51. A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough
- Author
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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, Chisholm, R L, Jarvik, G P, Crosslin, D R, Carrell, D S, Baldwin, E, Ralston, J, Larson, E B, Grafton, J, Scrol, A, Jouni, H, Kullo, I J, Tromp, G, Borthwick, K M, Kuivaniemi, H, Carey, D J, Ritchie, M D, Bradford, Y, Verma, S S, Chute, C G, Veluchamy, A, Siddiqui, M K, Palmer, C N A, Doney, A, Mahmoud Pour, Seyed Hamidreza, Maitland-van der Zee, A H, Morris, A D, Denny, J C, Roden, D M, 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, Chisholm, R L, Jarvik, G P, Crosslin, D R, Carrell, D S, Baldwin, E, Ralston, J, Larson, E B, Grafton, J, Scrol, A, Jouni, H, Kullo, I J, Tromp, G, Borthwick, K M, Kuivaniemi, H, Carey, D J, Ritchie, M D, Bradford, Y, Verma, S S, Chute, C G, Veluchamy, A, Siddiqui, M K, Palmer, C N A, Doney, A, Mahmoud Pour, Seyed Hamidreza, Maitland-van der Zee, A H, Morris, A D, Denny, J C, and Roden, D M
- 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.The Pharmacogenomics Journal advance online publication, 14 July 2015; doi:10.1038/tpj.2015.51.
- Published
- 2015