Genetic Variants Associated with Adverse Events after Angiotensin-Converting Enzyme Inhibitor Use: Replication after GWAS-Based Discovery

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 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.

A randomized trial of genotype-guided perindopril use

“…After genotyping, the presence of at least one risk allele in any of the two variants was considered a high-risk factor for ACEI-related cough. The association of NTSR1 SNP (rs6062847), reported in a recent European study [9], and cough was not significant in our previous study [10]. Furthermore, the frequency of CLASP1 SNP (rs62151109), which had a strong association with cough in a Swedish population [11], was 0 in Koreans.…”

“…NELL1 p.Arg382Trp (rs8176786) and NELL1 intron (rs10766756) were selected as target variants. These variants were among the five single-nucleotide polymorphisms replicated for association with ACEI-related cough in our previous study on Korean patients [10]. Briefly, five genes, including NELL1 , were identified near variants associated with ACEI-related adverse events in our GWAS.…”

A Relação Do Uso De Inibidores De Enzima Conversora De Angiotensina E a Tosse

“…Hoje, é a maior causa de abandono ao tratamento, sendo fator primário na troca do uso de inibidores de enzima conversora de angiotensina por outras classes de medicamentos, principalmente os bloqueadores de receptor de angiotensina (BRAs) (LEE et al, 2022;PINTO et al, 2020).…”

“…O uso dos IECAS é discutido mundialmente, já que a tosse causada por eles causa abandono ao tratamento por parte de alguns pacientes. Dentre os poucos efeitos, o mais comum é a tosse seca, que tem aparecimento variado de acordo com a etnia do paciente (LEE et al, 2022).…”

Genome-wide association study of ACE inhibitor-induced cough implicates neuropeptides and shows genetic overlap with chronic dry cough

“…Early hypotheses have suggested this is a response to the accumulation of inflammatory neuropeptides, particularly bradykinin and substance P, upon ACE inhibition 5,12 . Genes involved in these pathways have formed the basis of many candidate gene studies [13][14][15][16][17][18][19][20] , but these have failed to yield replicable findings and proved inconclusive about the role of these mediators in ACEI-induced cough. In light of this, several genomewide association studies 11,21,22 (GWASs) have since been performed, the largest of which included 1,595 cases and 5,485 controls from the Electronic Medical Records and Genomics (eMERGE) Network and identified a genome-wide significant signal within an intronic region of KCNIP4, which was replicated in two independent datasets 11 .…”