Babaresh Wahby M, Sohail Sohaib Ahmad, Baig Alija, Faisal Malik, Begum Aiman, Shah Haseenullah, Ul Hassan Zia, Ijaz Kiran, Shah Syed Muhammad Mukarram, Ullah Aftab
Department of Pharmacy, University of Peshawar, Pakistan.
Faculty of Pharmacy, University of Aden, Yemen.
PLoS One. 2025 Aug 1;20(8):e0329263. doi: 10.1371/journal.pone.0329263. eCollection 2025.
Hypertension affects over 1.28 billion individuals worldwide, yet response variability to calcium channel blockers (CCBs) like amlodipine remains a challenge. While pharmacogenomic studies have implicated genetic polymorphisms in treatment outcomes, the combined effects of multiple variants remain unclear. This study investigates the influence of CACNA1D (rs3774426), CACNA1C (rs2239050, rs7311382), and TRIB3 (rs2295490) variants, individually and in combination, on the antihypertensive response to amlodipine. A total of 133 hypertensive patients from Khyber Pakhtunkhwa, Pakistan, receiving amlodipine monotherapy were genotyped using ARMS-PCR and Sanger sequencing. Blood pressure response was defined as post-treatment systolic blood pressure (SBP) ≤140 mmHg and diastolic blood pressure (DBP) ≤90 mmHg. Statistical analyses were adjusted for age, gender, BMI, dose, family history of HTN and dietary habits. The CACNA1D rs3774426 TT genotype was significantly associated with non-response in 35 patients, showing higher SBP than the CC genotype (n = 69). Conversely, the CACNA1C rs2239050 GG genotype (n = 67) was linked to improved SBP and DBP control compared to the CC genotype (n = 25). Combined genotype models (CACNA1D-CACNA1C and CACNA1D-CACNA1C-TRIB3) showed strong unadjusted associations but lost significance after adjustment. These findings highlight the role of CACNA1D rs3774426 in predicting amlodipine non-response and demonstrate the potential of genetic screening for optimizing antihypertensive therapy. Integrating pharmacogenomics into clinical practice could enhance personalized treatment strategies, improving outcomes in hypertensive patients.
高血压影响着全球超过12.8亿人，但对氨氯地平这类钙通道阻滞剂（CCB）的反应变异性仍是一个挑战。虽然药物基因组学研究表明基因多态性与治疗结果有关，但多个变体的联合作用仍不清楚。本研究调查了CACNA1D（rs3774426）、CACNA1C（rs2239050、rs7311382）和TRIB3（rs2295490）变体单独及联合对氨氯地平降压反应的影响。对来自巴基斯坦开伯尔-普赫图赫瓦省的133例接受氨氯地平单药治疗的高血压患者，采用扩增阻滞突变系统聚合酶链反应（ARMS-PCR）和桑格测序进行基因分型。血压反应定义为治疗后收缩压（SBP）≤140 mmHg且舒张压（DBP）≤90 mmHg。统计分析对年龄、性别、体重指数、剂量、高血压家族史和饮食习惯进行了校正。在35例患者中，CACNA1D rs3774426 TT基因型与无反应显著相关，其收缩压高于CC基因型（n = 69）。相反，与CC基因型（n = 25）相比，CACNA1C rs2239050 GG基因型（n = 67）与收缩压和舒张压控制改善有关。联合基因型模型（CACNA1D-CACNA1C和CACNA1D-CACNA1C-TRIB3）显示出未经校正的强关联，但校正后失去显著性。这些发现突出了CACNA1D rs3774426在预测氨氯地平无反应中的作用，并证明了基因筛查对优化降压治疗的潜力。将药物基因组学整合到临床实践中可以加强个性化治疗策略，改善高血压患者的治疗效果。
