Association of IFNG gene methylation in peripheral blood cells with the development and prognosis of autoimmune thyroid diseases

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 + 2109 T (CT + 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.