Histocompatibility leucocyte antigens and closely linked immunomodulatory genes in autoimmune thyroid disease

Objectives Associations between autoimmune thyroid disease and antigens of the major histocompatibility complex (MHC) have long been recognized. Grave s' disease (GD) is associated with the histocompatibility leucocyte antigen (HLA) haplotype A*01-B*0801-DRB1*0301-DQA1*0501-DQB1*0201 (or B8/DR3) wher eas autoimmune hypothyroidism (AIH) has been weakly associated with HLA DRB 1*03, *04 and *11/*12 alleles (or DR3, DR4 and DR5). However, the presence of important immunoregulatory genes within the HLA Class II and III regions raises the possibility that these genes harbour the primary susceptibility locus. This study examines genetic variation across the MHC in UK Caucasoi d subjects with autoimmune thyroid disease. Patients and Methods DNA extracted from venous blood samples from 215 patie nts with autoimmune thyroid disease (GD 135, AIH 77) and 267 control subjec ts was analysed. Genotyping was performed using polymerase chain reaction a nd sequence specific primers for HLA Class I and II alleles and polymorphis ms within the TAP1, TAP2, tumour necrosis factor (TNF), lymphotoxin alpha ( LT alpha), heat shock protein (HSP)70-1, HSP70-2 and HSP70-Hom genes. Results For GD, the strongest association was with DRB1*03 [56% patients po sitive vs. 24% controls, P = 2 x 10(-10), odds ratio (OR) 4.0]. Positive as sociations were also seen for DRB1*03 linked alleles, B*0801, DRB3*01/02, D QA1*05, DQB1*02 and DPB1*0101 (OR 2.3-3.4). Specific TNF and LT alpha allel es were strongly associated with GD (P-c = 3 x 10(-5) and 0.001) and weak a ssociations were seen for HSP70-1 + 190C and HSP70-2 + 1267G polymorphisms (P-c = 0.05 and 0.01). These associations were not significant when DRB1*03 status was considered. Patients with AIH showed only a weak association wi th DQB1*03 (P = 0.02). Conclusions These results show that, of the polymorphisms tested within the MHC, GD is most strongly associated with DRB1*03, and associations with ot her immunoregulatory genes previously described in Caucasian subjects most likely reflect linkage disequilibrium. AIH differs from GD, being less infl uenced by the MHC region.