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Journal of Diabetes Research
Volume 2013, Article ID 737485, 10 pages
Research Article

The Missing Heritability in T1D and Potential New Targets for Prevention

1Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
2Department of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, PA 19129, USA
3Children’s Hospital Oakland Research Institute, Oakland, CA 94609, USA
4Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA

Received 7 January 2013; Accepted 13 February 2013

Academic Editor: Norihide Yokoi

Copyright © 2013 Brian G. Pierce et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Type 1 diabetes (T1D) is a T cell-mediated disease. It is strongly associated with susceptibility haplotypes within the major histocompatibility complex, but this association accounts for an estimated 50% of susceptibility. Other studies have identified as many as 50 additional susceptibility loci, but the effect of most is very modest (odds ratio (OR) <1.5). What accounts for the “missing heritability” is unknown and is often attributed to environmental factors. Here we review new data on the cognate ligand of MHC molecules, the T cell receptor (TCR). In rats, we found that one allele of a TCR variable gene, Vβ13A, is strongly associated with T1D (OR >5) and that deletion of Vβ13+ T cells prevents diabetes. A role for the TCR is also suspected in NOD mice, but TCR regions have not been associated with human T1D. To investigate this disparity, we tested the hypothesis in silico that previous studies of human T1D genetics were underpowered to detect MHC-contingent TCR susceptibility. We show that stratifying by MHC markedly increases statistical power to detect potential TCR susceptibility alleles. We suggest that the TCR regions are viable candidates for T1D susceptibility genes, could account for “missing heritability,” and could be targets for prevention.