Regression mapping of association between the human leukocyte antigen region and Graves disease.
The human leukocyte antigen class II genes DRB1, DQB1, and DQA1 are associated with Graves disease (GD), but, because of strong linkage disequilibrium within this region, the primary etiological variant(s) remains unknown. In the present study, 871 patients with GD and 621 control subjects were genotyped at the DRB1, DQB1, and DQA1 loci. All three loci were associated with GD (P=1.45 x 10(-12), P=3.20 x 10(-5), and P=9.26 x 10(-12), respectively). Stepwise logistic-regression analysis showed that the association could be explained by either DRB1 or DQA1 but not by DQB1. To extend previous results, the amino acid sequence of the exon 2-encoded peptide-binding domain of DRB1 was predicted for each subject, and, by use of logistic regression, each position was analyzed for association with GD. Of 102 amino acids, 70 were uninformative; of the remaining 32 amino acids, 13 were associated with GD (P values ranged from 2.20 x 10(-4) to 1.2 x 10(-12)). The strongest association was at position beta 74. This analysis is consistent with the possibility that position beta 74 of exon 2 of the DRB1 molecule may have a specific and central role in autoantigen presentation by DRB1 to T lymphocytes. However, we cannot yet exclude a primary role for DQA1 or for other polymorphisms that affect DRB1 function or expression.
Simmonds
Matthew J
MJ
Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, and Birmingham Heartlands Hospital, Birmingham B9 5SS, United Kingdom.
Howson
Joanna M M
JM
Heward
Joanne M
JM
Cordell
Heather J
HJ
Foxall
Helen
H
Carr-Smith
Jackie
J
Gibson
Sarah M
SM
Walker
Neil
N
Tomer
Yaron
Y
Franklyn
Jayne A
JA
Todd
John A
JA
Gough
Stephen C L
SC
D016022:Case-Control Studies; D002874:Chromosome Mapping; D005802:Genes, MHC Class II; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D000949:Histocompatibility Antigens Class II; D006801:Humans; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012044:Regression Analysis
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II