Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker–Induced Angioedema
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Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker–Induced Angioedema. / Maroteau, Cyrielle; Siddiqui, Moneeza Kalhan; Veluchamy, Abirami; Carr, Fiona; White, Myra; Cassidy, Andrew J.; Baranova, Ekaterina V.; Rasmussen, Eva R.; Eriksson, Niclas; Bloch, Katarzyna M.; Brown, Nancy J.; Bygum, Anette; Hallberg, Par; Karawajczyk, Malgorzata; Magnusson, Patrik K.E.; Yue, Qun Ying; Syvänen, Ann Christine; von Buchwald, Christian; Alfirevic, Ana; Maitland-van der Zee, Anke H.; Wadelius, Mia; Palmer, Colin N.A.; PREDICTION-ADR.
I: Clinical Pharmacology and Therapeutics, Bind 108, Nr. 6, 2020, s. 1195-1202.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker–Induced Angioedema
AU - Maroteau, Cyrielle
AU - Siddiqui, Moneeza Kalhan
AU - Veluchamy, Abirami
AU - Carr, Fiona
AU - White, Myra
AU - Cassidy, Andrew J.
AU - Baranova, Ekaterina V.
AU - Rasmussen, Eva R.
AU - Eriksson, Niclas
AU - Bloch, Katarzyna M.
AU - Brown, Nancy J.
AU - Bygum, Anette
AU - Hallberg, Par
AU - Karawajczyk, Malgorzata
AU - Magnusson, Patrik K.E.
AU - Yue, Qun Ying
AU - Syvänen, Ann Christine
AU - von Buchwald, Christian
AU - Alfirevic, Ana
AU - Maitland-van der Zee, Anke H.
AU - Wadelius, Mia
AU - Palmer, Colin N.A.
AU - PREDICTION-ADR
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1002/cpt.1927
DO - 10.1002/cpt.1927
M3 - Journal article
C2 - 32496628
AN - SCOPUS:85088125092
VL - 108
SP - 1195
EP - 1202
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
SN - 0009-9236
IS - 6
ER -
ID: 253398743