title: Genomic association analysis identifies multiple loci influencing antihypertensive response to an angiotensin II receptor blocker.
abstract: 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.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA. turner.stephen@mayo.edu
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.forename: Kent R
authors.initials: KR
authors.lastname: Bailey
authors.forename: Gary L
authors.initials: GL
authors.lastname: Schwartz
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.forename: High Seng
authors.initials: HS
authors.lastname: Chai
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D004232:Diuretics / Q000627:therapeutic use; D004334:Drug Administration Schedule; D053503:Epithelial Sodium Channels / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics; D013777:Tetrazoles / Q000627:therapeutic use; D044465:White People / Q000235:genetics
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004232:Diuretics; D053503:Epithelial Sodium Channels; C501983:GPR83 protein, human; D043562:Receptors, G-Protein-Coupled; C507052:SCNN1G protein, human; D013777:Tetrazoles; D006852:Hydrochlorothiazide; C081643:candesartan