Contribution of MIC-A polymorphism to type 1 diabetes mellitus in Basques

The maximum genetic susceptibility to type 1 diabetes (T1DM) in Basques is conferred by extended HLA haplotype F1C30-DR3-DQ2-DPB1*0202. Due to the strong linkage disequilibrium within the haplotype, it is difficult to determine which individual allele shows the strongest association with T1DM. Recent studies of the MIC-A gene have shown an HLA-independent association of allele A5 with T1DM and A5.1 with Addison's disease. In order to test for association of the MIC-A exon 5 polymorphism with T1DM and to further characterize risk and protection haplotypes in Basques, we typed 70 Basque families with T1DM for MIC-A exon 5 polymorphism using fluorescent PCR and electrophoresis on an ABI sequencing machine. When analyzed individually, allele A4 was associated with disease [OR = 2.93 (1.58-5.5)], while the presence of A9 conferred protection from T1DM [OR = 0.27 (0.08-0.74)]. In the context of HLA haplotypes, allele A4 was found to be associated to the F1C30-DR3-DQ2-DPB*0202 risk haplotype, both for T1DM and AFBAC alleles (P(c) = 0.0003). Allele A5.1 was strongly associated with protective haplotype SC31-DRB1*1501-DQB1*0602, present only in AFBAC alleles, but also with risk haplotype SC01-DR3-DQ2. In conclusion, polymorphisms in exon 5 of the MIC-A gene are associated with genetic susceptibility/protection to T1DM, but in the context of susceptibility HLA haplotypes. Nevertheless, the protective effect of A9 allele seems independent from HLA, since it does not appear to be associated with any particular extended haplotype.