High CR1 level and related polymorphic variants are associated with cerebral malaria in eastern-India

The complement receptor 1 (CR1/CD35) protein acts as the major rosetting receptor in Plasmodium falciparum infection and several genetic variants of CR1 gene have been shown to be associated with quantitative expression of erythrocyte CR1 (E-CR1) level. However, CR1 level and gene polymorphisms exhibit differences in clinical manifestation of malaria in regions of varying disease endemicity. The result of the present study which analyzed three SNPs (intron 27 HindIIIA>T, exon 22 3650 A>G, and exon 33 5507 C>G) of the CR1 gene in Orissa, a hyperendemic state in eastern-India showed that a significantly increased risk for cerebral malaria (CM) was associated with AA genotype of both intron 27 and exon 22 when compared with mild, severe malaria anemia (SMA) and CM + SMA group respectively. Further, the overall haplotype analysis for all the three loci showed predominantly two major haplotypes ‘AAC’ coding for higher expression of CR1 and ‘TGG’ haplotype coding for low expression of CR1 level with the former haplotype being significantly associated with CM (P value < 0.00619 after Bonferroni correction) compared to mild malaria. The ‘TGG’ haplotype was proportionately more in SMA cases compared to mild malaria though statistically not significant. These findings suggest that the mild malaria group had an intermediate level of E-CR1 and extremely low or high levels of CR1 can cause severity in malaria. Further large scale studies in different endemic regions are needed to explain the epidemiological differences between E-CR1 expression and clinical manifestation of malaria which may contribute to the understanding of malaria pathogenesis.

Research highlights▶ Mild malaria group had an intermediate level of E-CR1 and extremely low or high levels of CR1 can cause severe malaria anemia or cerebral malaria respectively. ▶ Despite its association with increased susceptibility to SMA, the low expression allele L was observed relatively frequently in the studied population. ▶ The reason for this might be due to unproved protective mechanisms against death from severe malaria (cerebral malaria being the leading cause of mortality) that needs to be examined.