The end or the start of understanding the genetics of type 2 diabetes.
Ontology highlight
ABSTRACT:
SUBMITTER: Chuang LM
PROVIDER: S-EPMC4020715 | biostudies-literature | 2010 Oct
REPOSITORIES: biostudies-literature
Publications
The end or the start of understanding the genetics of type 2 diabetes.
Journal of diabetes investigation 20101001 5
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Project description:The largest contribution of type 1 diabetes mellitus (T1DM) from a single locus comes from several genes located in the major histocompatibility complex on chromosome 6p21. Because DQB1 is the best single genetic marker for T1DM, it is the gene most often used to identify individuals with a high risk of developing disease. As per the data collected from the All India Institute of Medical Sciences, among the human leukocyte antigen (HLA)-DRB1 genes, HLA-DR3 showed strongest association with the disease; however, unlike Caucasians and other populations, DR4 was not significantly increased in these patients. HLA-DR10, 11, 13, and 15 showed a negative association with the disease as they were reduced in these patients. In India, the relative risk of developing T1DM is higher with the DR3-DQ2 haplotypes as compared to DR4-DQ8 haplotypes. Studies have shown that in North India, the relative risk for T1DM is comparatively higher (>30) with the DQ2/DQ8 genotype, but is relatively lower (approximately 18) for the DQ2/DQ2 genotype. In addition, the three sets of HLA-B-DR3 haplotypes, mainly B58-DR3, B50-DR3, and B8-DR3 have shown to have modulated susceptibility for T1DM in India and worldwide. New interventions that will be tested in the future will be conducted through T1DM TrialNet, a collaborative network of clinical centers and experts in diabetes and immunology. These studies will identify unaffected first-degree relatives with beta cell autoantibodies who will be eligible for new interventions.
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Project description:Purpose of reviewTo provide an overview of the genetics of type 2 diabetes in the context of recent progress in the understanding of the genetic architecture of the disease and its applicability to the pathogenesis of the disease as well as efforts to individualize therapy in type 2 diabetes. Efforts are underway to understand how these loci alter measurable physiologic processes in nondiabetic humans. However, it is important to understand the potential pitfalls in such studies and the limitations underlying measurement of insulin secretion and action using qualitative methodologies.Recent findingsThe availability of large population-based cohorts and the ease with which large numbers of common genetic variants can be genotyped has enabled the discovery of multiple loci and pathways associated with type 2 diabetes. Recent efforts examining quantitative traits such as fasting glucose concentrations have led to the discovery of other genes likely to be important in the development of diabetes.SummaryThe past 4 years have witnessed a significant increase in our understanding of genetic predisposition to type 2 diabetes. Hopefully more progress will be made in applying this knowledge to the pathophysiology of type 2 diabetes in the coming years.
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Project description:BackgroundType 1 diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic β cells. The major susceptibility locus maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene markers have been confirmed.ContentAlthough HLA class II alleles account for up to 30%-50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk with smaller effects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and other recently discovered loci. Genomewide association studies performed with high-density single-nucleotide-polymorphism genotyping platforms have provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remain to be performed. Children born with the high-risk genotype HLADR3/4-DQ8 comprise almost 50% of children who develop antiislet autoimmunity by the age of 5 years. Genetic risk for type 1 diabetes can be further stratified by selection of children with susceptible genotypes at other diabetes genes, by selection of children with a multiple family history of diabetes, and/or by selection of relatives that are HLA identical to the proband.SummaryChildren with the HLA-risk genotypes DR3/4-DQ8 or DR4/DR4 who have a family history of type 1 diabetes have more than a 1 in 5 risk for developing islet autoantibodies during childhood, and children with the same HLA-risk genotype but no family history have approximately a 1 in 20 risk. Determining extreme genetic risk is a prerequisite for the implementation of primary prevention trials, which are now underway for relatives of individuals with type 1 diabetes.
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Project description:Type 1 diabetes (T1D) results from immune-mediated loss of pancreatic beta cells leading to insulin deficiency. It is the most common form of diabetes in children, and its incidence is on the rise. This article reviews the current knowledge on the genetics of T1D. In particular, we discuss the influence of HLA and non-HLA genes on T1D risk and disease progression through the preclinical stages of the disease, and the development of genetic scores that can be applied to disease prediction. Racial/ethnic differences, challenges and future directions in the genetics of T1D are also discussed.
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Project description:Type 2 Diabetes Mellitus is an increasing public health problem that poses a severe social and economic burden affecting both developed and developing countries. Defects in insulin signaling itself are among the earliest indications that an individual is predisposed to the development of insulin resistance and subsequently Type 2 Diabetes Mellitus. To date, however, the underlying molecular mechanisms which result in resistance to the actions of insulin are poorly understood. Furthermore, it has been shown that maternal obesity is associated with an increased risk of obesity and insulin resistance in the offspring. However, the genetic and/or epigenetic modifications within insulin-sensitive tissues such as the liver and skeletal muscle, which contribute to the insulin-resistant phenotype, still remain unknown. More importantly, a lack of in-depth understanding of how the early life environment can have long-lasting effects on health and increased risk of Type 2 Diabetes Mellitus in adulthood poses a major limitation to such efforts. The focus of the current review is thus to discuss recent experimental and human evidence of an epigenetic component associated with components of nutritional programming of Type 2 Diabetes Mellitus, including altered feeding behavior, adipose tissue, and pancreatic beta-cell dysfunction, and transgenerational risk transmission.
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Project description:Since fulminant type 1 diabetes was reported as a distinct subtype of type 1 diabetes in 2000, the Committee on Type 1 diabetes, Japan Diabetes Society has continuously recruited patients and conducted genomic research to elucidate the genetic basis of fulminant type 1 diabetes. The contribution of the human leukocyte antigen complex (HLA) to genetic susceptibility to fulminant type 1 diabetes was compared with that of other subtypes in 2009. The alleles and haplotypes associated with fulminant type 1 diabetes were found to be different from acute-onset and slowly progressive type 1 diabetes. DRB1*15:01-DQB1*06:02, a protective haplotype against acute-onset type 1 diabetes, does not provide protection against fulminant type 1 diabetes and DRB1*08:02-DQB1*03:02, a susceptible haplotype to acute-onset type 1 diabetes, does not confer susceptibility to fulminant type 1 diabetes. Recently, the first genome-wide association study (GWAS) of fulminant type 1 diabetes was performed in Japanese individuals. A strong association was observed with multiple single nucleotide polymorphisms (SNPs) in the HLA region, and the strongest association was observed with rs9268853 in the class II DR region. In addition, 11 SNPs outside the HLA region showed some evidence of association with the disease. In particular, rs11170445 in CSAD/lnc-ITGB7-1 on chromosome 12q13.13 showed an association at a genome-wide significance level. Fine mapping revealed that rs3782151 in CSAD/lnc-ITGB7-1 showed the lowest P value. CSAD/lnc-ITGB7-1 was found to be strongly associated with susceptibility to fulminant, but not classical, autoimmune type 1 diabetes, implicating this locus in the distinct phenotype of fulminant type 1 diabetes.
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Project description:The global epidemic of type 2 diabetes mellitus (T2D) is one of the most challenging problems of the 21(st) century leading cause of and the fifth death worldwide. Substantial evidence suggests that T2D is a multifactorial disease with a strong genetic component. Recent genome-wide association studies (GWAS) have successfully identified and replicated nearly 75 susceptibility loci associated with T2D and related metabolic traits, mostly in Europeans, and some in African, and South Asian populations. The GWAS serve as a starting point for future genetic and functional studies since the mechanisms of action by which these associated loci influence disease is still unclear and it is difficult to predict potential implication of these findings in clinical settings. Despite extensive replication, no study has unequivocally demonstrated their clinical role in the disease management beyond progression to T2D from impaired glucose tolerance. However, these studies are revealing new molecular pathways underlying diabetes etiology, gene-environment interactions, epigenetic modifications, and gene function. This review highlights evolving progress made in the rapidly moving field of T2D genetics that is starting to unravel the pathophysiology of a complex phenotype and has potential to show clinical relevance in the near future.
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Project description:In this Perspective, Jose Florez discusses how information from genetics and genomics may be able to contribute to prevention of type 2 diabetes and predicting individual responses to behavioral and other interventions.
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Project description:Type 2 diabetes (T2D) is a global health problem showing substantial ethnic disparity in disease prevalence. African Americans have one of the highest prevalence of T2D in the USA but little is known about their genetic risks. This review summarizes the findings of genetic regions and loci associated with T2D and related glycemic traits using linkage, admixture, and association approaches in populations of African ancestry. In particular, findings from genome-wide association and exome chip studies suggest the presence of both ancestry-specific and shared loci for T2D and glycemic traits. Among the European-identified loci that are transferable to individuals of African ancestry, allelic heterogeneity as well as differential linkage disequilibrium and risk allele frequencies pose challenges and opportunities for fine mapping and identification of causal variant(s) by trans-ancestry meta-analysis. More genetic research is needed in African ancestry populations including the next-generation sequencing to improve the understanding of genetic architecture of T2D.
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