Understanding type 1 diabetes through genetics: advances and prospects

Departments of Pediatrics and Human Genetics, McGill University, Montreal, Québec, Canada H3H 1P3. Constantin.
Nature Reviews Genetics (Impact Factor: 39.79). 11/2011; 12(11):781-92. DOI: 10.1038/nrg3069
Source: PubMed

ABSTRACT Starting with early crucial discoveries of the role of the major histocompatibility complex, genetic studies have long had a role in understanding the biology of type 1 diabetes (T1D), which is one of the most heritable common diseases. Recent genome-wide association studies (GWASs) have given us a clearer picture of the allelic architecture of genetic susceptibility to T1D. Fine mapping and functional studies are gradually revealing the complex mechanisms whereby immune self-tolerance is lost, involving multiple aspects of adaptive immunity. The triggering of these events by dysregulation of the innate immune system has also been implicated by genetic evidence. Finally, genetic prediction of T1D risk is showing promise of use for preventive strategies.

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    • "DN is a common complication of type 1 and type 2 diabetes , which have been associated with very distinct disease risk loci [Figure 2 and reviewed in Ntzani and Kavvoura (2012), Polychronakos and Li (2011)]. Results of genetics studies are extensively discussed in two recent reviews (Gu and Brismar, 2012; Palmer and Freedman, 2012), we therefore will focus only on the genetic association of ELMO1, CNDP1, and FRDM3 loci with DN risk, as they were detected in both GWAS and candidate gene approach studies. "
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    ABSTRACT: Genetic studies of human diseases have identified multiple genetic risk loci for various fibrotic diseases. This has provided insights into the myriad of biological pathways potentially involved in disease pathogenesis. These discoveries suggest that alterations in immune responses, barrier function, metabolism and telomerase activity may be implicated in the genetic risks for fibrotic diseases. In addition to genetic disease-risks, the identification of genetic disease-modifiers associated with disease complications, severity or prognosis provides crucial insights into the biological processes implicated in disease progression. Understanding the biological processes driving disease progression may be critical to delineate more effective strategies for therapeutic interventions. This review provides an overview of current knowledge and gaps regarding genetic disease-risks and genetic disease-modifiers in human fibrotic diseases.
    Frontiers in Pharmacology 12/2013; 4:159. DOI:10.3389/fphar.2013.00159 · 3.80 Impact Factor
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    • "The main determinant of risk of developing CD is the HLA DQB1*02-DQA1*05 (HLA-DQ 2.5) haplotype and for T1DM both the HLA DRB1*03-DQB1*0201 and DRB1*04-DQB1*0302 (DR3-DQ2.5 and DR4-DQ8) haplotype [31] [32]. Our data confirm the high prevalence of HLA-DQ 2.5 haplotypes in patients with both T1DM and CD [7] [33]. "
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    ABSTRACT: BACKGROUND: Patients with type 1 diabetes mellitus (T1DM) are more prone to develop other auto-immune diseases, including coeliac disease (CD). Paediatric patients with T1DM are screened for CD, whereas in adult T1DM patients screening programs for CD are not standardised. The aim of this study was to investigate clinical and genetic characteristics of patients with both diagnoses so as to lead to better detection of CD in adult patients with T1DM. METHODS: We studied 118 patients with both T1DM and CD identified in The Netherlands. We retrospectively collected data on sex distribution, age of onset of T1DM, age of CD diagnosis, CD complaints, duration of CD complaints before CD diagnosis, family history of CD or T1DM, comorbidity and HLA-DQ type. RESULTS: Thirty-three percent of T1DM+CD patients reported CD related complaints for at least 5years before CD diagnosis. Two peaks in the age of CD diagnosis in T1DM patients were observed: around 10 and 45years of age. Women were diagnosed with CD at a younger age than men (median 25years (IQR 9-38) versus 39 (12-55) years, respectively, P<0.05). CONCLUSION: A delay of CD diagnosis is frequently found in adult T1DM patients and two peaks in the age of CD diagnosis are present in T1DM patients. This observational study emphasises that more frequent screening for CD in particularly adult T1DM patients is required, preferably by a 5years interval.
    European Journal of Internal Medicine 02/2013; DOI:10.1016/j.ejim.2013.01.016 · 2.30 Impact Factor
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    • "The aforementioned T1D therapies are directed only at the consequences of the disease rather than the causative agent(s). While the ultimate cause of T1D is not currently defined and is likely multifactorial [5], T cells specific for islet antigens are the proximate cause of β cell destruction. Diabetogenic T cells that have been inappropriately activated and allowed to escape central and peripheral tolerance mechanisms (possibly due to assistance from aberrant innate cells [6]) have been implicated in β cell damage in both the nonobese diabetic (NOD) mouse and the human form of disease. "
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    ABSTRACT: 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.
    Clinical and Developmental Immunology 05/2012; 2012:380289. DOI:10.1155/2012/380289 · 2.93 Impact Factor
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