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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 (author)
Univ Dundee, Ninewells Hosp & Med Sch, Div Populat Hlth & Genom, Dundee, Scotland
Siddiqui, Moneeza Kalhan (author)
Univ Dundee, Ninewells Hosp & Med Sch, Div Populat Hlth & Genom, Dundee, Scotland
Veluchamy, Abirami (author)
Univ Dundee, Ninewells Hosp & Med Sch, Div Populat Hlth & Genom, Dundee, Scotland
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Carr, Fiona (author)
Univ Dundee, Ninewells Hosp & Med Sch, Div Populat Hlth & Genom, Dundee, Scotland
White, Myra (author)
Univ Dundee, Ninewells Hosp & Med Sch, Div Populat Hlth & Genom, Dundee, Scotland
Cassidy, Andrew J. (author)
Univ Dundee, Tayside Ctr Genom Anal, Sch Med, Dundee, Scotland
Baranova, Ekaterina, V (author)
Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands
Rasmussen, Eva R. (author)
Univ Copenhagen, Rigshosp, Dept Otorhinolaryngol Head & Neck Surg & Audiol, Copenhagen, Denmark.; Odense Univ Hosp, OPEN Patient Data Explorat Network, Odense, Denmark
Eriksson, Niclas, 1978- (author)
Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinska vetenskaper,Uppsala kliniska forskningscentrum (UCR)
Bloch, Katarzyna M. (author)
Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England
Brown, Nancy J. (author)
Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA
Bygum, Anette (author)
Odense Univ Hosp, OPEN Patient Data Explorat Network, Odense, Denmark
Hallberg, Pär, 1974- (author)
Uppsala universitet,Klinisk farmakogenomik och osteoporos,Science for Life Laboratory, SciLifeLab
Karawajczyk, Malgorzata (author)
Uppsala universitet,Klinisk kemi
Magnusson, Patrik K. E. (author)
Karolinska Institutet
Yue, Qun-Ying (author)
WHO Collaborating Ctr, Uppsala Monitoring Ctr, Uppsala, Sweden
Syvänen, Ann-Christine, 1950- (author)
Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinska vetenskaper
von Buchwald, Christian (author)
Univ Copenhagen, Rigshosp, Dept Otorhinolaryngol Head & Neck Surg & Audiol, Copenhagen, Denmark
Alfirevic, Ana (author)
Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England
Maitland-van der Zee, Anke H. (author)
Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands.; Univ Amsterdam, Amsterdam Univ Med Ctr, Dept Resp Med, Locat AMC, Amsterdam, Netherlands
Wadelius, Mia (author)
Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinska vetenskaper
Palmer, Colin N. A. (author)
Univ Dundee, Ninewells Hosp & Med Sch, Div Populat Hlth & Genom, Dundee, Scotland
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 (creator_code:org_t)
2020-07-18
2020
English.
In: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 108:6, s. 1195-1202
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reactionto 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 analysisof 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

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