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

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.

J G Linneman | William K. Thompson | Pedro L. Teixeira | D J Carey | D M Roden | H Kuivaniemi | G Tromp | T. Manolio | D. Roden | J. Ralston | A. Doney | J. Denny | M. Brilliant | M. Ritchie | J. Denny | C. Palmer | J. Pacheco | I. Kullo | Rongling Li | R. Chisholm | D. Crawford | Wei-Qi Wei | E. Bottinger | G. Jarvik | C. Palmer | C. Shaffer | Y. Bradford | L. Bastarache | D. Carey | H. Kuivaniemi | G. Tromp | D. V. Edwards | C. McCarty | S. V. Van Driest | P. Weeke | J. Mosley | Q. Wells | J. Karnes | S. Verma | D. V. Velez Edwards | H. Jouni | A. Maitland‐van der Zee | D. Crosslin | K. Borthwick | M. Ritchie | J. Linneman | S. L. Driest | D. Carrell | E. Baldwin | R. Li | E. Larson | G. Jarvik | C. Chute | A. Morris | A. Scrol | T A Manolio | W. Thompson | P. L. Teixeira | R L Chisholm | D C Crawford | E B Larson | J C Denny | J. Grafton | S. H. Mahmoudpour | M H Brilliant | M. Siddiqui | A. Veluchamy | D R Crosslin | D S Carrell | E Baldwin | I J Kullo | K M Borthwick | C A McCarty | R Li | G P Jarvik | W-Q Wei | L Bastarache | J A Pacheco | J D Mosley | C M Shaffer | S L Van Driest | P E Weeke | Q S Wells | J H Karnes | D R Velez Edwards | P L Teixeira | E P Bottinger | W Thompson | J Ralston | J Grafton | A Scrol | H Jouni | 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 | C. Chute | W.-q. Wei | A. M. D. Zee | J. Ralston | Andrew D. Morris | E. Larson | R. L. Chisholm | T. Manolio | David Carrell | A. D. Morris | Aaron Scrol | Jane Grafton | C. Shaffer | Rongling Li

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