Document Detail


Genomic association analysis identifies multiple loci influencing antihypertensive response to an angiotensin II receptor blocker.
MedLine Citation:
PMID:  22566498     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
To identify genes influencing blood pressure response to an angiotensin II receptor blocker, single nucleotide polymorphisms identified by genome-wide association analysis of the response to candesartan were validated by opposite direction associations with the response to a thiazide diuretic, hydrochlorothiazide. We sampled 198 white and 193 blacks with primary hypertension from opposite tertiles of the race-sex-specific distributions of age-adjusted diastolic blood pressure response to candesartan. There were 285 polymorphisms associated with the response to candesartan at P<10(-4) in whites. A total of 273 of the 285 polymorphisms, which were available for analysis in a separate sample of 196 whites, validated for opposite direction associations with the response to hydrochlorothiazide (Fisher χ(2) 1-sided P=0.02). Among the 273 polymorphisms, those in the chromosome 11q21 region were the most significantly associated with response to candesartan in whites (eg, rs11020821 near FUT4, P=8.98 × 10(-7)), had the strongest opposite direction associations with response to hydrochlorothiazide (eg, rs3758785 in GPR83, P=7.10 × 10(-3)), and had the same direction associations with response to candesartan in the 193 blacks (eg, rs16924603 near FUT4, P=1.52 × 10(-2)). Also notable among the 273 polymorphisms was rs11649420 on chromosome 16 in the amiloride-sensitive sodium channel subunit SCNN1G involved in mediating renal sodium reabsorption and maintaining blood pressure when the renin-angiotensin system is inhibited by candesartan. These results support the use of genomewide association analyses to identify novel genes predictive of opposite direction associations with blood pressure responses to inhibitors of the renin-angiotensin and renal sodium transport systems.
Authors:
Stephen T Turner; Kent R Bailey; Gary L Schwartz; Arlene B Chapman; High Seng Chai; Eric Boerwinkle
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-07
Journal Detail:
Title:  Hypertension     Volume:  59     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-17     Completed Date:  2012-07-25     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1204-11     Citation Subset:  IM    
Affiliation:
Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA. turner.stephen@mayo.edu
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MeSH Terms
Descriptor/Qualifier:
Adult
African Americans / genetics
Angiotensin II Type 1 Receptor Blockers / therapeutic use*
Benzimidazoles / therapeutic use
Blood Pressure / drug effects,  genetics
Case-Control Studies
Chi-Square Distribution
Chromosomes, Human, Pair 11 / genetics
Chromosomes, Human, Pair 16 / genetics
Diuretics / therapeutic use
Drug Administration Schedule
Epithelial Sodium Channels / genetics
European Continental Ancestry Group / genetics
Female
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study / methods*
Genotype
Humans
Hydrochlorothiazide / therapeutic use
Hypertension / drug therapy*,  ethnology,  genetics*
Male
Middle Aged
Polymorphism, Single Nucleotide*
Receptors, G-Protein-Coupled / genetics
Renin-Angiotensin System / genetics
Tetrazoles / therapeutic use
Grant Support
ID/Acronym/Agency:
HL053335/HL/NHLBI NIH HHS; HL074735/HL/NHLBI NIH HHS; R01 HL053330/HL/NHLBI NIH HHS; R01 HL074735/HL/NHLBI NIH HHS; UL1 RR024148/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Benzimidazoles; 0/Diuretics; 0/Epithelial Sodium Channels; 0/GPR83 protein, human; 0/Receptors, G-Protein-Coupled; 0/SCNN1G protein, human; 0/Tetrazoles; 58-93-5/Hydrochlorothiazide; S8Q36MD2XX/candesartan
Comments/Corrections
Comment In:
Hypertension. 2013 Jan;61(1):e5   [PMID:  23150516 ]
Hypertension. 2012 Jun;59(6):1094-6   [PMID:  22566497 ]

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