Assuntos
Mielofibrose Primária/genética , Proteínas de Transporte Vesicular/deficiência , Anormalidades Múltiplas/genética , Transplante de Medula Óssea , Criança , Consanguinidade , Evolução Fatal , Feminino , Disgenesia Gonadal 46 XY/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Linhagem , Fenótipo , Mielofibrose Primária/congênito , Mielofibrose Primária/terapia , Síndrome , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/fisiologiaRESUMO
We mapped the genetic influences for type 1 diabetes (T1D), using 2,360 single-nucleotide polymorphism (SNP) markers in the 4.4-Mb human major histocompatibility complex (MHC) locus and the adjacent 493 kb centromeric to the MHC, initially in a survey of 363 Swedish T1D cases and controls. We confirmed prior studies showing association with T1D in the MHC, most significantly near HLA-DR/DQ. In the region centromeric to the MHC, we identified a peak of association within the inositol 1,4,5-triphosphate receptor 3 gene (ITPR3; formerly IP3R3). The most significant single SNP in this region was at the center of the ITPR3 peak of association (P=1.7 x 10(-4) for the survey study). For validation, we typed an additional 761 Swedish individuals. The P value for association computed from all 1,124 individuals was 1.30 x 10(-6) (recessive odds ratio 2.5; 95% confidence interval [CI] 1.7-3.9). The estimated population-attributable risk of 21.6% (95% CI 10.0%-31.0%) suggests that variation within ITPR3 reflects an important contribution to T1D in Sweden. Two-locus regression analysis supports an influence of ITPR3 variation on T1D that is distinct from that of any MHC class II gene.
Assuntos
Canais de Cálcio/genética , Mapeamento Cromossômico/métodos , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Receptores Citoplasmáticos e Nucleares/genética , Adolescente , Adulto , Centrômero , Criança , Pré-Escolar , Cromossomos Humanos Par 6 , Feminino , Genoma Humano , Haplótipos , Humanos , Lactente , Receptores de Inositol 1,4,5-Trifosfato , Complexo Principal de Histocompatibilidade/genética , Masculino , Polimorfismo de Nucleotídeo Único , SuéciaRESUMO
The 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are a widely used class of drugs for cholesterol reduction. The reduction in mortality and morbidity in statin-treated patients is incompletely explained by their effects on cholesterol, and an anti-inflammatory role for the drug has been proposed. We report in this work that, unexpectedly, simvastatin enhances LPS-induced IL-12p40 production by murine macrophages, and that it does so by activating the IL-12p40 promoter. Mutational analysis and dominant-negative expression studies indicate that both C/EBP and AP-1 transcription factors have a crucial role in promoter activation. This occurs via a c-Fos- and c-Jun-based mechanism; we demonstrate that ectopic expression of c-Jun activates the IL-12p40 promoter, whereas expression of c-Fos inhibits IL-12p40 promoter activity. Simvastatin prevents LPS-induced c-Fos expression, thereby relieving the inhibitory effect of c-Fos on the IL-12p40 promoter. Concomitantly, simvastatin induces the phosphorylation of c-Jun by the c-Jun N-terminal kinase, resulting in c-Jun-dependent activation of the IL-12p40 promoter. This appears to be a general mechanism because simvastatin also augments LPS-dependent activation of the TNF-alpha promoter, perhaps because the TNF-alpha promoter has C/EBP and AP-1 binding sites in a similar configuration to the IL-12p40 promoter. The fact that simvastatin potently augments LPS-induced IL-12p40 and TNF-alpha production has implications for the treatment of bacterial infections in statin-treated patients.
