Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci

Abstract

Aims To search for sequence variants associated with ACEi discontinuation and to test their association with ACEi-associated adverse drug reactions (ADRs). Methods and results A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR: 1.21; 95% CI: 1.17–1.24; P = 2.1 × 10–34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose–response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits. Conclusion This study showed the advantage of using prescription patterns to discover genetic links with ADRs. In total, seven genetic loci that associated with ACEi discontinuation were identified. There was evidence of a strong association between our ADR phenotype and ACEi-associated cough. Taken together, these findings increase insight into the pathophysiological processes that underlie ACEi-associated ADRs.

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.…”

“…With recent advances in genetic research [8], several genome-wide association studies (GWASs) have reported genetic loci associated with ACEI-related cough. Candidate genes include NTSR1 [9], NELL1 [10], and CLASP1 [11].…”

Association between angiotensin-converting enzyme inhibitor-induced cough and the risk of lung cancer: a Mendelian randomization study

“…These 11 SNPs were included in the main Asian population analysis ( Supplementary Table S3 ). Additionally, we selected seven SNPs from a published European GWAS ( Ghouse et al, 2022 ) and extracted correlations between SNPs and exposure relevant to the European population. These seven SNPs were included in the main European population analysis ( Supplementary Table S4 ).…”

“…We selected single nucleotide polymorphisms (SNPs) related to ACE inhibition and ACEI-induced cough from previous genome-wide association studies (GWAS) for use as genetic proxies for exposure. The whole-genome detection of ACE inhibition was obtained from a previous study, ( Yarmolinsky et al, 2022 ), and SNPs related to ACEI-induced cough in the European population were obtained from a meta-analysis ( Ghouse et al, 2022 ) of three independent European cohorts. Additionally, SNPs related to ACEI-induced cough in the Asian population were sourced from 396 Chinese individuals ( Mu et al, 2020 ).…”

From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis

“…It is important to note that while we have made certain genomic insights regarding the adverse effects (e.g., drug resistance) of first-generation NTRK inhibitors, more reliable conclusions about causality may require higher-level genetic evidence in the future. This could involve identifying single nucleotide polymorphism (SNP) loci significantly associated with ADEs through genome-wide association studies ( Ghouse et al, 2022 ; Giles et al, 2022 ). Such an approach could enable the screening and identification of patients susceptible to adverse effects, thereby improving efficacy and concurrently mitigating adverse effects.…”