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[Preprint]. 2024 Sep 15:2024.09.13.24313664.
doi: 10.1101/2024.09.13.24313664.

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

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

Jacquiline W Mugo et al. medRxiv. .

Update in

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<5.0×10-06). Some of these SNPs were found to be located close to the genes PRKCQ and RIMS1, previously linked with drug-induced angioedema, and also close to the CSMD1 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.

Keywords: Angioedema; Angiotensin-converting Enzyme Inhibitor; Genome-wide association studies.

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Figures

Figure 1:
Figure 1:
The PCA plot of the South African cohort clustered based on A) self-identified race and ethnicity: BLK1 – Black population from Western and Eastern Cape, BLK2 – Black population from Soweto, WHT – White, ADM – mixed ancestry, OTH- Other, UN – Unreported, and B) AE-ACEI status. This highlights the genomic diversity and the distribution of the cases and controls in study cohort.
Figure 2:
Figure 2:
A) The Manhattan plot of the standard GWAS of the South African cohort. The dashed red line corresponds to p-value=5.0×10−06, while the solid line is the GWAS significance threshold p-value=5.0×10−08. B) The corresponding QQ plot of the p-values of the standard GWAS (λ=0.99).
Figure 3:
Figure 3:
A) The Manhattan plot of the meta-analysis of the South African and Vanderbilt/Marshfield cohort summary statistics. The dashed red line corresponds to p-value=5.0×10−06, while the solid line is the GWAS significance threshold p-value=5.0×10−08. B) The corresponding QQ plot of the p-values of the standard GWAS (λ=0.99).

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