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.

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
  • Vereinigte Staaten

Substances

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