Insights into type 1 diabetes provided by genetic analyses

Centre for Diabetes Research, The Western Australian Institute for Medical Research, University of Western Australia, Perth, Western Australia, Australia.
Current opinion in endocrinology, diabetes, and obesity (Impact Factor: 3.37). 06/2012; 19(4):263-70. DOI: 10.1097/MED.0b013e328355b7fe
Source: PubMed


Recent identification of over 60 loci contributing to the susceptibility of developing type 1 diabetes (T1D) provides a timely opportunity to assess what is currently known of the genetics of T1D, and what these discoveries may tell us about the disease itself.
The major findings will be discussed under five main themes: T1D risk gene identification, molecular mechanisms of susceptibility, shared genetic cause with other diseases, development of novel analytical methods, and understanding disease heterogeneity.
The plethora of T1D risk genes that have been identified risk overwhelming clinicians with lists of gene names and symbols that have little bearing on management, and provide a challenge for researchers to place the genetics of T1D in a more amenable clinical context.

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    • "The HLA region on chromosome 6p contributes approximately half of the genetic susceptibility to T1D, yet the relative frequency of high risk HLA class II genotypes in children presenting with T1D has decreased as the incidence of the disease has increased [7]. Moreover, the recognition that over 60 gene loci are associated with T1D has led to speculation that T1D is a disease with discrete genetic subtypes whereby susceptibility genes interact differently with environmental exposures [8]. Variation in gene-environment interactions may explain different effects of environmental exposures in different populations at-risk of T1D. "
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    ABSTRACT: The incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes.Methods/design: ENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome-lipidome, insulin resistance, innate and adaptive immune function and viral infections. A systems biology approach will be used to integrate these. Investigation will be by 3-monthly assessments of the mother during pregnancy, then 3-monthly assessments of the child until 24 months of age and 6-monthly thereafter. The primary outcome measure is persistent islet autoimmunity, defined as the presence of autoantibodies to one or more islet autoantigens on consecutive tests. Defining gene-environment interactions that initiate and/or promote destruction of the insulin-producing beta cells in early life will inform approaches to primary prevention of type 1 diabetes. The strength of ENDIA is the prospective, comprehensive and frequent systems-wide profiling from early pregnancy through to early childhood, to capture dynamic environmental exposures that may shape the development of islet autoimmunity.Trial registration: Australia New Zealand Clinical Trials Registry ACTRN12613000794707.
    Full-text · Article · Aug 2013 · BMC Pediatrics
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    • "Genetic studies searching for diabetes susceptibility genes have identified more than 60 loci that contribute to susceptibility to T1D in humans. The products of these loci have been extensively investigated in order to understand their molecular mechanisms and to develop genetic prediction methods that show promise for use in preventive strategies [68]. Interestingly, more than 90% of patients who develop clinical diabetes have particular MHC haplotypes, which is also the case in autoimmune-prone rodent models [69]. "
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    ABSTRACT: Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that selectively destroy the insulin-producing β cells. Previous reports based on epidemiological and animal studies have demonstrated that both genetic factors and environmental parameters can either promote or attenuate the progression of autoimmunity. In recent decades, several inbred rodent strains that spontaneously develop diabetes have been applied to the investigation of the pathogenesis of T1D. Because the genetic manipulation of mice is well developed (transgenic, knockout, and conditional knockout/transgenic), most studies are performed using the nonobese diabetic (NOD) mouse model. This paper will focus on the use of genetically manipulated NOD mice to explore the pathogenesis of T1D and to develop potential therapeutic approaches.
    Full-text · Article · Mar 2013 · Journal of Diabetes Research
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    • "Corresponding author: Grant Morahan, Received 9 October 2012 and accepted 21 January 2013. DOI: 10.2337/db12-1398 Ó 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See -nc-nd/3.0/ for details. DI"
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    ABSTRACT: Evaluating risk of developing type 1 diabetes (T1D) depends on determining an individual's HLA type, especially of the HLA DRB1 and DQB1 alleles. Individuals positive for HLADRB1* 03 (DR3) and/or HLA-DRB1*04 (DR4) with DQB1*03:02 (DQ8) have the highest risk of developing T1D. Currently, HLA typing methods are relatively expensive and timeconsuming. We sought to determine the minimum number of SNPs that could rapidly define the HLA-DR types relevant to T1D, namely, DR3/4, DR3/3, DR4/4, DR3/X, DR4/X and DRX/X (where X is neither DR3 nor DR4) and could distinguish the highest risk DR4 type (DR4-DQB1*03:02) as well as the non-T1D associated DR4-DQB1*03:01 type. We analyzed 19,035 SNPs of 10,579 subjects (7,405 from a discovery set and 3,174 from a validation set) from the Type 1 Diabetes Genetics Consortium and developed a novel machine learning method to select as few as three SNPs that could define the HLA-DR and -DQ types accurately. The overall accuracy was 99.3%, area under curve was 0.997, true positive rates were >0.99 and false positive rates were <0.001. We confirmed the reliability of these SNPs by 10-fold cross-validation. Our approach predicts HLA-DR/DQ types relevant to T1D more accurately than existing methods and is rapid and cost-effective.
    Full-text · Article · Feb 2013 · Diabetes
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