MHC class I chain-related antigen A in mono- and polyglandular autoimmunity

We have evaluated whether the MHC-class-I-chain-related gene A (MICA), being closely located to HLA-B, predisposes for endocrine autoimmunity. It encodes a cell surface protein. The gene shows in its transmembrane segment a GCT repeat encoding 4, 5, 6, or 9 alanine residues (alleles A4, A5, A6, A9), and A5.1 has an additional 1-bp-insertion (GGCT, A5.1). We determined the polymorphism in 48 patients with Graves' disease (GD), 59 with Hashimoto's thyroiditis (HT) and 206 healthy unrelated controls. 43 patients had one endocrinopathy (monoglandular autoimmunity, MGA) and 64 at least two endocrinopathies (polyglandular autoimmunity, PGA). After extraction of genomic DNA from whole blood, the MICA microsatellites were amplified by PCR, and fragment sizes were determined with an automatic DNA sequencer (ABI PRISM 310). The exact test of Fisher and Odds ratios (OR) were applied for group comparisons. We identified the MICA alleles A4, A5, A5.1, A6, and A9 in either homozygous or heterozygous form in 21.5%, 25.2%, 70.1%, 21.5%, 22.4% of patients versus 24.8%, 27.2%, 62.1%, 36.9%, 23.8% of controls, respectively. Patients with GD (14.6%, 33.3%, 70.8%, 18.8%, 22.9%) and HT (27.1%, 18.6%, 69.5%, 23.7%, 22.0%) did not differ in their frequencies. Allele A6 was less frequent in patients (21.5%) than controls (36.9%; OR=0.468, 95%CI=0.273–0.805); this was more pronounced in patients with PGA (18.8%; OR=0.395, 0.198–0.786 vs. controls) than MGA (25.6%; OR=0.671, 0.265–1.700 vs. controls). Allele A5.1 was more frequent in patients with PGA (78.1%) than MGA (58%; OR=2.571, 1.102–6.001) or controls (62.1%; OR=2.176, 1.129–4.195). No significant relationships were observed between thyroid antibodies against TPO and TSH receptor and MICA frequencies. Allele A5.1 creates a frameshift resulting in a premature termination codon in the transmembrane region of the MICA protein, lacking for its cytoplasmatic domain. This truncated protein is regarded as a soluble, secreted form of MICA. These results indicate that the MICA gene influences susceptibility to endocrine autoimmunity.