A GWAS of ACE Inhibitor-Induced Angioedema in a South African Population

Overview

Journal medRxiv

Date 2024 Sep 24

PMID 39314982

Authors

Jacquiline W Mugo

Cascia Day

Ananyo Choudhury

Maria Deetlefs

Robert Freercks

Sian Geraty

Angelica Panieri

Christian Cotchbos

Melissa Ribeiro

Adelein Engelbrecht

Lisa K Micklesfield

Michele Ramsay

Pedretti Sarah

Jonny Peter

Affiliations

Soon will be listed here.

Abstract

Background: Angiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event and, globally, the commonest cause of emergency presentations with angioedema. Several large genome-wide association studies (GWAS) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWAS from Africa. The aim of this study was to conduct a case-control GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population.

Methods: The GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from Vanderbilt/Marshfield with 174 cases and 489 controls).

Results: No SNPs attained genome-wide significance. However, 26 SNPs in the post-imputation standard GWAS of the South African cohort and 37 SNPs in the meta-analysis were associated to AE-ACEI with suggestive threshold(p-value<5.0×10). Some of these SNPs were found to be located close to the genes and previously linked with drug-induced angioedema, and also close to the gene linked to ACEI cough, providing replication at the gene level, but with novel lead SNPs.

Conclusions: Our results highlight the importance of African populations to detect novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.

References

Cornejo-Garcia J, Liou L, Blanca-Lopez N, Dona I, Chen C, Chou Y . Genome-wide association study in NSAID-induced acute urticaria/angioedema in Spanish and Han Chinese populations. Pharmacogenomics. 2013; 14(15):1857-69. DOI: 10.2217/pgs.13.166. View

Lee C, Choi B, Pak H, Park J, Lee J, Lee S . Genetic Variants Associated with Adverse Events after Angiotensin-Converting Enzyme Inhibitor Use: Replication after GWAS-Based Discovery. Yonsei Med J. 2022; 63(4):342-348. PMC: 8965428. DOI: 10.3349/ymj.2022.63.4.342. View

Castellano J, Pocock S, Bhatt D, Quesada A, Owen R, Fernandez-Ortiz A . Polypill Strategy in Secondary Cardiovascular Prevention. N Engl J Med. 2022; 387(11):967-977. DOI: 10.1056/NEJMoa2208275. View

Day C, Van Der Walt J, Crombie K, Hendrikse C, Peter J . Acute angioedema in Cape Town emergency centres and a suggested algorithm to simplify and improve management. S Afr Med J. 2023; 113(8):51-57. DOI: 10.7196/SAMJ.2023.v113i8.717. View

Watanabe K, Taskesen E, van Bochoven A, Posthuma D . Functional mapping and annotation of genetic associations with FUMA. Nat Commun. 2017; 8(1):1826. PMC: 5705698. DOI: 10.1038/s41467-017-01261-5. View

Salek-Ardakani S, So T, Halteman B, Altman A, Croft M . Differential regulation of Th2 and Th1 lung inflammatory responses by protein kinase C theta. J Immunol. 2004; 173(10):6440-7. DOI: 10.4049/jimmunol.173.10.6440. View

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, Bender D . PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81(3):559-75. PMC: 1950838. DOI: 10.1086/519795. View

Flaten H, Monte A . The Pharmacogenomic and Metabolomic Predictors of ACE Inhibitor and Angiotensin II Receptor Blocker Effectiveness and Safety. Cardiovasc Drugs Ther. 2017; 31(4):471-482. PMC: 5727913. DOI: 10.1007/s10557-017-6733-2. View

. Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19·1 million participants. Lancet. 2016; 389(10064):37-55. PMC: 5220163. DOI: 10.1016/S0140-6736(16)31919-5. View

10.

Peter J, Ntusi N, Ntsekhe M . Are Recommendations That Favor Other Agents Over Angiotensin-Converting Enzyme Inhibitors in Africans With Hypertension Justified?. Circulation. 2024; 149(11):804-806. DOI: 10.1161/CIRCULATIONAHA.123.065887. View

11.

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood A, Teumer A . A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016; 48(10):1279-83. PMC: 5388176. DOI: 10.1038/ng.3643. View

12.

Ali S, Soo C, Agongo G, Alberts M, Amenga-Etego L, Boua R . Genomic and environmental risk factors for cardiometabolic diseases in Africa: methods used for Phase 1 of the AWI-Gen population cross-sectional study. Glob Health Action. 2018; 11(sup2):1507133. PMC: 6161608. DOI: 10.1080/16549716.2018.1507133. View

13.

Pare G, Kubo M, Byrd J, McCarty C, Woodard-Grice A, Teo K . Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet Genomics. 2013; 23(9):470-8. PMC: 3904664. DOI: 10.1097/FPC.0b013e328363c137. View

14.

Ramsay M, Crowther N, Tambo E, Agongo G, Baloyi V, Dikotope S . H3Africa AWI-Gen Collaborative Centre: a resource to study the interplay between genomic and environmental risk factors for cardiometabolic diseases in four sub-Saharan African countries. Glob Health Epidemiol Genom. 2017; 1:e20. PMC: 5732578. DOI: 10.1017/gheg.2016.17. View

15.

Abdellaoui A, Yengo L, Verweij K, Visscher P . 15 years of GWAS discovery: Realizing the promise. Am J Hum Genet. 2023; 110(2):179-194. PMC: 9943775. DOI: 10.1016/j.ajhg.2022.12.011. View

16.

Kubiniok P, Marcu A, Bichmann L, Kuchenbecker L, Schuster H, Hamelin D . Understanding the constitutive presentation of MHC class I immunopeptidomes in primary tissues. iScience. 2022; 25(2):103768. PMC: 8810409. DOI: 10.1016/j.isci.2022.103768. View

17.

Stone Jr C, Brown N . Angiotensin-converting Enzyme Inhibitor and Other Drug-associated Angioedema. Immunol Allergy Clin North Am. 2017; 37(3):483-495. DOI: 10.1016/j.iac.2017.04.006. View

18.

Han B, Eskin E . Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am J Hum Genet. 2011; 88(5):586-98. PMC: 3146723. DOI: 10.1016/j.ajhg.2011.04.014. View

19.

Das S, Forer L, Schonherr S, Sidore C, Locke A, Kwong A . Next-generation genotype imputation service and methods. Nat Genet. 2016; 48(10):1284-1287. PMC: 5157836. DOI: 10.1038/ng.3656. View

20.

Ghouse J, Ahlberg G, Andreasen L, Banasik K, Brunak S, Schwinn M . Association of Variants Near the Bradykinin Receptor B Gene With Angioedema in Patients Taking ACE Inhibitors. J Am Coll Cardiol. 2021; 78(7):696-709. DOI: 10.1016/j.jacc.2021.05.054. View