Association of chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression

J D Duarte, S T Turner, B Tran, A B Chapman, K R Bailey, Y Gong, J G Gums, T Y Langaee, A L Beitelshees, R M Cooper-Dehoff, E Boerwinkle, J A Johnson, J D Duarte, S T Turner, B Tran, A B Chapman, K R Bailey, Y Gong, J G Gums, T Y Langaee, A L Beitelshees, R M Cooper-Dehoff, E Boerwinkle, J A Johnson

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.

Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Locus on Chromosome 12 containing SNPs with evidence of association with HCTZ blood pressure response in African-Americans. SNPs in bold composed a haplotype that associated in Turner, et. al. SNPs in italics associated with response in PEAR. Total region represented is approximately 260 kb.
Figure 2
Figure 2
Blood pressure response to HCTZ and atenolol by rs7297610 genotype in PEAR African-Americans. Values are adjusted for age, sex, and baseline blood pressure. Error bars indicate standard error. * – P ≤ 0.05 compared to the common C/C genotype
Figure 3
Figure 3
Relative gene expression of LYZ (A), YEATS4 (B), and FRS2 (C) by rs7297610 genotype in 47 African-American PEAR participants, normalized to the housekeeping gene beta-2-microglobulin. Error bars indicate standard error.

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Source: PubMed

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