The Missing Heritability in T1D and Potential New Targets for Prevention
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,...
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| Format: | Article |
| Language: | English |
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Wiley
2013-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2013/737485 |
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| author | Brian G. Pierce Ryan Eberwine Janelle A. Noble Michael Habib Hennady P. Shulha Zhiping Weng Elizabeth P. Blankenhorn John P. Mordes |
| author_facet | Brian G. Pierce Ryan Eberwine Janelle A. Noble Michael Habib Hennady P. Shulha Zhiping Weng Elizabeth P. Blankenhorn John P. Mordes |
| author_sort | Brian G. Pierce |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3828f0d43429431f904e0992ab88cd92 |
| institution | Kabale University |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-3828f0d43429431f904e0992ab88cd922025-02-03T01:02:51ZengWileyJournal of Diabetes Research2314-67452314-67532013-01-01201310.1155/2013/737485737485The Missing Heritability in T1D and Potential New Targets for PreventionBrian G. Pierce0Ryan Eberwine1Janelle A. Noble2Michael Habib3Hennady P. Shulha4Zhiping Weng5Elizabeth P. Blankenhorn6John P. Mordes7Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, PA 19129, USAChildren’s Hospital Oakland Research Institute, Oakland, CA 94609, USADepartment of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USAProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USAProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, PA 19129, USADepartment of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USAType 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.http://dx.doi.org/10.1155/2013/737485 |
| spellingShingle | Brian G. Pierce Ryan Eberwine Janelle A. Noble Michael Habib Hennady P. Shulha Zhiping Weng Elizabeth P. Blankenhorn John P. Mordes The Missing Heritability in T1D and Potential New Targets for Prevention Journal of Diabetes Research |
| title | The Missing Heritability in T1D and Potential New Targets for Prevention |
| title_full | The Missing Heritability in T1D and Potential New Targets for Prevention |
| title_fullStr | The Missing Heritability in T1D and Potential New Targets for Prevention |
| title_full_unstemmed | The Missing Heritability in T1D and Potential New Targets for Prevention |
| title_short | The Missing Heritability in T1D and Potential New Targets for Prevention |
| title_sort | missing heritability in t1d and potential new targets for prevention |
| url | http://dx.doi.org/10.1155/2013/737485 |
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