RESUMEN
The prognosis of autoimmune thyroid diseases (AITDs), including Hashimoto's disease (HD) and Graves' disease (GD), is difficult to predict. DNA methylation regulates gene expression of immune mediating factors. Interleukin (IL)-10 is a Th2 cytokine that downregulates inflammatory cytokines produced by Th1 cells. To clarify the role of methylation of the IL10 gene in the prognosis of AITD, we evaluated the methylation levels of two CpG sites in the IL10 promoter using pyrosequencing. The methylation levels of the -185 CpG site of the IL10 gene were related to age and GD intractability in GD patients. Furthermore, the C carrier of the IL10-592 A/C polymorphism was related to low methylation levels of the -185 CpG site. The methylation levels of the IL10-185 CpG site of the IL10 gene were related to the intractability of GD and were lower in individuals with the C allele of the IL10-592 A/C polymorphism.
Asunto(s)
Islas de CpG , Metilación de ADN , Enfermedad de Graves , Interleucina-10 , Regiones Promotoras Genéticas , Humanos , Enfermedad de Graves/genética , Enfermedad de Graves/inmunología , Enfermedad de Graves/sangre , Interleucina-10/genética , Femenino , Adulto , Masculino , Persona de Mediana Edad , Islas de CpG/genética , Regiones Promotoras Genéticas/genética , Polimorfismo de Nucleótido Simple , Anciano , Adulto Joven , Predisposición Genética a la EnfermedadRESUMEN
Autoimmune thyroid diseases (AITDs), including Hashimoto's disease (HD) and Graves' disease (GD), are archetypes of organ-specific autoimmune diseases, but the prognosis of patients with AITD varies. Autoimmune diseases, including AITDs, are believed to develop in response to both genetic and environmental factors. Interleukin (IL)-6 plays a major role in B cell differentiation and T cell proliferation, and methylation of the IL6 gene is associated with IL-6 production. To clarify the role of IL6 gene methylation in the pathogenesis and prognosis of AITDs, we measured the methylation levels of -666, -664, -610, -491 and -426 CpG sites in the IL6 gene. We measured the methylation levels of 5 CpG sites in 29 patients with HD, 31 patients with GD and 16 healthy volunteers using pyrosequencing. The methylation level at each of the -664, -491 and -426 CpG sites was negatively correlated with the age at the time of sampling. Multiple regression analysis indicated that patients with HD, including severe or mild HD, showed higher methylation levels at the -426 CpG site than control subjects. Patients with intractable GD showed lower methylation levels at the -664 and -666 CpG sites than patients with GD in remission. In conclusion, IL6 gene methylation levels were related to the susceptibility to HD and the intractability of GD.
Asunto(s)
Metilación de ADN , Predisposición Genética a la Enfermedad , Enfermedad de Graves/genética , Enfermedad de Hashimoto/genética , Interleucina-6/genética , Adulto , Anciano , Alelos , Antitiroideos/uso terapéutico , Autoanticuerpos/sangre , Estudios de Casos y Controles , Islas de CpG , Progresión de la Enfermedad , Femenino , Expresión Génica , Frecuencia de los Genes , Enfermedad de Graves/diagnóstico , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/inmunología , Enfermedad de Hashimoto/diagnóstico , Enfermedad de Hashimoto/tratamiento farmacológico , Enfermedad de Hashimoto/inmunología , Humanos , Interleucina-6/sangre , Interleucina-6/inmunología , Masculino , Metimazol/uso terapéutico , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas , Índice de Severidad de la Enfermedad , Tirotropina/sangre , Tirotropina/inmunología , Tiroxina/sangre , Tiroxina/inmunología , Tiroxina/uso terapéutico , Triyodotironina/sangre , Triyodotironina/inmunologíaRESUMEN
The intractability of Graves' disease (GD) and the severity of Hashimoto's disease (HD) vary among patients. Both genetic and environmental factors may be associated with their prognoses. To clarify the role of methylation of the IFNG gene in the pathogenesis and prognosis of (AITDs), we examined interferon gamma (IFNG) methylation levels at various CpG sites and genotyped IFNG +874 A/T and +2109 C/T polymorphisms. We analyzed methylation 59 patients with HD, 57 patients with GD and 26 healthy volunteers by pyrosequencing. We genotyped IFNG gene polymorphisms from 207 patients with GD, 208 patients with HD, and 102 healthy controls. The methylation levels of IFNG -54 CpG were higher in patients with intractable GD than in those with GD in remission, but there was no difference between patients with severe and mild HD. In carriers of IFNG +2109â¯T (CTâ¯+â¯TT) (85.5% in controls), the -54 CpG methylation levels were significantly higher in patients with intractable GD than in those with GD in remission. On the other hand, in carriers of IFNG +2109 CC, the -4293 CpG methylation levels were higher in intractable GD patients. The methylation levels of IFNG -54 CpG and -4293 CpG were negatively correlated with the age in HD, especially severe HD, patients and GD patients, respectively. There was no circadian variation but considerable daily variation in the methylation levels of IFNG -54 CpG. In conclusion, both the methylation levels of CpG sites and the functional polymorphisms in the IFNG gene were associated with the pathogenesis and prognosis of AITD, especially with GD intractability.