A Functional Intronic Variant of LILRB1 Associated with Clinical Malaria in the Senegalese Population.

Abstract

Malaria remains a major health challenge in sub-Saharan Africa despite extensive control measures. Host genetic variation influences susceptibility, but the role of inhibitory receptors such as LILRB1-targeted by Plasmodium falciparum RIFINs-remains unclear. We investigated whether regulatory variants in LILRB1 modulate malaria risk. Regulatory variants were prioritized from African expression quantitative trait locus (eQTL) datasets by integrating linkage disequilibrium, chromatin accessibility, transcription factor binding, and immune cell-specific expression. Three non-coding variants (rs10416697, rs10423364, rs7246537) and one coding variant (rs1061680) were selected. Genotyping was performed in 267 Senegalese individuals (116 severe malaria, 74 mild malaria, 77 healthy controls). Logistic regression adjusted for age assessed genetic associations. The effect of rs7246537 on promoter activity was tested using luciferase assays. Among 10,110 candidate eQTLs, 49 were associated with LILRB1 expression in African populations; three overlapped open chromatin near the distal promoter. Only rs7246537 showed significant association with malaria: allele A carriers had lower risk of clinical malaria (OR = 0.50, 95% CI: 0.28-0.88, p = 0.0165) and cerebral malaria (OR = 0.44, 95% CI: 0.22-0.86, p = 0.0176). rs7246537 colocalized with a YY1-binding site, and luciferase assays confirmed allele-specific effects, with the A allele driving twofold lower promoter activity compared with the G allele. rs7246537 is a functional regulatory variant that reduces malaria susceptibility in Senegalese populations by modulating LILRB1 expression. These findings underscore the importance of non-coding variants and inhibitory immune pathways in malaria pathogenesis.