The association between IL-1RA gene, TNF-beta gene, TNF-alpha gene, IL-4 gene and IFN-gamma gene with graves disease in Thai

Abstract

Graves{174} disease (GD) is an organ-specific autoimmune disease affecting the thyroid gland, resulting in excessive secretion of thyroid hormone. The etiologic factors identified for GD include both environmental and genetic factors. A genetic contribution to disease was supported by the fact that the incidence of GD in monozygotic twins are much higher than dizygotic twins. Previous studies reported the association between GD with several candidate genes such as human leukocyte antigen and cytotoxic T-lymphocyte antigen-4 gene, but the explanation of this association is still unclear. Cytokine play a key role in the regulation of immune and inflammatory responses and therefore are another potential candidate genes for GD. Since polymorphisms in cytokine genes may effect gene transcription, causing individual variations in cytokine production, the aim of this study was to investigate the polymorphisms of IL-1Ra gene, TNF-alpha gene, TNF-beta gene, IL-4 gene and IFN-gamma gene in patients with GD compare with control group and determine the association with GD in Thai population. This population-based case-control study included 137 GD patients and 137 healthy control subjects with similar ethnic and geographic background. IL-1Ra and IFN-gamma gene polymorphisms were identified by using polymerase chain reaction (PCR) and PCR-sequence-specific primer (SSP), respectively. TNF-alpha, TNF-beta and IL-4 gene polymorphisms were detected by PCR-restriction fragment length polymorphism (RFLP). As the results, only the -863A allele within TNF- alpha gene, which has the effect on the binding affinity to NF-kappa B complex, was found to be significantly increased in GD patients compared to healthy controls (p=0.009, OR=1.8, 95% CI=1.15 to 2.84). The effect of -863A allele of TNF- alpha gene was similar to autosomal dominance mode of inheritance. The presence of one A allele (AA or AC) conferred the significant OR of 2 (p=0.01, 95% CI=1.16 to 3.44). There were no statistically significant difference between the study groups for the other cytokine gene polymorphisms. In conclusion, the -863 polymorphism in the promoter region of the TNF- alpha gene is the marker for genetic susceptibility to GD in Thai population, which may be involved in susceptibility to GD in part through their higher promoter activity of TNF-alpha production.