Histocompatibility leucocyte antigens and closely linked immunomodulatory genes in autoimmune thyroid disease.
OBJECTIVE
Associations between autoimmune thyroid disease and antigens of the major histocompatibility complex (MHC) have long been recognized. Graves' disease (GD) is associated with the histocompatibility leucocyte antigen (HLA) haplotype A*01-B*0801-DRB1*0301-DQA1*0501-DQB1*0201 (or B8/DR3) whereas autoimmune hypothyroidism (AIH) has been weakly associated with HLA DRB1*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 Caucasoid subjects with autoimmune thyroid disease.


METHODS
DNA extracted from venous blood samples from 215 patients with autoimmune thyroid disease (GD 135, AIH 77) and 267 control subjects was analysed. Genotyping was performed using polymerase chain reaction and sequence specific primers for HLA Class I and II alleles and polymorphisms within the TAP1, TAP2, tumour necrosis factor (TNF), lymphotoxin alpha (LTalpha), heat shock protein (HSP)70-1, HSP70-2 and HSP70-Hom genes.


RESULTS
For GD, the strongest association was with DRB1*03 [56% patients positive vs. 24% controls, P = 2 x 10(-10), odds ratio (OR) 4.0]. Positive associations were also seen for DRB1*03 linked alleles, B*0801, DRB3*01/02, DQA1*05, DQB1*02 and DPB1*0101 (OR 2.3-3.4). Specific TNF and LTalpha alleles were strongly associated with GD (Pc = 3 x 10(-5) and 0.001) and weak associations were seen for HSP70-1 + 190C and HSP70-2 + 1267G polymorphisms (Pc = 0.05 and 0.01). These associations were not significant when DRB1*03 status was considered. Patients with AIH showed only a weak association with 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 other immunoregulatory genes previously described in Caucasian subjects most likely reflect linkage disequilibrium. AIH differs from GD, being less influenced by the MHC region.
Hunt
P J
PJ
Department of Endocrinology, Radcliffe Infirmary, Oxford, Oxford Transplant Centre, Churchill Hospital, Oxford, UK.
Marshall
S E
SE
Weetman
A P
AP
Bunce
M
M
Bell
J I
JI
Wass
J A
JA
Welsh
K I
KI
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D026905:Amino Acid Transport Systems; D016022:Case-Control Studies; D005095:Exoribonucleases / Q000235:genetics; D005260:Female; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D029701:Saccharomyces cerevisiae Proteins; D013967:Thyroiditis, Autoimmune / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D026905:Amino Acid Transport Systems; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D018840:HSP70 Heat-Shock Proteins; D008233:Lymphotoxin-alpha; D029701:Saccharomyces cerevisiae Proteins; C429825:TAT2 protein, S cerevisiae; D014409:Tumor Necrosis Factor-alpha; C071692:TAP2 protein, human; D005095:Exoribonucleases