Microsatellite polymorphism of the MHC class I chain-related (MIC-A and MIC-B) genes marks the risk for autoimmune Addison's disease

The major histocompatibility complex class I chain-related MIG-A and MIC-B genes are located on chromosome 6 between the histocompatibility leucocyte antigen (HLA)-B and the B-associated transcript genes. The presence of 21-h ydroxylase autoantibodies is a sensitive acid specific marker of autoimmune Addison's disease. We studied the pulymorphism of exon 5 of the MIG-A gene , of intron 1 of the MIC-B gene, and of HLA-DRB1, -DQA1, and -DQB1 genes in 28 autoimmune (21-hydroxylase autoantibody positive) Addison's disease pat ients and in 75 healthy subjects from central Italy. The MIC-A5.1 allele wa s significantly more frequent in Addison's disease patients (79%) than in h ealthy subjects (36%) [odds ratio (OR) = 6.52, corrected P (Pc) = 0.0015],w hereas MIC-AG was significantly reduced in affected subjects (15% us. 56%, OR = 0.13, Pc = 0.002). The A5.1/ A5.1 genotype had an OR for autoimmune Ad dison's disease as high as 18.0 and an absolute risk of 1 per 1131. In the presence of MIC-A5.1, MICB-CA-25 was significantly increased in Addison's d isease pa tients (259 us. 4%, OR = 8.0, P = 0.0039, Pc = 0.047). The MICB-C A-17 allele was absent in Addison's disease patients, but present in more t han 25% healthy individuals (OR = 0.10, P = 0.0025, Pc = 0.03). Among HLA-D R and -DQ haplotypes, only DRB1*03-DQA1*0501-DQB1*C0201 (DR3/DQ2) was signi ficantly more frequent in Addison's disease patients than in healthy subjec ts, but only in the presence of MIC-A5.1. The frequency of MIC-A5.1 was sig nificantly increased in Addison's disease patients only in the presence of HLA-DR3-DQ2. Our study demonstrates that susceptibility to autoimmune Addis on's disease is linked to the MIG-A microsatellite allele 5.1 and that both MIC-A5.1 and HLA-DR3/DQ2 are necessary to confer increased genetic risk fo r Addison's disease.