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DRB1¹04 and DQ Alleles: Expression of 21-Hydroxylase Autoantibodies and Risk of Progression to Addison’s Disease^,1

Barbara Davis Center for Childhood Diabetes (L.Y., K.W.B., T.W., S.R.B., P.A.G., M.J.R., G.S.E.) and Clinical Immunology and Histocompatibility Laboratory (B.M.F.), University of Colorado, Denver, Colorado 80262; Stratton Veterans Affairs Medical Center (S.G., A.W.), Albany, New York 12208; and Roche Molecular Systems (H.A.E.), Alameda, California 95401

Address all correspondence and requests for reprints to: George S. Eisenbarth, M.D., Ph.D., Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box B140, Denver, Colorado 80262. E-mail: george.eisenbarth{at}uchsc.edu

Of 957 patients with type 1 diabetes without known Addison’s disease 1.6% (n = 15) were positive for 21-hydroxylase autoantibodies. Among DQ8/DQ2 heterozygous patients, the percentage expressing 21-hydroxylase autoantibodies was 5% (10 of 208) vs. less than 0.5% of patients with neither DQ8 nor DQ2. Three of the diabet-ic patients found to have 21-hydroxylase autoantibodies on screen-ing were subsequently diagnosed with Addison’s disease. Overall, the genotype DQ8/DQ2, consisting of DRB1*0404/DQ8 with DRB1*0301/DQ2, was present in 14 of 21 patients with Addison’s disease (8 of 12 with diabetes and 6 of 9 without diabetes or antiislet autoantibodies) vs. 0.7% of the general population (109 of 15,547; P < 10^-6) and 11% of patients with DM without Addison’s disease (62 of 578; P < 10^-6). Among patients with diabetes with DQ8, Addison’s disease was strongly associated with the specific DRB1 subtype, DRB1*0404 (8 of 9 patients from 8 families, in contrast to only 109 of 408 DQ8 DM patients with diabetes without Addison’s disease having DRB1*0404; P < 0.001). Among 21-hydroxylase autoantibody-positive DQ8 patients, 80% with DRB1*0404 (12 of 15) had Addison’s disease, in contrast to 1 of 10 autoantibody-positive patients with DRB1*0401 or DRB1*0402 (P < 0.001). We conclude that patients with DRB1*0404 and 21-hydroxylase autoantibodies are at high risk for Addison’s disease. Patients with DRB1*0401 and DRB1*0402 have more limited progression to Addison’s disease despite the presence of 21-hydroxylase autoantibodies.

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