Sequencing-Based Genotyping and Association Analysis of the MICA and MICB Genes in Type 1 Diabetes
- Sarah F. Field,
- Sergey Nejentsev,
- Neil M. Walker,
- Joanna M.M. Howson,
- Lisa M. Godfrey,
- Jennifer D. Jolley,
- Matthew P.A. Hardy and
- John A. Todd
- 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
Abstract
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.
- 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
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 10 March 2008. DOI: 10.2337/db07-1402.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1402.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted February 29, 2008.
- Received October 3, 2007.
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