Overdominance Effects between Malaria and Visceral Leishmaniasis in the 5q31 Region

Abstract

A group of SNPs in 5q31, genotyped from Hausa tribe of Koka village in eastern Sudan; an area endemic with malaria and visceral leishmaniasis, were analyzed by The Leishmaniasis research group and found to have significant excess of heterozygosis level and departure from HWE and assumed to be due to natural selection resulting from notorious deadly outbreaks since various ethnic groups from western Sudan settled the area although sequence information in the 5q31 region did not detect functional SNPs that could be associated with such drastic phenotypes. Malaria was thought to inflict inferior selective pressure due to the mild clinical phenotype observed. Taking advantage of follow up phenotype data sets available from the Malaria Gen study we re-analyzed these genotypes using different bioinformatics software to determine their effect on the regulation, function and expression of interleukins, miRNA binding and splicing mechanism. The SNPs were found to potentially affect the binding of many transcription factors that regulate the expression of IL-4 and IL-13 and stability of IL-5 mRNA. Association of haplotypes susceptibility revealed that the haplotype of low cytokine TH2 profile is associated with higher risk of malaria infection (P-value = 0.02). Through modulating TH2 cytokine response; the excess heterozygosity in 5q31 is explained with the phenomenon of overdominance between malaria and visceral leishmaniasis, acted by natural selection and driving the locus towards optimum response.