A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough

J D Mosley, C M Shaffer, S L Van Driest, P E Weeke, Q S Wells, J H Karnes, D R Velez Edwards, W-Q Wei, P L Teixeira, L Bastarache, D C Crawford, R Li, T A Manolio, E P Bottinger, C A McCarty, J G Linneman, M H Brilliant, J A Pacheco, W Thompson, R L ChisholmG P Jarvik, D R Crosslin, D S Carrell, E Baldwin, J Ralston, E B Larson, J Grafton, A Scrol, H Jouni, I J Kullo, G Tromp, K M Borthwick, H Kuivaniemi, D J Carey, M D Ritchie, Y Bradford, S S Verma, C G Chute, Abirami Veluchamy, Moneeza Siddiqui, C N A Palmer, A Doney, S H MahmoudPour, A H Maitland-van der Zee, A D Morris, J C Denny, D M Roden

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    Abstract

    The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10-8). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10-9). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

    Original languageEnglish
    Pages (from-to)231-237
    Number of pages7
    JournalPharmacogenomics Journal
    Volume16
    Issue number3
    Early online date14 Jul 2015
    DOIs
    Publication statusPublished - Jun 2016

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