He Fazhong, Sun Bao, Li Ling, Liu Mouze, Lin Weijie, Liu Lin, Sun Yinxiang, Luo Yuhong, Wu Lin, Lu Ligong, Zhang Wei, Zhou Zhiling
Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai 519000, China.
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410078, China.
Ann Transl Med. 2020 Apr;8(7):437. doi: 10.21037/atm.2020.03.176.
Our previous studies have found that single nucleotide polymorphisms (SNPs) of () are related to the hypotensive effects of calcium-channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors. In this study, we aimed at exploring and validating the effect of polymorphism on antihypertensive drugs responses.
A total of 830 hypertensive patients, who were administered with open-labeled hydrochlorothiazide (12.5 mg once daily) and randomly assigned to off-labeled felodipine (5 mg) or a matched placebo combination treatment (1:1), were selected from the Felodipine Event Reduction (FEVER) study. A strategy of screening 259 samples and validating the remaining 531 samples was implemented. Four functional SNPs were selected (rs2295490, rs11470129, rs4815567 and rs6037475 in ). A mixed linear model was performed to analyze the effects of SNPs on antihypertensive drugs responses.
We found that rs6037475 CC genotype was associated with a reduction of diastolic blood pressure (DBP) (P=6.3×10) in the felodipine treatment group of screening set, and was also associated with a reduction of systolic blood pressure (SBP) (P=0.021), DBP (P=6.0×10) and mean arterial pressure (MAP) (P=0.021) in the felodipine treatment group of the validation set. As for the reductions influenced by the rs2295490, rs11470129 and rs4815567 genetic variations, however, the adjusted P-value did not reach statistical significance. Combined screening and validation set analysis found that patients with rs6037475 CC genotype had a significant higher mean SBP, DBP and MAP than those with TT genotype in the felodipine treatment group (CC . TT -10.2±0.74 . -17.8±0.21, P=7.8×10; -4.6±0.50 . -10.2±0.23, P=3.0×10; -6.5±0.54 -12.7±0.14, P=3.0×10, respectively).
These results suggest that rs6037475 genetic variation can be useful as a bio-marker for predicting felodipine drug response in Chinese patients with hypertension.
我们之前的研究发现，（）的单核苷酸多态性（SNP）与钙通道阻滞剂（CCB）和血管紧张素转换酶（ACE）抑制剂的降压效果有关。在本研究中，我们旨在探索并验证该多态性对降压药物反应的影响。
从非洛地平降压疗效评估（FEVER）研究中选取830例高血压患者，给予开放标签的氢氯噻嗪（每日1次，每次12.5mg），并随机分为接受非标签使用的非洛地平（5mg）或匹配安慰剂联合治疗（1:1）。实施了筛选259个样本并验证其余531个样本的策略。选择了四个功能性SNP（中的rs2295490、rs11470129、rs4815567和rs6037475）。采用混合线性模型分析该SNP对降压药物反应的影响。
我们发现，在筛选集的非洛地平治疗组中，该rs6037475 CC基因型与舒张压（DBP）降低相关（P = 6.3×10），在验证集的非洛地平治疗组中也与收缩压（SBP）降低（P = 0.021）、DBP降低（P = 6.0×10）和平均动脉压（MAP）降低（P = 0.021）相关。然而，对于受rs2295490、rs11470129和rs4815567基因变异影响的降低情况，校正后的P值未达到统计学显著性。综合筛选和验证集分析发现，在非洛地平治疗组中，rs6037475 CC基因型患者的平均SBP、DBP和MAP显著高于TT基因型患者（CC：-10.2±0.74，TT：-17.8±0.21，P = 7.8×10；-4.6±0.50，-10.2±0.23，P = 3.0×10；-6.5±0.54，-12.7±0.14，P = 3.0×10）。
这些结果表明，该rs6037475基因变异可作为预测中国高血压患者非洛地平药物反应的生物标志物。
