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Abstract: Tumor necrosis factor (TNF)-related genes are thought to play a role in human malaria. TNF polymorphisms have been associated with severe malaria, mild malaria, and parasitemia. Lymphotoxin-alpha gene (LTA) that belongs to the TNF family is one such candidate gene. Here we report the family-based association analysis of a cis-regulatory lymphotoxin-α polymorphism with parasitemia in two independent populations living in Burkina Faso. Analysis of 199 subjects (34 families) living in an urban endemic area revealed the association of the low producing LTA +80A allele with reduced parasitemia. Furthermore, there was evidence of significant LTA +80-by-age and LTA +80-by-gender interactions. In another set of 318 residents (55 families) in a rural endemic area, we found both the association of the low producing LTA +80A allele with reduced parasitemia and LTA +80-by-age and LTA +80-by-gender interactions. This study suggests that LTA +80 polymorphism influences parasitemia and acts in an age- and gender-dependent manner. [Copyright &y& Elsevier]

Abstract: Plasmodium falciparum malaria is a major cause of morbidity and mortality in many developing countries especially in sub-Saharan Africa. A susceptibility locus for mild malaria has been mapped to the MHC region, and TNF polymorphisms have been associated with mild malaria. The Natural Cytotoxicity-triggering Receptor 3 (NCR3) gene is located in the peak region of linkage, and is 15kb distal to TNF. In this study, we considered NCR3 as a candidate gene, and we genotyped ten NCR3 single nucleotide polymorphisms (SNPs). Here, we report evidence of an association between mild malaria and NCR3 −412G>C polymorphism located within the promoter. Population-based association analysis showed that NCR3 −412C carriers had more frequent mild malaria attacks than NCR3 −412GG individuals (P = 0.001). Using the family-based association test (FBAT) program and its phenotype (PBAT) option, we further found that NCR3 −412C (P = 0.0009) and a haplotype containing NCR3 −412C (P = 0.008) were significantly associated with increased risk of mild malaria, and that the association was not due to the association of TNF with mild malaria. These observations suggest that there are at least two genes located on the central region of MHC involved in genetic control of human malaria. The association of NCR3 with malaria should provide new insights into the role of Natural Killer cells in this common disease. [Copyright &y& Elsevier]