Human Molecular Genetics Advance Access originally published online on April 15, 2008
Human Molecular Genetics 2008 17(14):2190-2195; doi:10.1093/hmg/ddn118
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A functional promoter variant in IL12B predisposes to cerebral malaria
1 INSERM, UMR906, Genetics and Immunology of Parasitic Diseases, Marseille F-13005, France 2 Faculty of Medicine Timone, Université de la Méditerranée, Marseille F-13005, France 3 Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Odonto-Stomatology, Department of Epidemiology of Parasitic Disease, University of Bamako, Bamako, Mali 4 Paediatric Wards, Gabriel Toure Hospital, Bamako, Mali 5 INSERM, U550, Laboratory of Human Genetics of Infectious Diseases, Necker Medical School, University of Paris René Descartes, Paris, France
* To whom correspondence should be addressed at: INSERM, UMR906, Genetics and Immunology of Parasitic Diseases, Faculty of Medicine Timone, 27 Bvd. Jean Moulin, Marseille 13005, France. Tel: +33 491324526; Fax: +33 491796063; Email: sandrine.marquet{at}univmed.fr
Received January 8, 2008; Accepted April 9, 2008
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-
. 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- and IL-12 levels in CM, support a protective role for the Th1 pathway in CM.