Document Detail


Pharmacogenetic association of NOS3 variants with cardiovascular disease in patients with hypertension: the GenHAT study.
MedLine Citation:
PMID:  22470539     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Xue Zhang; Amy I Lynch; Barry R Davis; Charles E Ford; Eric Boerwinkle; John H Eckfeldt; Catherine Leiendecker-Foster; Donna K Arnett
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Publication Detail:
Type:  Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, N.I.H., Extramural     Date:  2012-03-28
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-04-03     Completed Date:  2012-08-03     Revised Date:  2013-07-01    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e34217     Citation Subset:  IM    
Affiliation:
Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00000542;  NCT00006294
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MeSH Terms
Descriptor/Qualifier:
Aged
Alleles
Amlodipine / adverse effects,  therapeutic use
Antihypertensive Agents / adverse effects*,  therapeutic use*
Cardiovascular Diseases / etiology*,  genetics*,  mortality
Chlorthalidone / adverse effects,  therapeutic use
Double-Blind Method
Female
Follow-Up Studies
Genotype
Heart Failure / etiology
Humans
Hypertension / complications*,  drug therapy*,  genetics
Lisinopril / adverse effects,  therapeutic use
Male
Middle Aged
Nitric Oxide Synthase Type III / genetics*,  metabolism
Polymorphism, Single Nucleotide
Risk Factors
Stroke / etiology
Grant Support
ID/Acronym/Agency:
HL63082/HL/NHLBI NIH HHS; N01-HC-35130/HC/NHLBI NIH HHS; R01 HL083498/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antihypertensive Agents; 77-36-1/Chlorthalidone; 83915-83-7/Lisinopril; 88150-42-9/Amlodipine; EC 1.14.13.39/NOS3 protein, human; EC 1.14.13.39/Nitric Oxide Synthase Type III
Comments/Corrections

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