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

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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 (US)
Pages (from-to)231-237
Number of pages7
JournalPharmacogenomics Journal
Issue number3
StatePublished - Jun 1 2016

Bibliographical note

Funding Information:
This work was supported by the VUMC Clinical Pharmacology Training grant (T32 GM07569), the electronic MEdical Records and GEnomics (eMERGE) Network U01- HG-04603 (Vanderbilt), 1U02HG004608-01, 1U01HG006389 and NCATS/NIH grant UL1TR000427 (Marshfield/EIRH/Penn State), U01HG006375 and U01AG06781 (Group Health and University of Washington), U01-HG04599 (Mayo Clinic), U01-HG004609 (Northwestern University), U01HG006382 (Geisinger), an ARRA grant RC2 GM092618, R01 LM 010685, a Vanderbilt PGRN grant U19 HL065962 and the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. At Geisinger, the sample collection was supported by NIH (P30DK072488, R01DK088231 and R01DK091601), Pennsylvania Commonwealth Universal Research Enhancement Program, the Ben Franklin Technology Development Fund of PA, the Geisinger Clinical Research Fund and a Grant-In-Aid from the American Heart Association. GoDARTS was funded by the Wellcome Trust (084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program.

Publisher Copyright:
© 2016 Macmillan Publishers Limited.


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