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. 2016 Jun;16(3):231-7.
doi: 10.1038/tpj.2015.51. Epub 2015 Jul 14.

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

J D Mosley  1 , C M Shaffer  1 , S L Van Driest  1   2 , P E Weeke  1   3 , Q S Wells  1 , J H Karnes  1 , D R Velez Edwards  4 , W-Q Wei  5 , P L Teixeira  5 , L Bastarache  5 , D C Crawford  6 , R Li  7 , T A Manolio  7 , E P Bottinger  8 , C A McCarty  9 , J G Linneman  10 , M H Brilliant  10 , J A Pacheco  11 , W Thompson  11 , R L Chisholm  11 , G P Jarvik  12 , D R Crosslin  12 , D S Carrell  13 , E Baldwin  13 , J Ralston  13 , E B Larson  13 , J Grafton  13 , A Scrol  13 , H Jouni  14 , I J Kullo  14 , G Tromp  15 , K M Borthwick  15 , H Kuivaniemi  15 , D J Carey  15 , M D Ritchie  16 , Y Bradford  16 , S S Verma  16 , C G Chute  17 , A Veluchamy  18 , M K Siddiqui  18 , C N A Palmer  18 , A Doney  18 , S H MahmoudPour  19 , A H Maitland-van der Zee  19 , A D Morris  20 , J C Denny  1   5 , D M Roden  1
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A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough

J D Mosley et al. Pharmacogenomics J. 2016 Jun.

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.

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Figures

Figure 1
Figure 1
Manhattan plot of genotyped single-nucleotide polymorphisms associated with angiotensin-converting enzyme inhibitor-induced cough using an additive model adjusted for 10 principal components, age, sex, history of asthma, reflux, postnasal drip and lung disease. The red line indicates the genome-wide significance threshold of alpha=5 × 10−8.
Figure 2
Figure 2
LocusZoom plot of most strongly associated single-nucleotide polymorphisms (SNPs) from genome-wide association study located in the region of KCNIP4 (chr4:20330238–22350374), centered around SNP rs145489027 (shown in purple). Linkage disequilibrium (based on r2 values) with respect to rs145489027 are based on the CEU reference population. Imputed SNPs are denoted by squares and genotyped SNPs by circles.
Figure 3
Figure 3
Forest plot for the association between angiotensin-converting enzyme inhibitor cough and KCNIP4 intronic single-nucleotide polymorphism rs1495509 for the discovery (eMERGE (Electronic Medical Records and Genomics) Network) and replication (eMERGE and GoDARTS (Genetics of Diabetes Audit and Research in Tayside, Scotland)) data sets. There was no heterogeneity across studies (P=0.43). CI, confidence interval.
See this image and copyright information in PMC

References

    1. Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov 2002; 1: 621–636. - PubMed
    1. Overlack A. ACE inhibitor-induced cough and bronchospasm. Incidence, mechanisms and management. Drug Saf 1996; 15: 72–78. - PubMed
    1. Lee YJ, Tsai JC. Angiotensin-converting enzyme gene insertion/deletion, not bradykinin B2 receptor -58 T/C gene polymorphism, associated with angiotensin-converting enzyme inhibitor-related cough in Chinese female patients with non-insulin-dependent diabetes mellitus. Metab Clin Exp 2001; 50: 1346–1350. - PubMed
    1. Woo KS, Nicholls MG. High prevalence of persistent cough with angiotensin converting enzyme inhibitors in Chinese. Br J Clin Pharmacol 1995; 40: 141–144. - PMC - PubMed
    1. Wood R. Bronchospasm and cough as adverse reactions to the ACE inhibitors captopril, enalapril and lisinopril. A controlled retrospective cohort study. Br J Clin Pharmacol 1995; 39: 265–270. - PMC - PubMed

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