MBL2 Variations and Malaria Susceptibility in Indian Populations

Human mannose-binding lectin (MBL) encoded by the MBL2gene is a pattern recognition protein and has been associated with many infectious diseases, including malaria. We sought to investigate the contribution of functional MBL2gene variations to Plasmodium falciparum malaria in well-defined cases and in matched controls. We resequenced the 8.7 kb of the entire MBL2 gene in 434 individuals clinically classified with malaria from regions of India where malaria is endemic. The study cohort included 176 patients with severe malaria, 101 patients with mild malaria, and 157 ethnically matched asymptomatic individuals. In addition, 830 individuals from 32 socially, linguistically, and geographically diverse endogamous populations of India were investigated for the distribution of functional MBL2 variants. The MBL2 221C (X) allelic variant is associated with increased risk of malaria (mild malaria odds ratio [OR] 1.9, correctedPvalue [P Corr ]0.0036; severe malaria OR 1.6,P Corr 0.02). The exon1 variantsMBL2*B(severe malaria OR 2.1,P Corr 0.036; mild versus severe malaria OR 2.5,P Corr 0.039) and MBL2*C(mild versus severe malaria OR 5.4,P Corr 0.045) increased the odds of having malaria. The exon1 MBL2*D/*B/*C variant increased the risk for severe malaria (OR 3.4,P Corr 0.000045). The frequencies of low MBL haplotypes were significantly higher in severe malaria (14.2%) compared to mild malaria (7.9%) and asymptomatic (3.8%). The MBL2*LYPA haplotypes confer protection, whereas MBL2*LXPAincreases the malaria risk. Ourfindings in Indian populations demonstrate that MBL2functional variants are strongly associated with malaria and infection severity.