Associations of TNFRSF1A Polymorphisms with Autoimmune Thyroid Diseases: A Case-Control Study.

Previous studies have shown associations of polymorphisms in the tumor necrosis factor (TNF) receptor super family member 1A (TNFRSF1A) gene with several groups of inflammatory and autoimmune related diseases, but associations of TNFRSF1A polymorphisms with autoimmune thyroid diseases (AITD), mainly including two sub-types of Hashimoto's thyroiditis (HT) and Graves' disease (GD), in the Chinese Han population is unclear. A case-control study of 1812 subjects (965 AITD patients and 847 unrelated healthy controls) was conducted to assess AITD associations with five single nucleotide polymorphisms (SNPs), including rs4149576, rs4149577, rs4149570, rs1800693, and rs767455 in the TNFRSF1A gene locus. Genotyping was performed and evaluated using the platform of ligase detection reaction. No significant difference was observed in the allele and genotype frequencies between HT or GD patients and controls in any of the five SNPs in the TNFRSF1A gene (all p values >0.05). However, a moderate association of rs4149570 with HT was found after adjusting for age and gender [odds ratio (OR)=1.40, p=0.03]. No obvious difference was found in the haplotype distribution of any of the five SNPs in the TNFRSF1A gene between the AITD patients and controls. These data suggest that these five SNPs in the TNFRSF1A gene are not associated with AITD in the Chinese Han population, but rs4149570 shows a weak association with HT after adjusting for gender and age.

Tumor necrosis factor receptor-associated factor 1 (TRAF1) polymorphisms and susceptibility to autoimmune thyroid disease.

Former studies have revealed the link between the tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) polymorphisms and autoimmunity. In the present study, we took an opportunity to investigate the association between TRAF1 and autoimmune thyroid disease (AITD) in order to find a new susceptibility gene. A total of 1029 AITD patients [677 Graves' disease (GD) patients and 352 Hashimoto thyroiditis (HT) patients] and 899 controls were enrolled. We used matrix-assisted laser desorption ionization-time of flight mass spectrometer (MALDI-TOF-MS) to detect the polymorphisms of rs4836834, rs10760130, rs10818488, rs2239658, rs2900180. We also explored the association between polymorphisms and clinical subphenotypes. Genotype frequencies of the five loci in all AITD patients were significantly different from those of controls. Genotype frequencies of rs10760130, rs2239658 and rs2900180 in GD patients were significantly different from controls. Allele analysis found that T allele of rs4836834, G allele of rs10760130, A allele of rs10818488, T allele of rs2239658 and T allele of rs2900180 were significantly higher in GD and AITD patients. No significant differences were found between HT patients and controls. Haplotype analysis found three haplotypes including ACAGC, TTGAT and TCGAC. ACAGC frequencies were significantly lower in GD and HT patients. However, TTGAT frequency was only significantly higher in GD patients. No significant results were found between polymorphisms and clinical subphenotypes. Our study reveals TRAF1 as a susceptibility gene of AITD in Chinese Han population.

Differential cytokine expression detected by protein microarray screening in peripheral blood of patients with refractory Graves' disease.

OBJECTIVE: The prognosis of Graves' disease (GD) varies among patients. However, the immune pathogenesis of refractory GD is still unknown. The aim of this study was to explore the cytokine expression profile associated with refractory GD. METHODS: Preliminary cytokine protein microarray screening was performed to detect differentially expressed cytokines in the plasma of four patients with refractory GD and four patients with stable GD. Some differentially expressed cytokines were then validated in plasma by enzyme-linked immunosorbent assay (ELISA) and in peripheral blood mononuclear cells (PBMCs) by quantitative real-time polymerase chain reaction (qRT-PCR) on another independent set of samples. RESULTS: We found that 21 cytokines were differentially expressed between patients with intractable GD and those in remission, including 18 upregulated and 3 downregulated cytokines with a fold change >1·30 and <0·77, respectively. Intractability-related elevation of three cytokines (IL-4, IL-6 and IL-10) was validated by ELISA in plasma on another GD cohort with 30 patients in recurrence and 14 in remission (t-test, P = 0·035, 0·033 and 0·041, respectively). Furthermore, mRNA expression of IL-4, IL-6 and IL-10 in PBMCs, detected by qRT-PCR, was significantly elevated in patients with refractory GD compared with those in remission (P = 0·039, 0·047 and 0·042, respectively). CONCLUSION: The severity of GD is associated with the aberrant expression and secretion of several cytokines that may serve as potential biomarkers and predictors for disease prognosis. Targeting these cytokines or their receptors may also lead to a novel therapeutic intervention for GD.

Variants in IRAK1-MECP2 region confer susceptibility to autoimmune thyroid diseases.

Our objective was to investigate whether interleukin-1 receptor-associated kinase (IRAK1) and methyl-CpG-binding protein 2 (MECP2) are associated with autoimmune thyroid diseases (AITDs). We selected four single nucleotide polymorphisms (SNPs), rs3027898, rs1059703 in IRAK1 and rs2075596, rs2239464 in MECP2, for genotyping using PCR-based ligase detection reaction (LDR) method in 1042 AITDs patients and 897 controls. Minor alleles in the four SNPs were strongly associated with AITDs, and similar associations were found in Graves' disease (GD). In Hashimoto's thyroiditis (HT) patients, a significantly increased risk of T allele in rs1059703 was found. There were obvious differences in allele and genotype distributions in female AITDs, GD and HT patients. Moreover, the haplotypes CCAA and ATGG were the associated variants for AITDs and GD. Besides, these two haplotypes showed similar associations with AITDs and GD in female patients. Our results firstly indicated that IRAK1 and MECP2 genes are crucial risk factors for AITDs.

Polymorphisms of the TNFAIP3 region and Graves' disease.

Autoimmune thyroid disease (AITD) is a multifactorial organ-specific autoimmune disorder, and both genetic susceptibility and environmental factors are involved in its etiology. TNFAIP3 encodes the ubiquitin-modifying enzyme (A20), a key regulator of inflammatory signaling pathways. The aim of the present study was to evaluate the association between TNFAIP3 gene polymorphisms and AITD in Chinese Han population. Three single nucleotide polymorphisms (SNPs) in TNFAIP3 gene locus (rs598493, rs610604 and rs661561) were detected in a set of 667 patients with AITD and 301 controls in Han Chinese population using the Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform. Compared with those of the controls, the frequencies of GG genotype of rs598493, the AA genotype of rs610604, the allele G and GG genotype of rs661561 were significantly increased in Graves' disease (GD) patients. However, the frequencies of AG genotype of rs598493 and AC genotype of rs610604 were significantly decreased in GD patients. The ATC haplotype (rs598493, rs661561 and rs610604) was associated with a decreased risk of GD. No significant differences in the three SNPs were observed between HT patients and controls. Our study shows a clear association between the polymorphisms of TNFAIP3 gene and GD, not HT, suggesting that TNFAIP3 gene is likely to be a genetic susceptibility factor to GD.