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

Malaria remains a major health challenge in sub-Saharan Africa. Host genetic variation influences susceptibility, but the contribution of inhibitory receptors such as LILRB1-targeted by Plasmodium falciparum RIFINs-remains poorly defined. 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, and transcription factor binding. Three noncoding variants (rs10416697, rs10423364, and rs7246537) and one coding variant (rs1061680) were selected. Genotyping was performed in 267 Senegalese individuals with malaria or healthy status. Logistic regression adjusted for age assessed genetic associations. The functional effect of rs7246537 was evaluated using luciferase reporter assays.

Forty-nine variants were associated with LILRB1 expression in African populations, three overlapping open chromatin near the distal promoter. Only rs7246537 showed significant association with malaria. Carriers of the A allele had reduced risk of clinical malaria and cerebral malaria. rs7246537 colocalized with a YY1-binding site, and luciferase assays demonstrated allele-specific effects, with the A allele driving lower promoter activity.

rs7246537 is a functional regulatory variant that reduces malaria susceptibility by modulating LILRB1 expression, highlighting the role of noncoding variation in malaria pathogenesis. These findings support inhibitory immune pathways as important determinants of malaria outcomes.