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, A. Veluchamy, M. K. 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 x 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 x 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk
Original languageEnglish
Pages (from-to)231-237
Journalpharmacogenomics journal
Volume16
Issue number3
DOIs
Publication statusPublished - 2016

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