TY - JOUR
T1 - Regression mapping of association between the human leukocyte antigen region and Graves disease
AU - Simmonds, Matthew J.
AU - Howson, Joanna M.M.
AU - Heward, Joanne M.
AU - Cordell, Heather J.
AU - Foxall, Helen
AU - Carr-Smith, Jackie
AU - Gibson, Sarah M.
AU - Walker, Neil
AU - Tomer, Yaron
AU - Franklyn, Jayne A.
AU - Todd, John A.
AU - Gough, Stephen C.L.
N1 - Funding Information:
We acknowledge the Wellcome Trust, the Juvenile Diabetes Research Foundation, and the special trustees of the former United Birmingham Hospitals for their support. We thank all thyroid-research nurses, for assistance with data collection, and consultants at U.K. thyroid clinics, for access to their patients.
PY - 2005/1
Y1 - 2005/1
N2 - 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 × 10-12, P = 3.20 × 10-5, and P = 9.26 × 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 × 10-4 to 1.2 × 10-12). The strongest association was at position β74. This analysis is consistent with the possibility that position β74 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.
AB - 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 × 10-12, P = 3.20 × 10-5, and P = 9.26 × 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 × 10-4 to 1.2 × 10-12). The strongest association was at position β74. This analysis is consistent with the possibility that position β74 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.
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U2 - 10.1086/426947
DO - 10.1086/426947
M3 - Article
C2 - 15558498
AN - SCOPUS:19944422075
SN - 0002-9297
VL - 76
SP - 157
EP - 163
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -
