Yonsei Med J.
2022 Apr;63(4):342-348. 10.3349/ymj.2022.63.4.342.
Genetic Variants Associated with Adverse Events after Angiotensin-Converting Enzyme Inhibitor Use: Replication after GWAS-Based Discovery
- Affiliations
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- 1Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- 2Kyung Hee University College of Medicine, Seoul, Korea
- 3Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Korea
- 4Department of Biostatistics and Computing, Graduate School, Yonsei University, Seoul, Korea
- 5Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine, Seoul, Korea
- 6Department of Biomedical Science and Technology, Kyung Hee University, Seoul, Korea
- KMID: 2527515
- DOI: http://doi.org/10.3349/ymj.2022.63.4.342
Abstract
- Purpose
Angiotensin-converting enzyme inhibitors (ACEIs) are medications generally prescribed for patients with high cardiovascular risk; however, they are suboptimally used due to frequent adverse events (AEs). The present study aimed to identify and replicate the genetic variants associated with ACEI-related AEs in the Korean population.
Materials and Methods
A two-stage approach employing genome-wide association study (GWAS)-based discovery and replication through target sequencing was used. In total, 1300 individuals received ACEIs from 2001 to 2007; among these, 228 were selected for GWAS. An additional 336 patients were selected for replication after screening 1186 subjects treated from 2008 to 2018. Candidate genes for target sequencing were selected based on the present GWAS, previous GWASs, and data from the PharmGKB database. Furthermore, association analyses were performed between no AE and AE or cough groups after target sequencing.
Results
Five genes, namely CRIM1, NELL1, CACNA1D, VOPP1, and MYBPC1, were identified near variants associated with ACEIrelated AEs. During target sequencing of 34 candidate genes, six single-nucleotide polymorphisms (SNPs; rs5224, rs8176786, rs10766756, rs561868018, rs4974539, and rs10946364) were replicated for association with all ACEI-related AEs. Four of these SNPs and rs147912715 exhibited associations with ACEI-related cough, whereas four SNPs (rs5224, rs81767786, rs10766756, and rs4974539 near BDKRB2, NELL1, NELL1 intron, and CPN2, respectively) were significantly associated with both categories of AEs.
Conclusion
Several variants, including novel and known variants, were successfully replicated and found to have associations with ACEI-related AEs. These results provide rare and clinically relevant information for safer use of ACEIs.
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