Pharmacogenetic association of NOS3 variants with cardiovascular disease in patients with hypertension: the GenHAT study

Xue Zhang, Amy I Lynch, Barry R Davis, Charles E Ford, Eric Boerwinkle, John H Eckfeldt, Catherine Leiendecker-Foster, Donna K Arnett, Xue Zhang, Amy I Lynch, Barry R Davis, Charles E Ford, Eric Boerwinkle, John H Eckfeldt, Catherine Leiendecker-Foster, Donna K Arnett

Abstract

Nitric oxide synthase 3 (NOS3) catalyzes production of NO in the endothelium and may play a role in cardiovascular disease (CVD). We assessed the pharmacogenetic associations of three NOS3 polymorphisms and three antihypertensive drugs with CVD outcomes. Hypertensive subjects (n = 30,280) from a multi-center, double-blind clinical trial were randomized to chlorthalidone, amlodipine, or lisinopril treatment (mean follow up, 4.9 years). Outcomes included coronary heart disease (CHD: fatal CHD and nonfatal myocardial infarction); stroke; heart failure (fatal, requiring hospitalization, or outpatient treatment); all-cause mortality; and end-stage renal disease (ESRD). Main effects of NOS3 variants on outcome and genotype-treatment interactions were tested. For NOS3 -690 C>T (rs3918226), a higher hazard ratio (HR) was found in minor allele carriers for CHD (CC = 1.00, CT+TT = 1.12 (95% confidence interval (CI) = 1.00-1.26), P = 0.048). For NOS3 -922 A>G (rs1800779), a higher HR was found in minor allele carriers for heart failure (AA = 1.00, AG+GG = 1.10 (CI = 1.00-1.21), P = 0.046). Significant pharmacogenetic findings were observed for stroke and all-cause mortality. For -690 C>T, a lower HR was observed for stroke in minor allele carriers when treated with amlodipine versus lisinopril (CC = 0.85 (CI = 0.73-0.99), CT+TT = 0.49 (CI = 0.31-0.80), P = 0.04). For glu298asp G>T (rs1799983), a lower HR was observed for all-cause mortality in minor allele carriers when treated with amlodipine versus lisinopril (GG = 1.01 (CI = 0.91-1.13), GT+TT = 0.85 (CI = 0.75-0.97), P = 0.04). We observed significant associations with NOS3 variants and CHD and heart failure and significant pharmacogenetic effects for stroke and all cause mortality. This suggests that NOS3 variants may potentially provide useful clinical information with respect to treatment decisions in the future.

Trial registration: ClinicalTrials.gov NCT00000542 NCT00006294.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

References

    1. Chobanian AV. Control of hypertension–an important national priority. N Engl J Med. 2001;345:534–535.
    1. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. Jama. 2003;290:199–206.
    1. Arnett DK, Claas SA, Glasser SP. Pharmacogenetics of antihypertensive treatment. Vascul Pharmacol. 2006;44:107–118.
    1. Cooke GE, Doshi A, Binkley PF. Endothelial nitric oxide synthase gene: prospects for treatment of heart disease. Pharmacogenomics. 2007;8:1723–1734.
    1. Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, et al. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation. 1998;97:2494–2498.
    1. Colombo MG, Paradossi U, Andreassi MG, Botto N, Manfredi S, et al. Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease. Clin Chem. 2003;49:389–395.
    1. Colombo MG, Andreassi MG, Paradossi U, Botto N, Manfredi S, et al. Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298–>Asp polymorphism) to the presence, extent, and severity of coronary artery disease. Heart. 2002;87:525–528.
    1. Chang K, Baek SH, Seung KB, Kim PJ, Ihm SH, et al. The Glu298Asp polymorphism in the endothelial nitric oxide synthase gene is strongly associated with coronary spasm. Coron Artery Dis. 2003;14:293–299.
    1. Tangurek B, Ozer N, Sayar N, Terzi S, Yilmaz H, et al. The relationship between endothelial nitric oxide synthase gene polymorphism (T-786 C) and coronary artery disease in the Turkish population. Heart Vessels. 2006;21:285–290.
    1. Hibi K, Ishigami T, Tamura K, Mizushima S, Nyui N, et al. Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension. 1998;32:521–526.
    1. Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, et al. A common variant of the endothelial nitric oxide synthase (Glu298–>Asp) is a major risk factor for coronary artery disease in the UK. Circulation. 1999;100:1515–1520.
    1. Miyamoto Y, Saito Y, Kajiyama N, Yoshimura M, Shimasaki Y, et al. Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension. 1998;32:3–8.
    1. Moe KT, Lim ST, Wong P, Chua T, DeSilva DA, et al. Association analysis of endothelial nitric oxide synthase gene polymorphism with primary hypertension in a Singapore population. J Hum Hypertens. 2006;20:956–963.
    1. Markus HS, Ruigrok Y, Ali N, Powell JF. Endothelial nitric oxide synthase exon 7 polymorphism, ischemic cerebrovascular disease, and carotid atheroma. Stroke. 1998;29:1908–1911.
    1. Lenasi H, Kohlstedt K, Fichtlscherer B, Mulsch A, Busse R, et al. Amlodipine activates the endothelial nitric oxide synthase by altering phosphorylation on Ser1177 and Thr495. Cardiovasc Res. 2003;59:844–853.
    1. Lynch AI, Boerwinkle E, Davis BR, Ford CE, Eckfeldt JH, et al. Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension. Jama. 2008;299:296–307.
    1. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT, Jr, et al. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Research Group. Am J Hypertens. 1996;9:342–360.
    1. de Simone G, Palmieri V, Bella JN, Celentano A, Hong Y, et al. Association of left ventricular hypertrophy with metabolic risk factors: the HyperGEN study. J Hypertens. 2002;20:323–331.
    1. Burns JC, Shimizu C, Shike H, Newburger JW, Sundel RP, et al. Family-based association analysis implicates IL-4 in susceptibility to Kawasaki disease. Genes Immun. 2005;6:438–444.
    1. Kullo IJ, Greene MT, Boerwinkle E, Chu J, Turner ST, et al. Association of polymorphisms in NOS3 with the ankle-brachial index in hypertensive adults. Atherosclerosis. 2008;196:905–912.
    1. Howard TD, Giles WH, Xu J, Wozniak MA, Malarcher AM, et al. Promoter polymorphisms in the nitric oxide synthase 3 gene are associated with ischemic stroke susceptibility in young black women. Stroke. 2005;36:1848–1851.
    1. Xin Y, Song X, Xue H, Liu Z, Wang X, et al. A common variant of the eNOS gene (E298D) is an independent risk factor for left ventricular hypertrophy in human essential hypertension. Clin Sci (Lond) 2009;117:67–73.
    1. Arnett DK, Boerwinkle E, Davis BR, Eckfeldt J, Ford CE, et al. Pharmacogenetic approaches to hypertension therapy: design and rationale for the Genetics of Hypertension Associated Treatment (GenHAT) study. Pharmacogenomics J. 2002;2:309–317.
    1. Wang XL, Wang J. Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol Genet Metab. 2000;70:241–251.
    1. Persu A, Stoenoiu MS, Messiaen T, Davila S, Robino C, et al. Modifier effect of ENOS in autosomal dominant polycystic kidney disease. Hum Mol Genet. 2002;11:229–241.
    1. Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, et al. Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci U S A. 2000;97:2832–2835.
    1. Savvidou MD, Vallance PJ, Nicolaides KH, Hingorani AD. Endothelial nitric oxide synthase gene polymorphism and maternal vascular adaptation to pregnancy. Hypertension. 2001;38:1289–1293.
    1. Leeson CP, Hingorani AD, Mullen MJ, Jeerooburkhan N, Kattenhorn M, et al. Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function. Circ Res. 2002;90:1153–1158.
    1. Joshi MS, Bauer JA. Preliminary computational modeling of nitric oxide synthase 3 interactions with caveolin-1: influence of exon 7 Glu298Asp polymorphism. Acta Biochim Biophys Sin (Shanghai) 2008;40:47–54.
    1. Hingorani AD. Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep. 2003;5:19–25.
    1. Benjafield AV, Morris BJ. Association analyses of endothelial nitric oxide synthase gene polymorphisms in essential hypertension. Am J Hypertens. 2000;13:994–998.
    1. Cherney DZ, Scholey JW, Zhou J, Zimpelmann J, Kennedy C, et al. Endothelial nitric oxide synthase gene polymorphisms and the renal hemodynamic response to L-arginine. Kidney Int. 2009;75:327–332.
    1. Noiri E, Satoh H, Taguchi J, Brodsky SV, Nakao A, et al. Association of eNOS Glu298Asp polymorphism with end-stage renal disease. Hypertension. 2002;40:535–540.
    1. Thaha M, Pranawa, Yogiantoro M, Sutjipto, Sunarjo, et al. Association of endothelial nitric oxide synthase Glu298Asp polymorphism with end-stage renal disease. Clin Nephrol. 2008;70:144–154.
    1. Nagase S, Suzuki H, Wang Y, Kikuchi S, Hirayama A, et al. Association of ecNOS gene polymorphisms with end stage renal diseases. Mol Cell Biochem. 2003;244:113–118.
    1. Suzuki H, Nagase S, Kikuchi S, Wang Y, Koyama A. Association of a missense Glu298Asp mutation of the endothelial nitric oxide synthase gene with end stage renal disease. Clin Chem. 2000;46:1858–1860.
    1. Mollsten A, Wessman M, Svensson M, Forsblom C, Parkkonen M, et al. Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy. Ann Med. 2006;38:522–528.
    1. Dell'Omo G, Penno G, Pucci L, Fotino C, Lucchesi D, et al. Lack of association between endothelial nitric oxide synthase gene polymorphisms, microalbuminuria and endothelial dysfunction in hypertensive men. J Hypertens. 2007;25:1389–1395.
    1. Fischmann TO, Hruza A, Niu XD, Fossetta JD, Lunn CA, et al. Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation. Nat Struct Biol. 1999;6:233–242.
    1. Jachymova M, Horky K, Bultas J, Kozich V, Jindra A, et al. Association of the Glu298Asp polymorphism in the endothelial nitric oxide synthase gene with essential hypertension resistant to conventional therapy. Biochem Biophys Res Commun. 2001;284:426–430.
    1. Salvi E, Kutalik Z, Glorioso N, Benaglio P, Frau F, et al. Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase. Hypertension. 2012;59:248–255.
    1. Augeri AL, Tsongalis GJ, Van Heest JL, Maresh CM, Thompson PD, et al. The endothelial nitric oxide synthase −786 T>C polymorphism and the exercise-induced blood pressure and nitric oxide responses among men with elevated blood pressure. Atherosclerosis. 2009;204:e28–34.
    1. Asakimori Y, Yorioka N, Tanaka J, Takasugi N, Harada S, et al. Association between ENOS gene polymorphism and cardiovascular events in nondiabetic hemodialysis patients: a prospective study. Am J Kidney Dis. 2004;44:112–120.
    1. Rossi GP, Maiolino G, Zanchetta M, Sticchi D, Pedon L, et al. The T(−786)C endothelial nitric oxide synthase genotype predicts cardiovascular mortality in high-risk patients. J Am Coll Cardiol. 2006;48:1166–1174.
    1. Bhandary UV, Tse W, Yang B, Knowles MR, Demaine AG. Endothelial nitric oxide synthase polymorphisms are associated with hypertension and cardiovascular disease in renal transplantation. Nephrology (Carlton) 2008;13:348–355.

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