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Linkage Disequilibrium between the Human Leukocyte Antigen Class II Region of the Major Histocompatibility Complex and Graves’ Disease: Replication Using a Population Case Control and Family-Based Study¹

Department of Medicine, University of Birmingham, Queen Elizabeth Hospital (J.M.H., A.A., J.D., J.C.-S., A.D., M.C.S., A.H.B., J.A.F., S.C.L.G.), Birmingham, United Kingdom; Royal Bournemouth Hospital (M.A.), Bournemouth, United Kingdom; and Birmingham Heartlands Hospital (P.M.D., A.H.B., S.C.L.G.), Birmingham, United Kingdom B9 5SS

Address all correspondence and requests for reprints to: Dr. Stephen C. L. Gough, Department of Medicine, University of Birmingham, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, United Kingdom B9 5SS. E-mail: s.c.gough{at}bham.ac.uk

Early case control studies found association of the DRB1 allele, DR3, with Graves’ disease (GD). Recent reports, claim the DQA1 allele, DQA1*0501, to be the primary susceptibility determinant within the human leukocyte antigen (HLA) class II region. We typed 228 GD patients, 364 controls, and 98 families (parents, GD, and unaffected sibling) at the DRB1, DQB1, and DQA1 loci. The case control study showed an increased frequency in GD, compared to controls, of DRB1*0304 (47% vs. 24%; pc < 1.4 x 10^-5), DQB1*02 (58% vs. 46%; pc < 0.035), DQB1*0301/4 (42% vs. 28%; pc < 3.5 x 10^-3) and DQA1*0501 (67%, vs. 39%; pc < 7 x 10^-6). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) vs. controls (24%; pc < 1.8 x 10^-5; odds ratio = 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to GD siblings (72%) was seen in the families (² = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected siblings (53%; ² = 0.19; 1 d.f.; P = NS) excluded segregation distortion. These results show that linkage disequilibrium between GD and the HLA class II region is due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.

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