Analysis of HLA genes in families with autoimmune diabetes and thyroiditis

Type I diabetes (TID) and autoimmune thyroid disease (AITD) are the most common autoimmune endocrine disorders. The similar pathogenesis of TID and AITD and their tendency to occur together suggest that their etiology may involve common genetic factors. We hypothesized that the human leukocyte antigen (HLA) locus may contribute in part to the joint susceptibility to TID and AITD. We therefore analyzed a data set of 40 multiplex families in which TID and AITD clustered (TID-AITD families) for linkage and association with the HLA class 11 locus. We found evidence for linkage of the HLA region to TID (maximum logarithm of odds score [MLS] = 7.3), to Hashimoto thyroiditis (HT) (MLS = 1.5), and to both (MLS = 3-8). Transmission disequilibrium test analysis revealed significant association of both TID and AITD with HLADR3; however, only TID was associated with HLADR4. We concluded that the finding of evidence for linkage of HLA with HT is in contrast to the strong evidence against linkage found in previous studies of AlTD-only families; therefore, it is possible that the AITD phenotype seen in TID families has a different genetic etiology than the AITD phenotype in AITD-only families; that HLA-DR3 was the major HLA allele contributing to the joint genetic susceptibility to TID and AITD, whereas other alleles (e.g., DR4) are phenotype specific; and that because the logarithm of odds score for TID + HT was lower than for T1D alone, additional non-HLA loci must contribute to the shared genetic susceptibility to TID and AITD. (C) American Society for Histocompatibility and Immunogenetics, 2004. Published by Elsevier Inc.