A functional promoter variant in IL12B predisposes to cerebral malaria

Abstract

The role of the Th1 pathway in the pathogenesis of severe malaria is unclear. We recently reported that a polymorphism with increasing IFNG transcription is associated with protection against cerebral malaria (CM). Interleukin-12 is required for Th1 cell differentiation, which is characterized by the production of interferon-gamma. We investigated 21 markers in IL12-related genes, including IL12A and IL12B encoding the two IL-12 (IL12p70) subunits, IL12p35 and IL12p40. We performed a family-based association study using a total sample set of 240 nuclear families. The IL12Bpro polymorphism was associated with susceptibility to CM. The CTCTAA allele and the GC/CTCTAA genotype are over-transmitted to children with CM (P = 0.0002 and 0.00002, respectively). We estimated the odds ratio to be 2.11 for risk of CM in heterozygous children [(95% confidence interval, 1.49-2.99); P < 0.0001]. Although the CTCTAA allele had a dominant effect on CM susceptibility, this effect is much stronger in heterozygous children, consistent with the functional effects of this allele in a heterozygous form. Heterozygosity for this polymorphism has been associated with reduced expression of the gene encoding IL12p40 and a low level of IL12p70 production. These results, together with the findings from immunological studies of low interferon-gamma and IL-12 levels in CM, support a protective role for the Th1 pathway in CM.

IL-12Rβ2 Is Essential for the Development of Experimental Cerebral Malaria

“…In humans, depending on the populations studied, polymorphisms in promoters or genes coding for IL-12p35 and IL-12p40 have been associated with P. falciparum parasitemia (31), linked with mortality from severe malaria in children (32), associated with protection from severe malaria anemia (33), or associated with susceptibility to cerebral malaria (6).…”

“…IL-12 was implicated in the control of early parasite development (5). Low serum levels of IL-12 and IFN-g have been shown in children with cerebral malaria, supporting a protective role for the Th1 pathway (6). However, a role for Th1 response was reported in the initiation of CNS vascular permeability, a CD8 + T cell perforin-dependent process (7,8).…”

Evidence for epistasis between hemoglobin C and immune genes in human P. falciparum malaria: a family study in Burkina Faso

“…Interestingly, significant multilocus models involved SNPs that were not associated with mild malaria, maximum parasitemia or asymptomatic parasitemia in the population studied: these are TNF-863 and TNF-857 within TNF, 24 IL12Bpro and IL12B 3 0 UTR within IL12B, 26 and IL4-590. Nevertheless, TNF-863, TNF-857, IL12Bpro and IL12B 3 0 UTR have been associated with severe malaria, [27][28][29][30] and IL4-590 has been associated with antibody levels in malaria-infected individuals. 31,32 The statistical epistatic interactions that we detected may correspond to interactions on the biological level.…”

“…25 Table 1 presents the SNPs that were selected on the basis of their association with malaria phenotypes. [22][23][24][27][28][29][30][31][32]46,[53][54][55][56][57] The PGMDR is a score-based multifactor dimensionality reduction method that uses the same data reduction strategy as does the original multifactor dimensionality reduction method to detect nonlinear genetic interactions, 58 that is to classify multilocus genotype combinations as high risk or low risk ones. The original multifactor dimensionality reduction method uses the ratio of cases and controls to identify the combinations of genotypes that show the strongest association with the phenotype.…”

Infectious disease — a genetic view

“…To date more than ten different genes controlling resistance have been identified [5,64], many of which were discovered by case-control studies. These include the genes for globin [65], glucose-6-phosphate dehydrogenase [66], pyruvate kinase [67], erythrocyte protein 3 (SLC4A1) [14], genes for the system of blood groups ABO (glycophorin A, glycophorin B) [68], glycophorin C [69], chemokine receptor Duffy [70], CD36 [71], ICAM1 (intercellular adhesion molecule 1 / CD54) [72], HLA Class I [51], HLA Class II [51], TNF [73], and genes FCGR2A (CD32 -low-affinity receptor for IgG Fc fragment) [74], IFNGRI (interferon gamma receptor 1) [75], IL12B (β chain of the interleukin 12) [76] and NOS2A (inducible nitric oxide synthase) [77] (see Table 1). Some of these will be discussed in more detail because they illustrate mechanisms the body uses to resist infection.…”