Journal Article

A functional promoter variant in <i>IL12B</i> predisposes to cerebral malaria

Sandrine Marquet, Ogobara Doumbo, Sandrine Cabantous, Belco Poudiougou, Laurent Argiro, Innocent Safeukui, Salimata Konate, Sibiri Sissoko, Estelle Chevereau, Abdoulaye Traore, Mamadou M. Keita, Christophe Chevillard, Laurent Abel and Alain J. Dessein

in Human Molecular Genetics

Volume 17, issue 14, pages 2190-2195
Published in print July 2008 | ISSN: 0964-6906
Published online April 2008 | e-ISSN: 1460-2083 | DOI:
A functional promoter variant in IL12B predisposes to cerebral malaria

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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-γ. 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-γ and IL-12 levels in CM, support a protective role for the Th1 pathway in CM.

Journal Article.  3709 words. 

Subjects: Genetics and Genomics

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