1. Center for Genomic Medicine (C.A.E., A.V.K., D.K., P.N., S.M.Z., A.N., M.H., K.A., A.P., N.G., S.G., S.K.). 2. Department of Medicine, Cardiology Division (C.A.E., A.V.K., P.N., S.M.Z., A.N., P.G., A.P., M.H., K.A., S.K.). 3. Massachusetts General Hospital, Harvard Medical School, Boston, MA. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (C.A.E., A.V.K., D.K., P.N., S.M.Z., A.N., M.H., P.G., A.P., K.A., S.K.). 4. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA (D.K.). 5. Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy (D.A.). 6. Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy (D.A.). 7. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.). 8. Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany (H.S.). 9. University of Ottawa Heart Institute, Ontario, Canada (R.M.). 10. Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom (H.W.). 11. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, United Kingdom (H.W.). 12. Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain (R.E). 13. CIBER Enfermedades Cardiovasculares, Barcelona, Spain (R.E.). 14. Facultat de Medicina, Universitat de Vic-Central de Cataluña, Spain (R.E.). 15. Department of Cardiovascular Sciences, University of Leicester, National Institute for Health Research, Leicester Biomedical Research Centre, United Kingdom (M.J.B., N.J.S.). 16. The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York (U.B.). 17. Institute for Integrative and Experimental Genomics, University of Lübeck, Germany (J.E.). 18. Departments of Medicine and Genetics, Cardiovascular Division, McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO (N.O.S.). 19. Department of Public Health and Primary Care, Cardiovascular Epidemiology Unit, University of Cambridge, United Kingdom (J.D.). 20. Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (J.D). 21. National Institute of Health Research Blood and Transplant, Research Unit in Donor Health and Genomics, University of Cambridge, United Kingdom (J.D.). 22. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (D.S.). 23. Center for Non-Communicable Diseases, Karachi, Pakistan (D.S.). 24. Center for Genomic Medicine (C.A.E., A.V.K., D.K., P.N., S.M.Z., A.N., M.H., K.A., A.P., N.G., S.G., S.K.) skathiresan1@mgh.harvard.edu.
Abstract
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.
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.
Authors: Hossein-Ardeschir Ghofrani; Nazzareno Galiè; Friedrich Grimminger; Ekkehard Grünig; Marc Humbert; Zhi-Cheng Jing; Anne M Keogh; David Langleben; Michael Ochan Kilama; Arno Fritsch; Dieter Neuser; Lewis J Rubin Journal: N Engl J Med Date: 2013-07-25 Impact factor: 91.245
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