The Past, Present, and Future of Genetic Associations in Type 1 Diabetes

Baker, Peter R.; Steck, Andrea K.

doi:10.1007/s11892-011-0212-0

Cited by 10 publications

(7 citation statements)

References 63 publications

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“…A region on chromosome 2 is almost significant (genome-wide adjusted P -value 0.20). A recent review (Baker and Steck 2011) lists two known associations with type 1 diabetes on chromosome 2. These are IFIH1 at 2q24.2 and CTLA4 (cytotoxic T lymphocyte associated antigen 4) at 2q33.2.…”

Section: Resultsmentioning

confidence: 99%

Detecting Rare Variant Associations by Identity-by-Descent Mapping in Case-Control Studies

2012

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Identity-by-descent (IBD) mapping tests whether cases share more segments of IBD around a putative causal variant than do controls. These segments of IBD can be accurately detected from genome-wide SNP data. We investigate the power of IBD mapping relative to that of SNP association testing for genome-wide case-control SNP data. Our focus is particularly on rare variants, as these tend to be more recent and hence more likely to have recent shared ancestry. We simulate data from both large and small populations and find that the relative performance of IBD mapping and SNP association testing depends on population demographic history and the strength of selection against causal variants. We also present an IBD mapping analysis of a type 1 diabetes data set. In those data we find that we can detect association only with the HLA region using IBD mapping. Overall, our results suggest that IBD mapping may have higher power than association analysis of SNP data when multiple rare causal variants are clustered within a gene. However, for outbred populations, very large sample sizes may be required for genome-wide significance unless the causal variants have strong effects.

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Section: Resultsmentioning

confidence: 99%

Detecting Rare Variant Associations by Identity-by-Descent Mapping in Case-Control Studies

2012

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“…T1D is a complex disease resulting from both genetic predisposition as well as environmental triggers. The autoimmune attack may be triggered by environmental factors such as diet, which affects the intestinal microbiome (Mathis and Benoist, 2012), and viral infections (Coppieters et al, 2012) in people who are genetically predisposed (Baker and Steck, 2011). Lack of insulin (little or none) in T1D disturbs glucose homeostasis and results in ketoacidosis.…”

Section: Types Of Diabetes and Metabolic Syndromesmentioning

confidence: 99%

New Opportunities: Harnessing Induced Pluripotency for Discovery in Diabetes and Metabolism

2013

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The landmark discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka has transformed regenerative biology. Previously, insights into the pathogenesis of chronic human diseases have been hindered by the inaccessibility of patient samples. However, scientists are now able to convert patient fibroblasts into iPSCs and differentiate them into disease-relevant cell types. This ability opens new avenues for investigating disease pathogenesis and designing novel treatments. In this review, we highlight the uses of human iPSCs to uncover the underlying causes and pathological consequences of diabetes and metabolic syndromes, multi-factorial diseases whose etiologies have been difficult to unravel using traditional methodologies.

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“…Thus, a limited number of antigen-specific agents presumably would cover a large percentage of the diabetic patient population. This restriction is reinforced by the relative dominance of some class I (HLA-A*0201, B*3906, or C*0501) and class II (DPA1*0103-DPB1*0202 or DRB1*0405-DQA1*0301-DQB1*0302) alleles in T1D [35]. …”

Section: Peptide-major Histocompatibility Complex Multimers In T1dmentioning

confidence: 99%

Making the Most of Major Histocompatibility Complex Molecule Multimers: Applications in Type 1 Diabetes

Gojanovich

Hess

2012

Clinical and Developmental Immunology

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Classical major histocompatibility complex (MHC) class I and II molecules present peptides to cognate T-cell receptors on the surface of T lymphocytes. The specificity with which T cells recognize peptide-MHC (pMHC) complexes has allowed for the utilization of recombinant, multimeric pMHC ligands for the study of minute antigen-specific T-cell populations. In type 1 diabetes (T1D), CD8+ cytotoxic T lymphocytes, in conjunction with CD4+ T helper cells, destroy the insulin-producing β cells within the pancreatic islets of Langerhans. Due to the importance of T cells in the progression of T1D, the ability to monitor and therapeutically target diabetogenic clonotypes of T cells provides a critical tool that could result in the amelioration of the disease. By administering pMHC multimers coupled to fluorophores, nanoparticles, or toxic moieties, researchers have demonstrated the ability to enumerate, track, and delete diabetogenic T-cell clonotypes that are, at least in part, responsible for insulitis; some studies even delay or prevent diabetes onset in the murine model of T1D. This paper will provide a brief overview of pMHC multimer usage in defining the role T-cell subsets play in T1D etiology and the therapeutic potential of pMHC for antigen-specific identification and modulation of diabetogenic T cells.

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The Past, Present, and Future of Genetic Associations in Type 1 Diabetes

Cited by 10 publications

References 63 publications

Detecting Rare Variant Associations by Identity-by-Descent Mapping in Case-Control Studies

Detecting Rare Variant Associations by Identity-by-Descent Mapping in Case-Control Studies

New Opportunities: Harnessing Induced Pluripotency for Discovery in Diabetes and Metabolism

Making the Most of Major Histocompatibility Complex Molecule Multimers: Applications in Type 1 Diabetes

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