Abstract

Objective: The non-classical major histocompatibility complex (MHC) class I chain related molecules (MIC), 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 if 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 UK and USA (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 diabetes cases and 1,748 controls from Great Britain. We analysed 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=0.08, MICA-STR P=0.76, MICB P=0.03, after conditioning on HLA-DRB1 and HLA-DQB1).

Conclusions: Common MICA and MICB genetic variations including the MICA-STR are not associated, in a primary way, with susceptibility to type 1 diabetes.

Introduction Approximately 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 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, 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).