Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves’ disease

Abstract

Graves' disease (GD) and Hashimoto's thyroiditis (HT) represent the commonest forms of autoimmune thyroid disease (AITD) each presenting with distinct clinical features. Progress has been made in determining association of HLA class II DRB1, DQB1 and DQA1 loci with GD demonstrating a predisposing effect for DR3 (DRB1*03-DQB1*02-DQA1*05) and a protective effect for DR7 (DRB1*07-DQB1*02-DQA1*02). Small data sets have hindered progress in determining HLA class II associations with HT. The aim of this study was to investigate DRB1-DQB1-DQA1 in the largest UK Caucasian HT case control cohort to date comprising 640 HT patients and 621 controls. A strong association between HT and DR4 (DRB1*04-DQB1*03-DQA1*03) was detected (P ¼ 6.79 Â 10 À7 , OR ¼ 1.98 (95% CI ¼ 1.51-2.59)); however, only borderline association of DR3 was found (P ¼ 0.050). Protective effects were also detected for DR13 (DRB1*13-DQB1*06-DQA1*01) (P ¼ 0.001, OR ¼ 0.61 (95% CI ¼ 0.45-0.83)) and DR7 (P ¼ 0.013, OR ¼ 0.70 (95% CI ¼ 0.53-0.93)). Analysis of our unique cohort of subjects with well characterized AITD has demonstrated clear differences in association within the HLA class II region between HT and GD. Although HT and GD share a number of common genetic markers this study supports the suggestion that differences in HLA class II genotype may, in part, contribute to the different immunopathological processes and clinical presentation of these related diseases.

Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents

“…Additionally, our finding of a weak association between TGAb and DQ2 in part confirms previously reported associations between AITD and DQ2 [24,25]. However, our data were not consistent with an association between AITD and HLA-DQB1*03:02 (DQ8) [13,24,37]. The differences in results could partly be explained by the fact that our study was primarily focused on thyroid autoimmunity and not on clinical thyroid disease.…”

“…Our findings, that DQ5.1 was protective for TPOAb and TGAb, confirm the results of a previous study [13]. Additionally, our finding of a weak association between TGAb and DQ2 in part confirms previously reported associations between AITD and DQ2 [24,25]. However, our data were not consistent with an association between AITD and HLA-DQB1*03:02 (DQ8) [13,24,37].…”

“…Our study therefore indicates that primarily HLA-DQ5.1, but perhaps also DQ8, protects children with type 1 diabetes against developing AITD. These results and the association between AITD and DQ2, as earlier described [24,25], draw attention to the probable importance of HLA-DQ alleles for the risk of AITD in type 1 diabetes. However, the associations between thyroid autoimmunity and HLA-DQ were weak and did not fully explain the cooccurrence of islet and thyroid autoimmunity.…”

“…An association between AITD and HLA-DR3 [36], HLA-DR4 [24,37] and DRB1*04-DQB1*03:01 [38] has been reported. In addition, HLA-DR3 and DR3/DQB1*03:02 has also been reported to contribute to both type 1 diabetes and AITD in a study of families with both diseases, while DR4 was associated with type 1 diabetes but not with AITD [25,28,39].…”

Clustering of additional autoimmunity behaves differently in Hashimoto's patients compared with Graves' patients

“…Furthermore, a recent study on Hashimoto's thyroiditis has demonstrated differences in HLA class II associations compared with Graves' disease (5).…”