Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling

Connor A Emdin; Amit V Khera; Derek Klarin; Pradeep Natarajan; Seyedeh M Zekavat; Akihiro Nomura; Mary Haas; Krishna Aragam; Diego Ardissino; James G Wilson; Heribert Schunkert; Ruth McPherson; Hugh Watkins; Roberto Elosua; Matthew J Bown; Nilesh J Samani; Usman Baber; Jeanette Erdmann; Padhraig Gormley; Aarno Palotie; Nathan O Stitziel; Namrata Gupta; John Danesh; Danish Saleheen; Stacey Gabriel; Sekar Kathiresan

doi:10.1161/CIRCULATIONAHA.117.028021

Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling

Circulation. 2018 Jan 16;137(3):222-232. doi: 10.1161/CIRCULATIONAHA.117.028021. Epub 2017 Oct 5.

Authors

Connor A Emdin^{1

2

3}, Amit V Khera^{1

2

3}, Derek Klarin^{1

3

4}, Pradeep Natarajan^{1

2

3}, Seyedeh M Zekavat^{1

2

3}, Akihiro Nomura^{1

2

3}, Mary Haas^{1

2

3}, Krishna Aragam^{1

2

3}, Diego Ardissino^{5

6}, James G Wilson⁷, Heribert Schunkert⁸, Ruth McPherson⁹, Hugh Watkins^{10

11}, Roberto Elosua^{12

13

14}, Matthew J Bown¹⁵, Nilesh J Samani¹⁵, Usman Baber¹⁶, Jeanette Erdmann¹⁷, Padhraig Gormley^{2

3}, Aarno Palotie^{1

2

3}, Nathan O Stitziel¹⁸, Namrata Gupta¹, John Danesh^{19

20

21}, Danish Saleheen^{22

23}, Stacey Gabriel¹, Sekar Kathiresan^{24

2

3}

Affiliations

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.

Keywords: cardiovascular disease; genetics; nitric oxide; nitric oxide synthase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Blood Pressure / genetics*
Coronary Disease / enzymology
Coronary Disease / epidemiology
Coronary Disease / genetics*
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Mutation*
Nitric Oxide / metabolism*
Nitric Oxide Synthase Type III / genetics*
Nitric Oxide Synthase Type III / metabolism
Peripheral Arterial Disease / enzymology
Peripheral Arterial Disease / epidemiology
Peripheral Arterial Disease / genetics*
Phenotype
Polymorphism, Single Nucleotide*
Protective Factors
Risk Factors
Signal Transduction / genetics*
Soluble Guanylyl Cyclase / genetics*
Soluble Guanylyl Cyclase / metabolism
Stroke / enzymology
Stroke / epidemiology
Stroke / genetics*

Substances

GUCY1A1 protein, human
Nitric Oxide
NOS3 protein, human
Nitric Oxide Synthase Type III
Soluble Guanylyl Cyclase

Abstract

Publication types

MeSH terms

Substances

Grants and funding