A functional promoter variant in IL12B predisposes to cerebral malaria.
Hum Mol Genet
; 17(14): 2190-5, 2008 Jul 15.
Article
em En
| MEDLINE
| ID: mdl-18413324
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regiões Promotoras Genéticas
/
Malária Cerebral
/
Predisposição Genética para Doença
/
Subunidade p40 da Interleucina-12
Tipo de estudo:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Risk_factors_studies
Limite:
Child
/
Humans
Idioma:
En
Revista:
Hum Mol Genet
Assunto da revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
França