title: SLCO1B1 Variants and Angiotensin Converting Enzyme Inhibitor (Enalapril)-Induced Cough: a Pharmacogenetic Study.
abstract: Clinical 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.
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; P. R. China.|Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; P. R. China.|Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China.
authors.forename: Jian-Quan
authors.initials: JQ
authors.lastname: Luo
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; P. R. China.|Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; P. R. China.|Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China.
authors.forename: Fa-Zhong
authors.initials: FZ
authors.lastname: He
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; P. R. China.|Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; P. R. China.|Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China.
authors.forename: Zhen-Min
authors.initials: ZM
authors.lastname: Wang
authors.affiliation: Department of Cardiology, People's Hospital, Peking University, Beijing 100044, P. R. China.
authors.forename: Ning-Ling
authors.initials: NL
authors.lastname: Sun
authors.affiliation: Department of Cardiology, People's Hospital, Peking University, Beijing 100044, P. R. China.
authors.forename: Lu-Yan
authors.initials: LY
authors.lastname: Wang
authors.affiliation: School of Health Administration, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Gen-Fu
authors.initials: GF
authors.lastname: Tang
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; P. R. China.|Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; P. R. China.|Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China.
authors.forename: Mou-Ze
authors.initials: MZ
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; P. R. China.|Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; P. R. China.|Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; P. R. China.|Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; P. R. China.|Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Chen
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; P. R. China.|Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; P. R. China.|Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China.
authors.forename: Zhao-Qian
authors.initials: ZQ
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; P. R. China.|Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; P. R. China.|Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China.
authors.forename: Hong-Hao
authors.initials: HH
authors.lastname: Zhou
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; P. R. China.|Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; P. R. China.|Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D003371:Cough / Q000139:chemically induced*; D004656:Enalapril / Q000009:adverse effects*; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D004656:Enalapril