Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker–Induced Angioedema

Abstract

Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89-4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10 −3. A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49-3.27, P = 6.30 × 10 −9) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.

Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes

“…Association analysis at the individual variant level revealed no statistically significant differences in identified variants between cases and controls, neither for common nor for rare variants. This appears to be consistent with the results of the exome study of Maroteau et al (2020) , which did not report any of the presently investigated genes in their list of the most strongly associated genes. However, given the limited sample size of the present study, the non-significant results could also be attributable to a lack of statistical power.…”

“…These include intronic variants in the KCNMA1 gene as well as variants located in an upstream region of the BDKRB2 gene ( Rasmussen et al, 2020 ; Ghouse et al, 2021 ). Furthermore, a recent exome sequencing study revealed associations between ACEi/ARB-induced angioedema and the common factor V Leiden mutation, as well as other rare variants in the F5 gene ( Maroteau et al, 2020 ). Despite these advances, however, the precise underlying genetic causes of ACEi/ARB-induced angioedema remain largely unclear.…”

Common variants near the bradykinin receptor B2 gene are associated with angioedema induced by angiotensin-converting-enzyme inhibitor treatment - a genome wide association study

“…Several other genes, including XPNPEP2, MME, F5, ETV6, KCNMA1, have been implicated in ACEi-associated angioedema, with biologically plausible roles in angioedema pathology. [10][11][12][13][14][15][16] However, the majority of genes have been linked with angioedema through candidate gene methods, and only two studies to date, have used a GWAS approach. [12,16] None of the studies that have investigated the role of common variants in autosomal genes have been successfully replicated in independent cohorts.…”

“…In fact, through early candidate gene studies, variations in the genes XPNPEP2, MME, ETV6, F5 have been associated with ACEi-associated angioedema. [10][11][12][13][14][15] Although many of these loci are biologically plausible, only the XPNPEP2 locus, located on the X chromosome, has successfully been replicated. [11,13,14] In recent years, two genome-wide association studies (GWAS) have been conducted on ACEi-associated angioedema, however, none of the findings reported in these two studies were validated in independent replication cohorts.…”

Common Statin Intolerance Variants in ABCB1 and LILRB5 Show Synergistic Effects on Statin Response: An Observational Study Using Electronic Health Records

“…The cohorts have been used extensively for pharmacogenetic research: to establish associations between statin intolerance and genetic variants, such as SLCO1B1 and LILRB5 genotypes (Donnelly et al, 2011;Siddiqui et al, 2017). These cohorts were also used in the discovery of the association between variants of the F5 gene and an increased risk of ADRs to ACE-I therapy (angiotensinconverting enzyme inhibitors; Maroteau et al, 2020).…”