PMID- 35352885 OWN - NLM STAT- MEDLINE DCOM- 20220331 LR - 20221207 IS - 1976-2437 (Electronic) IS - 0513-5796 (Print) IS - 0513-5796 (Linking) VI - 63 IP - 4 DP - 2022 Apr TI - Genetic Variants Associated with Adverse Events after Angiotensin-Converting Enzyme Inhibitor Use: Replication after GWAS-Based Discovery. PG - 342-348 LID - 10.3349/ymj.2022.63.4.342 [doi] AB - 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 ACEI-related 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. CI - (c) Copyright: Yonsei University College of Medicine 2022. FAU - Lee, Chan Joo AU - Lee CJ AUID- ORCID: 0000-0002-8756-409X AD - Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. FAU - Choi, Bogeum AU - Choi B AUID- ORCID: 0000-0002-7256-6922 AD - Kyung Hee University College of Medicine, Seoul, Korea. FAU - Pak, Hayeon AU - Pak H AUID- ORCID: 0000-0001-8110-2225 AD - Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Korea. FAU - Park, Jung Mi AU - Park JM AUID- ORCID: 0000-0003-1572-5832 AD - Department of Biostatistics and Computing, Graduate School, Yonsei University, Seoul, Korea. FAU - Lee, Ji Hyun AU - Lee JH AUID- ORCID: 0000-0003-3640-2928 AD - Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine, Seoul, Korea. AD - Department of Biomedical Science and Technology, Kyung Hee University, Seoul, Korea. hyunihyuni@khu.ac.kr. FAU - Lee, Sang-Hak AU - Lee SH AUID- ORCID: 0000-0002-4535-3745 AD - Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. shl1106@yuhs.ac. LA - eng GR - 18182MFDS410/Ministry of Food and Drug Safety/Korea PT - Journal Article PL - Korea (South) TA - Yonsei Med J JT - Yonsei medical journal JID - 0414003 RN - 0 (Angiotensin-Converting Enzyme Inhibitors) RN - 0 (Transcription Factors) RN - 0 (VOPP1 protein, human) SB - IM MH - *Angiotensin-Converting Enzyme Inhibitors/adverse effects MH - Asian People/genetics MH - Cough/chemically induced/drug therapy/genetics MH - *Genome-Wide Association Study MH - Humans MH - Polymorphism, Single Nucleotide/genetics MH - Transcription Factors/genetics PMC - PMC8965428 OTO - NOTNLM OT - Pharmacogenomics OT - antihypertensive agents OT - drug therapy OT - heart failure OT - safety COIS- The authors have no potential conflicts of interest to disclose. EDAT- 2022/03/31 06:00 MHDA- 2022/04/01 06:00 PMCR- 2022/04/01 CRDT- 2022/03/30 08:42 PHST- 2021/10/15 00:00 [received] PHST- 2021/12/13 00:00 [revised] PHST- 2022/01/11 00:00 [accepted] PHST- 2022/03/30 08:42 [entrez] PHST- 2022/03/31 06:00 [pubmed] PHST- 2022/04/01 06:00 [medline] PHST- 2022/04/01 00:00 [pmc-release] AID - 63.342 [pii] AID - 10.3349/ymj.2022.63.4.342 [doi] PST - ppublish SO - Yonsei Med J. 2022 Apr;63(4):342-348. doi: 10.3349/ymj.2022.63.4.342.