From Genome-wide Association Studies to Functional Variants: ARL14 Cis - regulatory Variants Are Associated With Severe Malaria - Archive ouverte HAL
Journal Articles Journal of Infectious Diseases Year : 2024

From Genome-wide Association Studies to Functional Variants: ARL14 Cis - regulatory Variants Are Associated With Severe Malaria

Abstract

Abstract Background Genome-wide association studies have identified several nonfunctional tag single-nucleotide polymorphisms (SNPs) associated with severe malaria. We hypothesized that causal SNPs could play a significant role in severe malaria by altering promoter or enhancer activity. Here, we sought to identify such regulatory SNPs. Methods SNPs in linkage disequilibrium with tagSNPs associated with severe malaria were identified and were further annotated using FUMA. Then, SNPs were prioritized using the integrative weighted scoring method to identify regulatory ones. Gene reporter assays were performed to assess the regulatory effect of a region containing candidates. The association between SNPs and severe malaria was assessed using logistic regression models in a Senegalese cohort. Results Among 418 SNPs, the best candidates were rs116525449 and rs79644959, which were in full disequilibrium between them, and located within the ARL14 promoter. Our gene reporter assay results revealed that the region containing the SNPs exhibited cell-specific promoter or enhancer activity, while the SNPs influenced promoter activity. We detected an association between severe malaria and those 2 SNPs using the overdominance model and we replicated the association of severe malaria with the tagSNP rs116423146. Conclusions We suggest that these SNPs regulate ARL14 expression in immune cells and the presentation of antigens to T lymphocytes, thus influencing severe malaria development.
Fichier principal
Vignette du fichier
jiae159b.pdf (793.65 Ko) Télécharger le fichier
Origin Publication funded by an institution
Licence

Dates and versions

hal-04549763 , version 1 (17-04-2024)

Licence

Identifiers

Cite

Mathieu Adjemout, Frederic Gallardo, Magali Torres, Alassane Thiam, Babacar Mbengue, et al.. From Genome-wide Association Studies to Functional Variants: ARL14 Cis - regulatory Variants Are Associated With Severe Malaria. Journal of Infectious Diseases, 2024, pp.jiae159. ⟨10.1093/infdis/jiae159⟩. ⟨hal-04549763⟩
55 View
19 Download

Altmetric

Share

More