Exome sequencing reveals common and rare variants in F5 associated with ACE inhibitor and ARB induced angioedema.

Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Only 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- or ARB-induced angioedema (ACEI-AE, ARB-AE) and controls were recruited at five different centres. Sequencing of 1066 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 5 Leiden), was significantly associated with both ACEI-AE and ARB-AE [OR: 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=2.09x10-3 . A combined genetic risk score (GRS) 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= 6.30x10-9 ) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a GWAS study from the USA. 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.