Identification of a haplotype block in the 5q31 cytokine gene cluster associated with the susceptibility to severe malaria

A total of 82 SNPs spanning 522 kb of the 5q31 region were analysed in 368 patients with Plasmodium falciparum malaria (203 mild malaria and 165 severe malaria patients).Only rs1881457 located in the promoter region of IL13, which is in linkage disequilibrium with rs1800925 (r2 = 0.73), showed a significant association with severe malaria after adjusting for multiple testing (P = 0.046 by permutation test). This SNP was in a haplotype block spanning 97 kb (from rs2069812 to rs2240032). The detected haplotype block contained the RAD50 gene and the promoter of IL13, but not the other genes.A haplotype block in which a primary polymorphism associated with severe malaria is likely to be encoded was identified in Thai malaria patients.Over the course of the last decade a number of studies have provided evidence for a linkage between the blood infection level of Plasmodium falciparum and the human chromosome 5q31 region in African populations [1-4]. In addition to malaria, the 5q31 region shows a linkage to the response against other infectious diseases such as schistosomiasis [5] and leishmaniasis [6]. The 5q31-33 region contains genes encoding the T helper 2-type cytokines (the interleukin genes IL3, IL4, IL5, IL9, and IL13) and other immunologically active genes such as interferon regulatory factor-1 (IRF1). These genes are strong candidates for controlling the outcome of malaria infection.In a previous study, three single nucleotide polymorphisms (SNPs) in the promoter regions of IL3, IL4, and IL13 were investigated. Of which, a SNP in the IL13 promoter region, IL13 -1055T>C (rs1800925), was found to be associated with susceptibility to severe malaria in Thais [7]. However, a number of candidate genes or polymorphisms still remain to be analyzed. In addition, no other polymorphisms surrounding rs1800925 were analyzed and thus the possibility that the association of rs1800925 with severe malaria may have resulted from linkage disequilibrium (LD) from other polymorphism