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 drugs (ACEi) is a cough. We conducted a genome wide association study (GWAS) of ACEi-induced cough among 7,080 subjects of diverse ancestries in the 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 (1,595 cases and 5,485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (MAF=0.33, OR=1.3 [95%CI: 1.2–1.4], p=1.0×10−8). Replication for six SNPs in KCNIP4 was tested in a second eMERGE population (n=926) and in the GoDARTS cohort (n=4,309). Replication was observed at rs7675300 (OR=1.32 [1.01–1.70], p=0.04) in eMERGE and 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.

Phenome-Wide Association Studies as a Tool to Advance Precision Medicine

“…EHR data have been used to replicate known associations with clopidogrel drug response (13) and warfarin stable dose (64). Novel drug-response associations have been identified using EHR data for vancomycin stable dose (74), bleeding events associated with chronic warfarin use (34), heparin-induced thrombocytopenia (32), and angiotensin-converting enzyme (ACE) inhibitor–induced cough (49). A large meta-analysis combined both clinical trial data and EHR data to identify genetic loci associated with the cholesterol-lowering effect of statins, demonstrating that EHR and trial data can be combined and show similar effects for pharmacologic endpoints (61).…”

Performance of an electronic health record-based phenotype algorithm to identify community associated methicillin-resistant Staphylococcus aureus cases and controls for genetic association studies

“…Details of the assembly of an imputed GWAS dataset for the eMERGE II Network have been published previously [23, 24]. In brief, SNPs were genotyped on a number of different platforms at different sites.…”

Pharmacogenetics of angiotensin‐converting enzyme inhibitor‐induced angioedema

“…13 Another recent GWAS on ACEi intolerance (a mix of angioedema and cough) also reported several variants expressed in the nervous system. 13 Another recent GWAS on ACEi intolerance (a mix of angioedema and cough) also reported several variants expressed in the nervous system.…”

“…4 They were amongst the top five most prescribed drugs globally with spending estimated to reach 34 billion dollars in 2015. 12,13 In complete contrast, ACEi-induced angioedema (ACEi-A) is relatively rare with an estimated incidence of 0.1% -0.7%. 6 Although generally safe, a number of adverse reactions have been reported with ACEi, including rash, 8 cough, 9 hypotensive transfusion reaction 10 and angioedema.…”