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*

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Scopus citations

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 (US)
Pages (from-to)231-237
Number of pages7
JournalPharmacogenomics Journal
Volume16
Issue number3
DOIs
StatePublished - Jun 1 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

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    Mosley, J. D., Shaffer, C. M., Van Driest, S. L., Weeke, P. E., Wells, Q. S., Karnes, J. H., Velez Edwards, D. R., Wei, W. Q., Teixeira, P. L., Bastarache, L., Crawford, D. C., Li, R., Manolio, T. A., Bottinger, E. P., McCarty, C. A., Linneman, J. G., Brilliant, M. H., Pacheco, J. A., Thompson, W., ... Roden, D. M. (2016). A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough. Pharmacogenomics Journal, 16(3), 231-237. https://doi.org/10.1038/tpj.2015.51