A functional promoter variant in IL12B predisposes to cerebral malaria.
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.
Marquet
Sandrine
S
INSERM, UMR906, Genetics and Immunology of Parasitic Diseases, Marseille F-13005, France. sandrine.marquet@univmed.fr
Doumbo
Ogobara
O
Cabantous
Sandrine
S
Poudiougou
Belco
B
Argiro
Laurent
L
Safeukui
Innocent
I
Konate
Salimata
S
Sissoko
Sibiri
S
Chevereau
Estelle
E
Traore
Abdoulaye
A
Keita
Mamadou M
MM
Chevillard
Christophe
C
Abel
Laurent
L
Dessein
Alain J
AJ
D002648:Child; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D053762:Interleukin-12 Subunit p40 / Q000235:genetics*; D016779:Malaria, Cerebral / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D053707:Receptors, Interleukin-12 / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000235:genetics
C508858:IL12A protein, human; C500879:IL12B protein, human; C508438:IL12RB1 protein, human; C508439:IL12RB2 protein, human; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human