Human Molecular Genetics Advance Access published online on April 15, 2008
Human Molecular Genetics, 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 Université de la Méditerranée, Faculty of Medicine Timone Marseille, F-13005, France 3 Malaria Research and Training Center, Department of Epidemiology of Parasitic Disease, Faculty of Medicine, Pharmacy and Odonto-Stomatology, University of 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
* Corresponding author:Dr Sandrine Marquet, Genetics and Immunology of Parasitic Diseases, INSERM UMR906, Faculty of Medicine Timone, 27 Bvd. Jean Moulin, Marseille 13005, France. Phone: +33 4 91 32 45 26, Fax: +33 4 91 79 60 63, e.mail: sandrine.marquet{at}univmed.fr
Received January 8, 2008; Revised April 9, 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 increasing IFNG transcription is associated with protection against cerebral malaria. 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=.0002, P=.00002, respectively). We estimated the OR for risk of CM in heterozygous children to be 2.11 ([95% CI, 1.49-2.99]; P < .0001). Although the CTCTAA allele had a dominant effect on CM susceptibility, this effect is much stronger in heterozygous children, consistent with functional effects of this allele in 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 findings from immunological studies of low IFN- and IL-12 levels in CM, support a protective role for the Th1 pathway in CM.