Atenolol Induced HDL-C Change in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study

We sought to identify novel pharmacogenomic markers for HDL-C response to atenolol in participants with mild to moderate hypertension. We genotyped 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study on the Illumina HumanCVD Beadchip. During PEAR, participants were randomized to receive atenolol or hydrochlorothiazide. Blood pressure and cholesterol levels were evaluated at baseline and after treatment. This study focused on participants treated with atenolol monotherapy. Association with atenolol induced HDL-C change was evaluated in 232 whites and 152 African Americans using linear regression. No SNPs achieved a Bonferroni corrected P-value. However, we identified 13 regions with consistent association across whites and African Americans. The most interesting of these regions were seven with prior associations with HDL-C, other metabolic traits, or functional implications in the lipid pathway: GALNT2, FTO, ABCB1, LRP5, STARD3NL, ESR1, and LIPC. Examples are rs2144300 in GALNT2 in whites (P=2.29x10-4, β=-1.85 mg/dL) and rs12595985 in FTO in African Americans (P=2.90x10-4, β=4.52 mg/dL), both with consistent regional association (PGALNT2 expression differed by rs2144300 genotype in whites (P=0.0279). In conclusion, we identified multiple gene regions associated with atenolol induced HDL-C change that were consistent across race groups, several with functional implications or prior associations with HDL-C.

本研究旨在识别轻中度高血压受试者中，阿替洛尔（atenolol）治疗后高密度脂蛋白胆固醇（High-Density Lipoprotein Cholesterol, HDL-C）应答相关的新型药物基因组学标记物。本研究使用Illumina人类心血管疾病分型芯片（Illumina HumanCVD Beadchip），对来自抗高血压应答药物基因组学评估（Pharmacogenomic Evaluation of Antihypertensive Responses, PEAR）研究的768名高血压受试者进行了基因分型。在PEAR研究中，受试者被随机分配接受阿替洛尔或氢氯噻嗪（hydrochlorothiazide）治疗。研究人员在基线及治疗后对受试者的血压与胆固醇水平进行了检测评估。本研究聚焦于接受阿替洛尔单药治疗的受试者队列。本研究针对232名白人及152名非裔美国人受试者，采用线性回归（linear regression）分析评估了其阿替洛尔诱导的HDL-C变化与基因位点的关联情况。未发现任何单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）达到邦费罗尼校正P值（Bonferroni corrected P-value）的显著性阈值。不过，本研究共识别出13个在白人与非裔美国人中均存在一致关联的基因区域。其中最受关注的7个基因区域，此前已有研究报道其与HDL-C、其他代谢性状相关，或在脂质代谢通路（lipid pathway）中发挥功能作用，分别为GALNT2、FTO、ABCB1、LRP5、STARD3NL、ESR1及LIPC。例如，在白人受试者中，GALNT2基因的rs2144300位点（P=2.29×10^-4，β=-1.85 mg/dL）以及非裔美国人受试者中FTO基因的rs12595985位点（P=2.90×10^-4，β=4.52 mg/dL）均呈现出一致的区域关联特征；且在白人受试者中，GALNT2的基因表达量随rs2144300基因型不同存在显著差异（P=0.0279）。综上，本研究识别出多个与阿替洛尔诱导的HDL-C变化相关的基因区域，这些关联在不同种族人群中均具有一致性，其中多个区域此前已有相关报道或在脂质代谢通路中存在功能意义。