OBJECTIVE-The nonclassical major histocompatibility complex (MHC) class I chain-related molecules (MICs), encoded within the MHC, function in immunity. The transmembrane polymorphism in MICA (MICA-STR) has been reported to be associated with type 1 diabetes. In this study, we directly sequenced both of the highly polymorphic MIC genes (MICA and MICB) in order to establish whether they are associated with type 1 diabetes independently of the known type 1 diabetes MHC class II genes HLA-DRB1 and HLA-DQB1.
RESEARCH DESIGN AND METHODS-We developed a sequencing-based typing method and genotyped MICA and MICB in 818 families (2,944 individuals) with type 1 diabetes from the U.K. and U.S. (constructing the genotype from single nucleotide polymorphisms in exons 2-4 of MICA and 2-5 of MICB) and additionally genotyped the MICA-STR in 2,023 type 1 diabetic case subjects and 1,748 control subjects from the U.K. We analyzed the association of the MICA and MICB alleles and genotypes with type 1 diabetes using regression methods.RESULTS-We identified known MICA and MICB alleles and discovered four new MICB alleles. Based on this large-scale and detailed genotype data, we found no evidence for association of MICA and MICB with type 1 diabetes independently of the MHC class II genes (MICA P Ï 0.08, MICA-STR P Ï 0.76, MICB P Ï 0.03, after conditioning on HLA-DRB1 and HLA-DQB1). A pproximately 50% of the familial clustering of type 1 diabetes is attributable to the major histocompatibility complex (MHC) region on human chromosome 6p21, and the MHC class II genes HLA-DRB1 and HLA-DQB1 account for a large proportion of this clustering (1). However, association studies in the MHC region indicate that other genes have effects in type 1 diabetes independently of the class II genes (2-4). Identification of these genes is complicated because genes in the MHC have multiple alleles and exhibit extensive linkage disequilibrium (LD), and the class II genes HLA-DQB1 and HLA-DRB1 show complicated dominance and epistatic effects. Importantly, any putative new effect must be distinguished from the effect of these class II genes (2,3).
CONCLUSIONS-CommonThe nonclassical MHC class I chain-related molecule (MIC) genes MICA and MICB are located 46.4 and 141.2 kb, respectively, centromeric of HLA-B and Ïł2 Mb telomeric of HLA-DRB1 (5) and have been associated both with immunity and with autoimmune diseases (5). In common with most MHC HLA genes, alleles of MICA and MICB are named based on haplotypes of nonsynonymous single nucleotide polymorphisms (nsSNPs). However, the most studied polymorphism in either of these genes is a short tandem repeat (STR) in the transmembrane domain of MICA (MICA-STR). Whether these genes are associated with type 1 diabetes is uncertain, with multiple conflicting reports in the literature (3,6 -14). Most of these studies failed to demonstrate convincingly that the association is independent of the MHC class II genes, and all were restricted to analyses of the MICA-STR. The MICA-STR is a GCT repeat microsatellite in MICA ex...