Association Between Tumor Necrosis Factor-α Gene-1031T/C,-863C/A Polymorphisms And Thyroid Associated Ophthalmopathy

Objective: To explore the relationship between tumor necrosis factor- (TNF- ) gene-1031T/C, -863C/A polymorphisms and thyroid associated ophthalmopathy(TAO).Methods: TNF- a gene polymorphisms at position -1031 and -863 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 114 patients with autoimmune thyroid disease (AITD) and 76 healthy controls. Patients with AITD were devided into two subgroups: TAO group:54 patients,ATA class 3-6 and AN group:60 patients who had no or mild ophthalmopathy,ATA class 0-2. Because there is no available restriction endonuclease site at the -863 position, we performed PCR using a special primer which had a mismatched nucleotide to form a restriction enzyme site artificially. The difference of their frequencies was analyzed by Chi-square test.Results: (1)There were TNF- a gene -1031T/C and -863C/A polymorphisms in the 190 cases. And the frequencies were not different between male and female in CON and AITD group. But the frequencies of-1031 TC+CC genotype , C allele and -863 CA+AA genotype of female patients were significantly higher than those of male patients in AN group (P<0.05) . (2) The statistic results of-1031 TC+CC genotype and C allele: (1)The frequencies of TC+CC genotype and C allele in AITD group were significantly higher than those in CON group (P=0.021, OR=2.19; P=0.01, OR=2.21). (2)The frequencies of TC+CC genotype and C allele in TAO group were significantly higher than those in AN and CON groups. (TAO vs AN P=0.018 and 0.004, OR=2.56 and 2.62 respectively; TAO vs CON P=0.001 and P<0.001 , OR=3.48 and 3.42 respectively). Furthermore the strength of the association increased with the deteriorating of ophthalmopathy. (3)When the three groups were stratified according to sex, the frequencies of TC+CC genotype and C allele in male TAO patients were notably greater than those in CON group (P=0.019, OR=4.31: P=0.003, OR=4.81) and AN group (P=0.009, OR=7.69; P=0.003, OR=8.27). There were remarkable difference between female TAO patients and CON group,but no statistic difference compared female TAO patients to AN patients. (3) The statistic results of-863 CA+AA genotype and A allele:(1)The frequency of A allele in AITD group was significantly higher than that in CON group (P=0.032, OR=1.87). (2) The frequency of A allele in TAO group was significantly higher than that in CON(P=0.002, OR=2.09) and AN(P=0.018, OR=2.18) groups. Furthermore the frequency increased with the deteriorating of ophthalmopathy (except for ATA 3 patients). The frequency of CA+AA genotype in TAO group was slightly higher than that in AN group but the difference was not statistically significant. (3)When the three groups were stratified according to sex, the frequencies of -863 CA+AA genotype and A allele in male TAO patients were significantly higher than those in CON group(P=0.019, OR=4.31; P=0.003, OR=4.81) and AN group(P=0.027, OR=4.87; P=0.008, OR=5.38). No significant difference was found in female patients. (4) In neither male nor female patients of AN and CON group, significant difference of the frequencies of-1031 and -863 genotype or allele was found.Conclusions: There were TNF- a gene -1031T/C and -863C/A polymorphisms in northern Chinese Han population, and the frequencies were not different in healthy male and female. Both TNF- α gene -1031T/C and -863C/A polymorphism may contribute to the development of TAO in northern Chinese Han population, especially to male patients. And these two gene polymorphisms may predispose to the severity of TAO.