title: A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.
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.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Mosley
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Shaffer
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Pediatrics, Vanderbilt University, Nashville, TN, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Van Driest
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cardiology, Copenhagen University, Copenhagen, Denmark.
authors.forename: P E
authors.initials: PE
authors.lastname: Weeke
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Q S
authors.initials: QS
authors.lastname: Wells
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Karnes
authors.affiliation: Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, TN, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Velez Edwards
authors.affiliation: Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
authors.forename: W-Q
authors.initials: WQ
authors.lastname: Wei
authors.affiliation: Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Teixeira
authors.affiliation: Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bastarache
authors.affiliation: Department of Epidemiology and Biostatistics; Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Manolio
authors.affiliation: Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: E P
authors.initials: EP
authors.lastname: Bottinger
authors.affiliation: Essentia Institute of Rural Health, Duluth, MN, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: McCarty
authors.affiliation: Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Linneman
authors.affiliation: Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Brilliant
authors.affiliation: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Pacheco
authors.affiliation: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Thompson
authors.affiliation: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Chisholm
authors.affiliation: Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: G P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: Group Health Research Institute, Seattle, WA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Carrell
authors.affiliation: Group Health Research Institute, Seattle, WA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Baldwin
authors.affiliation: Group Health Research Institute, Seattle, WA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ralston
authors.affiliation: Group Health Research Institute, Seattle, WA, USA.
authors.forename: E B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Group Health Research Institute, Seattle, WA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Grafton
authors.affiliation: Group Health Research Institute, Seattle, WA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Scrol
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester MN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Jouni
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester MN, USA.
authors.forename: I J
authors.initials: IJ
authors.lastname: Kullo
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Tromp
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Borthwick
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kuivaniemi
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Carey
authors.affiliation: Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Bradford
authors.affiliation: Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Verma
authors.affiliation: Schools of Medicine, Public Health, and Nursing, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Chute
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: A
authors.initials: A
authors.lastname: Veluchamy
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: M K
authors.initials: MK
authors.lastname: Siddiqui
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: C N A
authors.initials: CN
authors.lastname: Palmer
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: A
authors.initials: A
authors.lastname: Doney
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
authors.forename: S H
authors.initials: SH
authors.lastname: MahmoudPour
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Maitland-van der Zee
authors.affiliation: School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: A D
authors.initials: AD
authors.lastname: Morris
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.|Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D016022:Case-Control Studies; D019295:Computational Biology; D003371:Cough / Q000139:chemically induced* / Q000208:ethnology / Q000235:genetics*; D030541:Databases, Genetic; D057286:Electronic Health Records; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D012606:Scotland; D014481:United States
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C496753:KCNIP4 protein, human; D051605:Kv Channel-Interacting Proteins