Insights into type 1 diabetes provided by genetic analyses.
ABSTRACT 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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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.Diabetes 02/2013; DOI:10.2337/db12-1398 · 8.47 Impact Factor
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ABSTRACT: Diabetes and diabetic nephropathy are complex diseases affected by genetic and environmental factors. Identification of the susceptibility genes and investigation of their roles may provide useful information for better understanding of the pathogenesis and for developing novel therapeutic approaches. Intercellular adhesion molecule 1 (ICAM1) is a cell surface glycoprotein expressed on endothelial cells and leukocytes in the immune system. The ICAM1 gene is located on chromosome 19p13 within the linkage region of diabetes. In the recent years, accumulating reports have implicated that genetic polymorphisms in the ICAM1 gene are associated with diabetes and diabetic nephropathy. Serum ICAM1 levels in diabetes patients and the icam1 gene expression in kidney tissues of diabetic animals are increased compared to the controls. Therefore, ICAM1 may play a role in the development of diabetes and diabetic nephropathy. In this review, we present genomic structure, variation, and regulation of the ICAM1 gene, summarized genetic and biological studies of this gene in diabetes and diabetic nephropathy and discussed about the potential application using ICAM1 as a biomarker and target for prediction and treatment of diabetes and diabetic nephropathy.Frontiers in Endocrinology 01/2012; 3:179. DOI:10.3389/fendo.2012.00179
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ABSTRACT: Diabetes mellitus type 1 (T1D) is a complex disease resulting from the interplay of genetic, epigenetic, and environmental factors. Recent progress in understanding the genetic basis of T1D has resulted in an increased recognition of childhood diabetes heterogeneity. After the initial success of family-based linkage analyses, which uncovered the strong linkage and association between HLA gene variants and T1D, genome-wide association studies performed with high-density single-nucleotide polymorphism genotyping platforms provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remains to be performed. T1D is one of the most heritable common diseases, and among autoimmune diseases it has the largest range of concordance rates in monozygotic twins. This fact, coupled with evidence of various epigenetic modifications of gene expression, provides convincing proof of the complex interplay between genetic and environmental factors. In T1D, epigenetic phenomena, such as DNA methylation, histone modifications, and microRNA dysregulation, have been associated with altered gene expression. Increasing epidemiologic and experimental evidence supports the role of genetic and epigenetic alterations in the etiopathology of diabetes. We discuss recent results related to the role of genetic and epigenetic factors involved in development of T1D.PEDIATRICS 11/2013; 132(6). DOI:10.1542/peds.2013-1652 · 5.30 Impact Factor