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 Chisholm; G 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

doi:10.1038/tpj.2015.51

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

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

Authors

J D Mosley¹, C M Shaffer¹, S L Van Driest^{1

2}, P E Weeke^{1

3}, Q S Wells¹, J H Karnes¹, D R Velez Edwards⁴, W-Q Wei⁵, P L Teixeira⁵, L Bastarache⁵, D C Crawford⁶, R Li⁷, T A Manolio⁷, E P Bottinger⁸, C A McCarty⁹, J G Linneman¹⁰, M H Brilliant¹⁰, J A Pacheco¹¹, W Thompson¹¹, R L Chisholm¹¹, G P Jarvik¹², D R Crosslin¹², D S Carrell¹³, E Baldwin¹³, J Ralston¹³, E B Larson¹³, J Grafton¹³, A Scrol¹³, H Jouni¹⁴, I J Kullo¹⁴, G Tromp¹⁵, K M Borthwick¹⁵, H Kuivaniemi¹⁵, D J Carey¹⁵, M D Ritchie¹⁶, Y Bradford¹⁶, S S Verma¹⁶, C G Chute¹⁷, A Veluchamy¹⁸, M K Siddiqui¹⁸, C N A Palmer¹⁸, A Doney¹⁸, S H MahmoudPour¹⁹, A H Maitland-van der Zee¹⁹, A D Morris²⁰, J C Denny^{1

5}, D M Roden¹

Affiliations

¹ Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
² Department of Pediatrics, Vanderbilt University, Nashville, TN, USA.
³ Department of Cardiology, Copenhagen University, Copenhagen, Denmark.
⁴ Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, TN, USA.
⁵ Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
⁶ Department of Epidemiology and Biostatistics; Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
⁷ Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD, USA.
⁸ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Essentia Institute of Rural Health, Duluth, MN, USA.
¹⁰ Marshfield Clinic Research Foundation, Marshfield, WI, USA.
¹¹ Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹² Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA, USA.
¹³ Group Health Research Institute, Seattle, WA, USA.
¹⁴ Division of Cardiovascular Diseases, Mayo Clinic, Rochester MN, USA.
¹⁵ The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA, USA.
¹⁶ Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA, USA.
¹⁷ Schools of Medicine, Public Health, and Nursing, Johns Hopkins University, Baltimore, MD, USA.
¹⁸ Medical Research Institute, University of Dundee, Dundee, UK.
¹⁹ Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
²⁰ School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, Edinburgh, UK.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Angiotensin-Converting Enzyme Inhibitors / adverse effects*
Case-Control Studies
Computational Biology
Cough / chemically induced*
Cough / ethnology
Cough / genetics*
Databases, Genetic
Electronic Health Records
Female
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Kv Channel-Interacting Proteins / genetics*
Logistic Models
Male
Multivariate Analysis
Odds Ratio
Phenotype
Polymorphism, Single Nucleotide*
Risk Assessment
Risk Factors
Scotland
United States

Substances

Angiotensin-Converting Enzyme Inhibitors
KCNIP4 protein, human
Kv Channel-Interacting Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding