SLCO1B1 variants and enalapril-induced cough: a pharmacogenetics study in China

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• 作者：Jian-Quan Luo ; MD^a ; ^b ; ^c ; Prof Ning-Ling Sun ; PhD^d ; Fa-Zhong He ; MD^a ; ^b ; ^c ; Lu-Yan Wang ; PhD^d ; Prof Gen-Fu Tang ; PhD^e ; Qing Li ; PhD^a ; ^b ; ^c ; Xiao-Ping Chen ; PhD^a ; ^b ; ^c ; Prof Zhao-Qian Liu ; PhD^a ; ^b ; ^c ; Prof Hong-Hao Zhou ; MD^a ; ^b ; ^c ; Prof Wei Zhang ; PhD^a ; ^b ; ^c ; ^{yjsd2003@163.com" class="auth_mail" title="E-mail the corresponding author}
• 刊名：The Lancet
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：386
• 期：supp_S1
• 页码：S74
• 全文大小：66 K

文摘

Clinical observations suggest that the incidence of cough in Chinese patients taking angiotensin-converting enzyme (ACE) inhibitors is much higher than other racial groups. The aim of this study was to investigate whether SLCO1B1 genetic polymorphisms, previously reported to be important determinants of the inter-individual pharmacokinetic differences of enalapril, are associated with the enalapril-induced cough.

Methods

This pharmacogenetics study took place in rural communities in Anhui Province in China between May, 2008 and July, 2009. Eligible participants were of Han Chinese origin, women or men, had systolic blood pressure of 140 mmHg or higher or diastolic blood pressure of 90 mmHg or higher, or both, or were taking 10 mg enalapril antihypertensive durgs. DNA samples obtained from patients were genotyped for the functional genetic polymorphisms in SLCO1B1, 388A→G (Asn130Asp, rs2306283) and 521T→C (Val174Ala, rs4149056), using Sequenom MassArray technology. The primary endpoint was cough, which was recorded when participants were bothered by respiratory symptoms and cough during enalapril treatment without an identifiable cause. The association of SLCO1B1 polymorphisms with enalapril-induced cough was assessed through odds ratios (ORs) and corresponding 95% CIs, estimated by logistic regression model using SPSS v.19.0. A two-sided p value less than 0·05 was considered statistically significant. Ethics approval was granted by the Ethical Committee of Institute of Clinical Pharmacology, Central South University, and informed consent was obtained from each participating patient. This trial is registered with Chinese Clinical Trial Register, number ChiCTR-OCH-12002611.

Findings

Between May, 2008, and July, 2009, we recruited 450 Han Chinese patients. Enalapril-induced cough was recorded in 144 (32%) patients. Sex was significantly associated with enalapril-induced cough (104 [72%] participants were women in the cough group vs 108 [59%] in the no-cough group, p=0·006). The SLCO1B1*5 (521T→C) variant was associated with a statistically increased risk of cough incidence (50 [18%] patients had the C allele in the cough group vs 58 [10%] in the no-cough groups), OR 2·02 [1·34–3·04]; p=0·0006). Additionally, we found strong evidence for a gene-dose effect (97 [28%] patients with cough had no copies of the C allele, 40 [43%] patients with cough had one copy of the C allele, and 5 [71%] patients with cough had two copies of the C allele; p_trend=0·0007). Haplotype analysis of the two SLCO1B1 polymorphisms revealed that the risk of enalapril-induced cough might be substantially increased in patients carrying SLCO1B1*15 (388A→G and 521T→C; OR=1·99 [1·26–3·14]; p=0·003).

Interpretation

We have identified that the SLCO1B1 common variants and female sex are strongly associated with an increased risk of enalapril-induced cough. Genotyping SLCO1B1 variants might be a useful strategy to achieve the benefits of enalapril treatment more effectively and safely in China. Our current findings are from an independent retrospective study cohort and the clinical application deserves to be confirmed in a prospective trial.

Funding

National High Technology Research and Development Program of China, “863” Project (No. 2012AA02A517, 2012AA02A518), National Scientific Foundation of China (No. 81522048, 81573511, 81273595, 81302850), Hunan Provincial Innovation Foundation for Postgraduate (No. CX2014B100).