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Sequencing-Based Genotyping and Association Analysis of the MICA and MICB Genes in Type 1 Diabetes

From the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K

Corresponding author: John A. Todd, JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, U.K. E-mail: john.todd{at}cimr.cam.ac.uk

Abbreviations: LD, linkage disequilibrium; MHC, major histocompatibility complex; MIC, MHC class I chain-related molecule, nsSNP, nonsynonymous single nucleotide polymorphism; rpart, recursive partitioning; SBT, sequencing-based typing; SNP, single nucleotide polymorphism; STR, short tandem repeat

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 = 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.

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