title: Association of chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression.
abstract: A recent genome-wide analysis discovered an association between a haplotype (from rs317689/rs315135/rs7297610) on Chromosome 12q15 and blood pressure response to hydrochlorothiazide (HCTZ) in African-Americans. Our aim was to replicate this association and investigate possible functional mechanisms. We observed similar associations between this haplotype and HCTZ response in an independent sample of 746 Caucasians and African-Americans randomized to HCTZ or atenolol treatment. The haplotype association was driven by variation at rs7297610, where C/C genotypes were associated with greater mean (systolic: 3.4 mmHg, P=0.0275; diastolic: 2.5 mmHg, P=0.0196) responses to HCTZ vs T-allele carriers. Such an association was absent in atenolol-treated participants, supporting this as HCTZ specific. Expression analyses in HCTZ-treated African-Americans showed differential pre-treatment leukocyte YEATS4 expression between rs7297610 genotype groups (P=0.024), and reduced post-treatment expression in C/C genotypes (P=0.009), but not in T-carriers. Our data confirm previous genome-wide findings at 12q15 and suggest differential YEATS4 expression could underpin rs7297610-associated HCTZ response variability, which may have future implications for guiding thiazide treatment.
authors.affiliation: Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Duarte
authors.forename: S T
authors.initials: ST
authors.lastname: Turner
authors.forename: B
authors.initials: B
authors.lastname: Tran
authors.forename: A B
authors.initials: AB
authors.lastname: Chapman
authors.forename: K R
authors.initials: KR
authors.lastname: Bailey
authors.forename: Y
authors.initials: Y
authors.lastname: Gong
authors.forename: J G
authors.initials: JG
authors.lastname: Gums
authors.forename: T Y
authors.initials: TY
authors.lastname: Langaee
authors.forename: A L
authors.initials: AL
authors.lastname: Beitelshees
authors.forename: R M
authors.initials: RM
authors.lastname: Cooper-Dehoff
authors.forename: E
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: J A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001262:Atenolol; D001794:Blood Pressure / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002986:Clinical Trials as Topic; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage*; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D000959:Antihypertensive Agents; D014157:Transcription Factors; C109446:YEATS4 protein, human; D006852:Hydrochlorothiazide; D001262:Atenolol