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Pharmacogenomics J. 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.

Author information

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.

PMID:
26169577
PMCID:
PMC4713364
DOI:
10.1038/tpj.2015.51
[Indexed for MEDLINE]
Free PMC Article

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