HLA DQ2 and/or DQ8 Is Associated With Celiac Disease–Specific Autoantibodies To Tissue Transglutaminase in Families With Thyroid Autoimmunity

TO THE EDITOR: Celiac disease (CD) is characterized by a T cell–mediated destruction of intestinal architecture that can lead to global malabsorption but presents with atypical symptoms in the majority of patients. In CD the ingestion of dietary gluten and related cereals drives intestinal inflammation and a mucosal autoimmune response to the ubiquitous enzyme tissue transglutaminase (tTG) (1, 2). Interestingly, tTG can potentiate gluten antigen presentation and immunogenicity in genetically predisposed individuals bearing the CD-predisposing major histocompatibility complex human leukocyte antigen (HLA) DQ2 or DQ8, which is found in 95% and 5% of patients, respectively (2, 3). Long-lasting CD is associated with a variety of autoimmune diseases, mainly type 1 diabetes and dermatitis herpetiformis (4). Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are the most common autoimmune disorders. They affect more than 2% of the female population in the US. These autoimmune endocrinopathies occur frequently in patients and relatives with other autoimmune diseases, such as type 1 diabetes mellitus or CD, sharing immunogenetic susceptibility loci on chromosome 6p. Thus the haplotype allele DQA1*0501 of the HLA DQ2 heterodimer DQA1*0501/ DQB1*0201, and the HLA DQ8 heterodimer DQA1*0301/ DQB1*0302, characteristic for CD patients, are also frequently found in patients with type 1 diabetes mellitus or GD (5). An association of CD with thyroid autoimmunity has been reported in patients from Italy, Finland, and the US (6–9). Because IgA autoantibodies to tTG (tTG-Ab) are a sensitive, highly specific tool for detecting atypical or subclinical CD, we measured the prevalence of these autoantibodies in patients and families with thyroid autoimmune diseases and correlated the findings with HLA DQ status. We enrolled 105 patients with thyroid autoimmune disorders (81 with GD, 24 with HT) and 95 of their first degree relatives (43 fathers, 43 mothers, and nine siblings). The diagnosis of GD was based on hyperthyroidism with thyroid stimulating hormone receptor autoantibodies, and that of HT on hypothyroidism with thyroid peroxidase autoantibodies. tTG-Ab were measured as described (10), and HLA DQA1 and DQB1 alleles determined by polymerase chain reaction (5). There was one patient with HT and known CD who also suffered from type 1 diabetes. This patient displayed high titer tTG-Ab (93 U). Another patient with HT showed a slightly elevated titer (12 U). With these two patients a prevalence of 8% among the studied patients with HT was found, whereas we did not detect tTG-Ab among patients with GD. However, five of 43 fathers (12%) and one mother (2%) of the patients with GD had slightly or clearly elevated tTG-Ab (n 5 5, 10–17 U; n 5 1, 41 U, respectively). Three of the six (50%) tTG-Ab positive parents had the HLA DQ2 specificity, as compared with only 20 of 80 (25%) of the tTG-Ab negative parents (reflecting the frequency in the normal population) (Table 1). Furthermore, these alleles were inherited by their children who had GD. In addition, HLA DQ2 and/or DQ8 were found in all five tTG-Ab positive fathers, as compared with only 17 of 38 (45%) tTG-Ab negative fathers (p 5 0.02). Remarkably, the single patient who displayed both HLA DQ2 and HLA DQ8 suffered from triple autoimmunity (type I diabetes, GD, and CD). The finding that unaffected parents of patients with autoimmune disorders transmit the susceptibility genes to their