title: Pharmacogenetic association of NOS3 variants with cardiovascular disease in patients with hypertension: the GenHAT study.
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.
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.forename: Amy I
authors.initials: AI
authors.lastname: Lynch
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davis
authors.forename: Charles E
authors.initials: CE
authors.lastname: Ford
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: John H
authors.initials: JH
authors.lastname: Eckfeldt
authors.forename: Catherine
authors.initials: C
authors.lastname: Leiendecker-Foster
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D000368:Aged; D000483:Alleles; D017311:Amlodipine / Q000009:adverse effects / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000235:genetics* / Q000401:mortality; D002752:Chlorthalidone / Q000009:adverse effects / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006333:Heart Failure / Q000209:etiology; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics; D017706:Lisinopril / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D020521:Stroke / Q000209:etiology
chemical_list: D000959:Antihypertensive Agents; D017311:Amlodipine; D017706:Lisinopril; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D002752:Chlorthalidone