<Backgrounds> Type 1 diabetes (T1D) is an organ-specific autoimmune disease against pancreatic beta-cells in genetically susceptible individuals. A susceptibility gene contributing to organ-specificity, such as INS, confers susceptibility to T1D only, whereas genes contributing to immune regulation, such as CTLA4 and PTPN22, confer susceptibility to multiple autoimmune diseases including autoimmune thyroid disease (AITD). AITD and alopecia areata (AA) are organ-specific autoimmune diseases against thyroid and hair follicles. To clarify susceptibility genes contributing to organ-specificity in T1D, we studied the association of candidate genes with T1D, AITD and AA in relation to positivity of islet-related autoantibody.
<Methods> A total of 461 cases (161 patients with T1D, 190 patients with AITD, and 110 patients with AA) and 209 control subjects were studied. INS (-23HpnI), CTLA4 (rs3087243), PTPN22 (rs2476601, R620W), FCRL3 (rs7528684), IFIH1 (rs1990760), MAFA (rs62521874), HLA DRB1 and DQB1 were genotyped.
<Results> INS was associated with T1D (OR [95%CI]: 0.20 [0.10-0.38], p=0.00001), but not with AITD (OR: 0.86, NS) nor AA (OR: 1.00, NS). MAFA was associated with T1D (OR [95%CI]: 0.51[0.33-0.78], p<0.002), but not with AITD (OR: 0.6, NS) nor AA (OR: 1.00, NS). CTLA4 was associated with AITD (OR [95%CI]: 1.45[1.14-1.84], p<0.003), but not with T1D (OR: 1.08, NS) nor AA (OR: 0.93, NS). The SNP (R620W) of PTPN22 was not identified in any subjects we tested. FCRL3 was associated with AITD (OR [95%CI]: 1.37[1.03-1.81], p<0.03), but not with T1D (OR: 1.11, NS) nor AA (OR: 0.97, NS). IFIH1 was associated with AITD (OR [95%CI]: 1.40[1.02-1.91], p=0.04), but not with T1D (OR: 1.02, NS) nor AA (OR: 1.3, NS). DRB1*04:05-DQB1*04:01 was associated with AITD patients with islet-related autoantibody, and DRB1*08:03-DQB1*06:01 was associated with those without.
<Conclusion> These data suggest that INS, MAFA and HLA DRB1*04:05-DQB1*04:01 contribute to beta-cell-specific autoimmunity, whereas CTLA4, FCRL3, IFIH1 and DRB1*08:03-DQB1*06:01 contribute to thyroid-related autoimmunity.