Table 1_Pharmacogenomic biomarkers of ACE inhibitor–induced cough in a multi-ethnic UAE cohort.docx

Background and objectivesAngiotensin-converting enzyme inhibitors (ACEIs) are widely used to manage hypertension and cardiovascular diseases. However, dry cough is a common side effect, affecting 5%–35% of patients and often leading to discontinuation. This study aimed to investigate genetic variants involved in ACEI-induced cough and ACE plasma levels in UAE multi-ethnic hypertensive patients.
MethodThe study cohort was pragmatically selected from the larger EmHeart Study (n = 900), a UAE-based pharmacogenomic initiative. Patients prescribed ACEIs were screened for inclusion. This multi-center, retrospective exploratory study involved genotyping 107 patients treated with ACEIs, including n = 35 in the cough group and n = 72 in the non-cough group. Variants of ACE; rs1799752 I/D, BDKRB2; rs1799722 (C>T), and KCNIP4; rs7675300 (C>A), rs1495509 (T>C), rs7661530 (T>C), and rs16870989 (T>A) were genotyped using standard technologies. A sandwich ELISA was done to investigate the ACE plasma levels in our cohort.
ResultsWe found that the ACE rs1799752 I/D genotype in the over-dominant model, was statistically significantly associated with ACEI-induced cough (p = 0.046) after adjusting for gender. Similarly, the T/T genotype of the KCNIP4 rs7661530 (T>C) variant was associated with significantly higher risk of cough compared to the combined C/C and T/C genotypes (p = 0.035). In contrast, the variants BDKRB2 rs1799722 (C>T), KCNIP4 rs7675300 (C>A), rs1495509 (T>C), and rs16870989 (T>A) were not significantly associated with ACEI-induced cough in our study. Moreover, ACE plasma levels were significantly lower in the cough group compared to the non-cough group (p = 0.0014). Stratified analysis by rs1799752 I/D genotypes revealed a significant difference within the I/D genotype (p = 0.0061), with higher levels in the non-cough group. No significant differences were found for the D/D or I/I genotypes.
Conclusion and limitationsOur data showed a significant association between ACEI-induced cough and the ACE rs1799752 I/D genotype, as well as lower ACE plasma levels in the cough group. This is the first study in the UAE and Middle East to report such findings and include all these variants in a single analysis. Although the sample size is small, our results contribute cumulative evidence on the genetic predisposition to ACEI-induced cough among hypertensive patients.

研究背景与研究目的：血管紧张素转换酶抑制剂（Angiotensin-converting enzyme inhibitors，ACEIs）被广泛用于高血压及心血管疾病的临床管理。然而，干咳是其常见不良反应，影响5%~35%的患者，常导致患者停药。本研究旨在探究阿联酋多民族高血压人群中，与ACEIs诱导性咳嗽及血管紧张素转换酶（ACE）血浆水平相关的遗传变异。
研究方法：本研究队列从规模更大的EmHeart研究（n=900）中务实性选取，该研究是一项总部位于阿联酋的药物基因组学计划。研究人员对使用ACEIs治疗的患者进行入组筛选。这项多中心回顾性探索性研究共对107名接受ACEIs治疗的患者开展了基因分型检测，其中咳嗽组35例，非咳嗽组72例。采用标准技术对以下遗传变异进行基因分型：ACE基因rs1799752 I/D、缓激肽B2受体（BDKRB2）基因rs1799722（C>T），以及钾离子通道相互作用蛋白4（KCNIP4）基因rs7675300（C>A）、rs1495509（T>C）、rs7661530（T>C）与rs16870989（T>A）。同时采用夹心酶联免疫吸附试验（sandwich ELISA）检测本队列患者的ACE血浆水平。
研究结果：在校正性别因素后，超显性模型中的ACE rs1799752 I/D基因型与ACEIs诱导性咳嗽具有统计学显著性关联（p=0.046）。类似地，与C/C和T/C基因型合并组相比，KCNIP4 rs7661530（T>C）变异的T/T基因型与更高的咳嗽风险显著相关（p=0.035）。与之相反，BDKRB2 rs1799722（C>T）、KCNIP4 rs7675300（C>A）、rs1495509（T>C）及rs16870989（T>A）变异在本研究中与ACEIs诱导性咳嗽无显著相关性。此外，咳嗽组患者的ACE血浆水平显著低于非咳嗽组（p=0.0014）。按rs1799752 I/D基因型进行分层分析显示，在I/D基因型亚组中存在显著差异（p=0.0061），非咳嗽组的ACE血浆水平更高；而D/D或I/I基因型亚组未发现显著差异。
研究结论与局限性：本研究数据显示，ACEIs诱导性咳嗽与ACE rs1799752 I/D基因型存在显著关联，且咳嗽组患者的ACE血浆水平更低。本研究是阿联酋及中东地区首个报道此类发现并同时分析上述所有遗传变异的研究。尽管样本量较小，但本研究结果为高血压患者发生ACEIs诱导性咳嗽的遗传易感性提供了累积证据。