SLCO1B1 Variants and Angiotensin Converting Enzyme Inhibitor (Enalapril) -Induced Cough: a Pharmacogenetic Study

• DOI: 10.1038/srep17253
• Publication Date: 2015-11-26T11:42:33Z
• Authors: Jian-Quan Luo; Fa-Zhong He; Zhen-Min Wang; Ning-Ling Sun; Lu-Yan Wang; Gen-Fu Tang; Mou-Ze Liu; Qing Li; Xiao-Ping Chen; Zhao-Qian Liu; Hong-Hao Zhou; Wei Zhang
• Keywords: Male; Pulmonary and Respiratory Medicine; 0301 basic medicine; Genotype; Physiology; Gene Dosage; Organic Anion Transporters; Angiotensin-Converting Enzyme Inhibitors; Polymorphism, Single Nucleotide; Gene; Article; Linkage Disequilibrium; 03 medical and health sciences; Enalapril; Risk Factors; Health Sciences; Genetics; Humans; Genetic Predisposition to Disease; Diagnosis and Management of Chronic Cough; Internal medicine; Biology; Cough Hypersensitivity Syndrome; Pharmacology; Liver-Specific Organic Anion Transporter 1; Middle Aged; Asthma; SLCO1B1; 3. Good health; Cough; Haplotypes; Cough Reflex Sensitivity; Pharmacogenetics; FOS: Biological sciences; Management of Hyperkalemia in Kidney Diseases; Blood pressure; Medicine; Female; Angiotensin-converting enzyme

AbstractClinical observations suggest that incidence of cough in Chinese taking angiotensin converting enzyme inhibitors is much higher than other racial groups. Cough is the most common adverse reaction of enalapril. We investigate whether SLCO1B1 genetic polymorphisms, previously reported to be important determinants of inter-individual variability in enalapril pharmacokinetics, are associated with the enalapril-induced cough. A cohort of 450 patients with essential hypertension taking 10 mg enalapril maleate were genotyped for the functional SLCO1B1 variants, 388A > G (Asn130Asp, rs2306283) and 521T > C (Val174Ala, rs4149056). The primary endpoint was cough, which was recorded when participants were bothered by cough and respiratory symptoms during enalapril treatment without an identifiable cause. SLCO1B1 521C allele conferred a 2-fold relative risk of enalapril-induced cough (95% confidence interval [CI] = 1.34–3.04, P = 6.2 × 10−4) and haplotype analysis suggested the relative risk of cough was 6.94-fold (95% CI = 1.30–37.07, P = 0.020) in SLCO1B1*15/*15 carriers. Furthermore, there was strong evidence for a gene-dose effect (percent with cough in those with 0, 1, or 2 copy of the 521C allele: 28.2%, 42.5% and 71.4%, trend P = 6.6 × 10−4). Our study highlights, for the first time, SLCO1B1 variants are strongly associated with an increased risk of enalapril-induced cough. The findings will be useful to provide pharmacogenetic markers for enalapril treatment.