Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.
Pharmacogenomics J. 2013 Jun;13(3):257-63. doi: 10.1038/tpj.2012.4. Epub 2012 Feb 21.
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.
最近的全基因组分析发现，12 号染色体 q15 上的单倍型（来自 rs317689/rs315135/rs7297610）与非洲裔美国人氢氯噻嗪（HCTZ）的血压反应之间存在关联。我们的目的是复制这种关联，并研究可能的功能机制。我们在 746 名随机接受 HCTZ 或阿替洛尔治疗的白种人和非洲裔美国人的独立样本中观察到了该单倍型与 HCTZ 反应之间的类似关联。该单倍型的关联是由 rs7297610 的变异驱动的，其中 C/C 基因型与 HCTZ 反应的平均（收缩压：3.4mmHg，P=0.0275；舒张压：2.5mmHg，P=0.0196）更大相关。在接受阿替洛尔治疗的参与者中没有这种关联，这支持了这种关联是 HCTZ 特异性的。在接受 HCTZ 治疗的非洲裔美国人中进行的表达分析显示，rs7297610 基因型组之间治疗前白细胞 YEATS4 表达存在差异（P=0.024），C/C 基因型的治疗后表达降低（P=0.009），但 T-载体则没有。我们的数据证实了之前在 12q15 上的全基因组发现，并表明差异的 YEATS4 表达可能是 rs7297610 相关 HCTZ 反应变异性的基础，这可能对指导噻嗪类药物治疗具有未来意义。
