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.

• Authors: Cyrielle Maroteau, Moneeza Kalhan Siddiqui, Abirami Veluchamy, Fiona Carr, Myra White, Andrew J Cassidy, Ekaterina V Baranova, Eva R Rasmussen, Niclas Eriksson, Katarzyna M Bloch, Nancy J Brown, Anette Bygum, Par Hallberg, Malgorzata Karawajczyk, Patrik K E Magnusson, Qun-Ying Yue, Ann-Christine Syvänen, Christian von Buchwald, Ana Alfirevic, Anke H Maitland-van der Zee, Mia Wadelius, Colin N A Palmer, PREDICTION-ADR
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 108 Issue 6 Pg. 1195-1202 (12 2020) ISSN: 1532-6535 [Electronic] United States
• PMID: 32496628 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Angiotensin Receptor Antagonists
• Angiotensin-Converting Enzyme Inhibitors
• factor V Leiden
• Factor V

Topics

• Aged
• Angioedema (chemically induced, ethnology, genetics)
• Angiotensin Receptor Antagonists (adverse effects)
• Angiotensin-Converting Enzyme Inhibitors (adverse effects)
• Case-Control Studies
• DNA Mutational Analysis
• Europe (epidemiology)
• Exome
• Factor V (genetics)
• Female
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Male
• Middle Aged
• Mutation Rate
• Mutation, Missense
• Risk Assessment
• Risk Factors
• United States (epidemiology)
• Exome Sequencing