[ Diabetes Solutions ]

Genetics of Type 2 Diabetes Revealed in Unprecedented Detail

Type 2 diabetes affects over 300 million people worldwide. A total of 42 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 380 African-American type 2 diabetic case subjects with end-stage renal disease (ESRD) and 276 African-American control subjects. In recent years, there has been a surge in the number of genetic studies of T2D in attempts to identify some of the underlying risk factors. We have summarized what we have learned so far about the genes that affect T2D risk and their functions. No significant association with type 2 diabetes was found at any of the polymorphic loci. Egeberg, J. Previous studies have identified over 80 areas in the genome that are associated with type 2 diabetes.


However, these studies focused on the role of common DNA differences that appear frequently in the population, and they generally stopped short of identifying exactly which DNA sequence changes, or which specific genes, were responsible for this risk. 3). Most importantly, however, the addition of a known TCF7L2 genotype in a validated model for predicting prevalent diabetes was not able to improve the performance of the risk score: area under ROC curve in both models equal to 0.776, ie the inclusion of TCF7L2 genotype is not better than the utilization of only clinical characteristics to predict diabetes risk in our population. Using various models of the mouse FTO gene, we discovered that reduced function of the gene led to lean mice, whereas overexpression resulted in overeating and obesity. Future strategies to develop a personalized prevention or treatment approach should take into account a patient’s genetic profile as well as environmental risk factors, the researchers suggested. This variant was one of 18, each found by other researchers to have a mild association with type-2 diabetes risk, that the Butte team incorporated into its analysis. We designate the promoter at 72.11 Mb as P1 and the promoter at 72.14 Mb as P2.

This finding means that future efforts to develop a personalized approach to treatment and prevention will need to be tailored toward an individual’s broader genetic profile, non-genetic risk factors and clinical features. In the study, a group of mice was treated with a lipid metabolism-altering drug and DNA microarray technology was used for mRNA expression profiling of various tissues. Approximately 38% of siblings and one-third of children of people with type 2 diabetes will develop diabetes or abnormal glucose metabolism at some point. One such variant – in the TM6SF2 gene – has been shown to alter the amount of fat stored in the liver, which in turn results in an increase in the risk of type 2 diabetes. These studies suggest that we reconsider our current thinking of the pathogenesis of type 2 diabetes; three different concepts seem to emerge (A). “This study highlights both the challenges we face, and the opportunities that exist, in resolving the complex processes underlying a disease such as type 2 diabetes. In this study, we have been able to highlight, with unprecedented precision, a number of genes directly involved in the development of type 2 diabetes.

Disclaimer: AAAS and EurekAlert! More alternative measures of adiposity need to be considered in future studies. With this in-depth analysis we have obtained a more complete picture of the number and characteristics of the genetic variants that influence type 2 diabetes risk,” added joint senior author Michael Boehnke, Richard G Cornell Distinguished University Professor of Biostatistics, Director, Center for Statistical Genetics, University of Michigan School of Public Health. “Our study tells us that genetic risk for type 2 diabetes reflects hundreds or even thousands of different genetic variants, most of them shared across populations. The search for T2D associated genes and variants continues, with many scientists questioning where the ‘missing heritability’ lies. Neurogenin3, NeuroD1, MafA and Pdx1 [9], [10].

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[ Diabetes Solutions ]

Genetics of Type 2 Diabetes Revealed in Unprecedented Detail

South Asians are up to four times more likely to develop type 2 diabetes than white Europeans. (Nasdaq:DCGN) publish in the journal Nature the discovery of a version of a common single-letter variant in the sequence of the human genome (SNP) with a major impact on susceptibility to type 2 diabetes (T2D). However, most of these variants have only modest effects on the risk for T2D; identification of definitive ‘causal variant’ or ‘causative loci’ is typically lacking. Two major developments mean that we now know of 65 regions of the human genome that influence type 2 diabetes risk. A better understanding of precisely how these factors contribute to type 2 diabetes will enable researchers to develop new ways of treating and preventing this condition, as well as offering the prospect for targeting those treatments towards those most likely to benefit, and those least likely to suffer harm. The research first involved analysis of large-scale genetic data from over 200,000 people, one quarter of whom had diabetes. Furthermore, we show that these patterns contribute to disparities in predicted genetic risk across 1,397 HapMap individuals, T2D genetic risk being consistently higher for individuals in the African populations and lower in the Asian populations, irrespective of the ethnicity considered in the initial discovery of risk alleles.


However, these studies focused on the role of common DNA differences that appear frequently in the population, and they generally stopped short of identifying exactly which DNA sequence changes, or which specific genes, were responsible for this risk. Today’s study explored the impact of changes in the DNA sequence on diabetes risk at a more detailed level. and R.C.W.M. Scientists compared the genetic variation between individuals who had type 2 diabetes and those who did not. They found that most of the genetic risk of type 2 diabetes can be attributed to common, shared differences in the genetic code, each of which contributes a small amount to an individual’s risk of disease. It’s a win-win. If rare mutations were important genetic drivers of diabetes, then the task of understanding diabetes genetics would likely be easier.

In the “Diabetes Prevention Program”, 55 percent of participants were Caucasian, 45 percent were minorities, most were obese, and most had a family history of T2D [12]. Limited information exists whether genetic risk information can motivate individuals to adopt healthier behaviors and so far, results have been mixed. One such variant – in the TM6SF2 gene – has been shown to alter the amount of fat stored in the liver, which in turn results in an increase in the risk of type 2 diabetes. One such variant – in the TM6SF2 gene – has been shown to alter the amount of fat stored in the liver, which in turn results in an increase in the risk of type 2 diabetes. Discoveries such as these point to new opportunities for developing drugs that might interrupt the development of the disease. PCR and sequencing reactions were performed as described in Supplementary Note 1 and Supplementary Table S2. In this study, we have been able to highlight, with unprecedented precision, a number of genes directly involved in the development of type 2 diabetes.

These represent promising avenues for efforts to design new ways to treat or prevent the disease,” said Mark McCarthy, from the Wellcome Trust Centre for Human Genetics at the University of Oxford, one of three senior authors on the paper. “Our study has taken us to the most complete understanding yet of the genetic architecture of type 2 diabetes. With this in-depth analysis we have obtained a more complete picture of the number and characteristics of the genetic variants that influence type 2 diabetes risk,” added joint senior author Michael Boehnke, Richard G Cornell Distinguished University Professor of Biostatistics, Director, Center for Statistical Genetics, University of Michigan School of Public Health. “Our study tells us that genetic risk for type 2 diabetes reflects hundreds or even thousands of different genetic variants, most of them shared across populations. This large range of genetic effects may challenge efforts to deliver personalized (or precision) medicine. However, to ensure that these challenges can be taken up by the wider research community, we have made the data from our study publicly accessible for researchers around the world in the hope that this will accelerate efforts to understand, prevent and treat this condition,” said Jason Flannick, co-lead author and senior group leader at the Broad Institute of Harvard and MIT.

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[ Diabetes Type 1 ]

Genetics of type 2 diabetes revealed in unprecedented detail

There are many risk factors for type 2 diabetes. Earlier studies used a lower-cost, coarse-grained scan of the subjects’ DNA. Despite the stringent standards exacted by the Woolf test, genotypic heterogeneity between obese and non-obese individuals was detected for TCF7L2 rs7903146 and ENPP1 K121Q, and suggested for ADIPOQ 11377C>G and HNF1A I27L SNPs. Seventy-two phenotypically high-risk participants received counseling that included their diabetes genetic risk score, general education about diabetes risk factors, and encouragement to participate in a diabetes prevention program. A better understanding of precisely how these factors contribute to type 2 diabetes will enable researchers to develop new ways of treating and preventing this condition, as well as offering the prospect for targeting those treatments towards those most likely to benefit, and those least likely to suffer harm. Previous studies have identified over 80 areas in the genome that are associated with type 2 diabetes. The fact that recurrence-risk ratios were elevated only in families with one or two diabetic parents indicates that susceptibility to Type 2 diabetes is transmitted primarily through an affected parent.

A handful of studies have investigated the signatures of selection on candidate genes for T2D,23, 24, 25, 26, 27, 28, 29 but most of them did not assess whether the risk or the protective alleles were targeted by selection. In multilocus analyses including both INS polymorphisms, significant associations were seen with hypertriglyceridemia (P=0.006), hypercholesterolemia (P=0.031) and with presence of at least one metabolic abnormality (P=0.009). Scientists compared the genetic variation between individuals who had type 2 diabetes and those who did not. But the seven variants may together increase the risk association,” she says. They found that most of the genetic risk of type 2 diabetes can be attributed to common, shared differences in the genetic code, each of which contributes a small amount to an individual’s risk of disease. Some researchers had thought that genetic risk would instead be dominated by rare changes, unique to an individual and their relatives. This finding means that future efforts to develop a personalised approach to treatment and prevention will need to be tailored toward an individual’s broader genetic profile, non-genetic risk factors and clinical features.

They found that most of the genetic risk of type 2 diabetes can be attributed to common, shared differences in the genetic code, each of which contributes a small amount to an individual’s risk of disease. One possible explanation for this may be that the fine-mapping studies have concentrated on evaluating the role of common polymorphisms. One such variant – in the TM6SF2 gene – has been shown to alter the amount of fat stored in the liver, which in turn results in an increase in the risk of type 2 diabetes. Discoveries such as these point to new opportunities for developing drugs that might interrupt the development of the disease. Discoveries such as these point to new opportunities for developing drugs that might interrupt the development of the disease. We’re a global charitable foundation, both politically and financially independent. About deCODE deCODE is a global leader in analysing and understanding the human genome.

About the University of Oxford Oxford University’s Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. A candidate gene study combined with meta-analysis of multiple case control studies identified the E23K variant in the KCNJ11 gene (Gloyn et al Diabetes 2003). The University is rated the best in the world for medicine and life sciences, and it is home to the UK’s top-ranked medical school. Prof McCarthy’s research is based at the Wellcome Trust Centre for Human Genetics (www.well.ox.ac.uk), the Oxford Centre for Diabetes, Endocrinology and Metabolism (www.ocdem.ox.ac.uk), and the Oxford NIHR Biomedical Research Centre (http://oxfordbrc.nihr.ac.uk). However, the potential disparities in genetic risks for T2D and other major diseases across different ethnic groups and subpopulations are poorly characterized. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods, and data openly to the entire scientific community. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods, and data openly to the entire scientific community.

Broad, the Broad Institute includes faculty, professional staff, and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to www.broadinstitute.org. About the University of Michigan The University of Michigan School of Public Health has been Doing a World of Good in promoting health and preventing disease since 1941, and is consistently ranked among the top schools in the country. Many women who have gestational diabetes develop type 2 diabetes years later. We also offer myriad opportunities for students to experience public health in the real world through public health practice, internships, entrepreneurial training, and more. Prospective data indicates that impaired beta cell function, not insulin resistance, predicts future T2D in non-obese subjects [41].

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[ Diabetes Solutions ]

Genetics Of Type 2 Diabetes Revealed In Unprecedented Detail

The pathophysiology of latent autoimmune diabetes in adults (LADA) is considered less understood than its much better characterized counterparts of type 1 and type 2 diabetes (T1D and T2D), where its clinical presentation exhibits some features of each of these two main diseases, earning it a reputation as being “type 1.5 diabetes”. In skeletal muscle, low-molecular-weight as well as high-molecular-weight adiponectin up-regulates PPARα and activates AMPK (AMP kinase) through the AdipoR1 receptors. Initially, we were able to confirm the association between polymorphism rs7903146 and T2D in a cohort of patients from the MASS II protocol, whose diabetes prevalence was 31.1%. Together with our collaborators, we use information from the identification of coding mutations from exome sequencing, fine genetic mapping in different human populations, expression QTL analysis in relevant cells and from tissues and experiments with patient samples of a known genotype. One in 10 people globally either has type 2 diabetes or is predicted to develop it, according to background research with the study. The first author, Chirag Patel, PhD, is a former graduate student in Butte’s lab and now a postdoctoral scholar at the Stanford Prevention Research Center. Electrophoretic mobility shift assays demonstrated decreased binding of pancreatic beta cell transcriptional regulators PAX6 and PAX4 to the rs11603334 C allele.

The data deposited in EGA will include all the Swedish, Finnish, UK, and German samples. The recent advances in nutrigenomics studies are owed to the completion of human genome project and the new biomics technologies that provide means for the simultaneous determination of the expression of many thousands of genes at the mRNA (transcriptomics), metabolites (metabolomics) and protein (proteomics) levels. This disease exists in all populations, but prevalence varies greatly, ie, 1% in Japan, and greater than 40% in the Pima Indians of Arizona. Scientists compared the genetic variation between individuals who had type 2 diabetes and those who did not. Thus, even though obesity and insulin resistance clearly increase the likelihood of developing diabetes (11), a substantial percentage of obese individuals remain free of diabetes throughout life, and, in turn, pancreas transplantation has been shown to restore normoglycemia even in insulin-resistant patients with type 2 diabetes (12). They found that most of the genetic risk of type 2 diabetes can be attributed to common, shared differences in the genetic code, each of which contributes a small amount to an individual’s risk of disease. Chapter 5 presents a study designed to utilise metabolic features of monogenic forms of insulin resistance in a novel approach to characterise less penetrant variants associated with common form of insulin resistance.

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The exact function of the gene product of FTO is not yet understood and how the polymorphism affects the risk of T2D is unclear. Disclaimer: AAAS and EurekAlert! One such variant – in the TM6SF2 gene – has been shown to alter the amount of fat stored in the liver, which in turn results in an increase in the risk of type 2 diabetes. The majority of loci have an impact on beta-cell dysfunction.

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