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ARRA Investments in the Genetics and Epigenetics of Diabetes

Public Health Burden
Diabetes mellitus afflicts nearly 24 million people in the U.S.  Diabetes was the seventh leading cause of death in 2006, and is a major cause of other deadly and costly diseases, including cardiovascular disease and kidney disease.  Total U.S. direct and indirect costs of diabetes have been estimated at $174 billion in 2007.  Type 2 diabetes is also a growing problem in the developing world.

High Throughput Genomic Analyses of Type 2 Diabetes
Type 2 diabetes—which represents at least 90 percent of cases of diabetes—results from a complex interplay of genetic and environmental causes.  Teasing out these causes has been a major scientific challenge for decades, but new genomic technologies including “genome wide association studies” (GWAS) have created important breakthroughs, and represent key opportunities.  ARRA-funded projects exploring diabetes genetics via such technologies include:
  • A study building on recent discoveries of common genetic variants that contribute to type 2 diabetes by using next-generation sequencing platforms to study low frequency variants, which may have a more pronounced effect on development of the disease.1
  • A study to identify genetic contributors to diabetes and cardiovascular risk factors in African Americans, who are at elevated risk for type 2 diabetes and heart disease.2
  • A project correlating measurable biological parameters with GWAS data from a study of 10,000 people in Pakistan, to identify markers of the metabolic syndrome linking type 2 diabetes and myocardial infarction in this population.3
Genetic Approaches to Understanding the Development of Type 1 Diabetes
Recent years have seen an explosion in the number of genes recognized to contribute in some way to risk for type 1 diabetes, which results from autoimmune destruction of insulin-producing pancreatic beta cells.  However, in most cases is it not clear how these genes exert their effects in autoimmunity.  ARRA funded grants to explore the roles of such genes include:
  • A project to generate new mouse models to determine the relationship between CTLA-4—an important genetic risk factor for type 1 diabetes—and other factors that regulate progression to beta cell autoimmunity.4
Advancing Understanding of Diabetes Epigenetics
Epigenetics is the study of differences in the way genes are expressed that are not caused by variations in DNA sequence.  Epigenetic phenomena are thought to play an important role in the development of diabetes and many other diseases, and new technologies are creating key opportunities to better understand these effects.  Among several epigenetic approaches to the study of diabetes facilitated by ARRA funding are:
  • A project that investigates the epigenetic effects of maternal diet during pregnancy on the later development of obesity, a major risk factor for type 2 diabetes, in offspring.5
  • A project to identify the genes regulated by rev-erb (a nuclear receptor), an epigenetic effector of the circadian rhythm and a known modulator of metabolic function.  This is important because of established links between sleep patterns and diseases including diabetes and obesity.6

  1. 1RC2DK088389-01 -- Low-Pass Sequencing and High-Density SNP Genotyping for Type 2 Diabetes -- Altshuler, David; Boehnke, Michael (MI)
  2. 1R01DK084350-01 -- Genetic Contributors to Diabetes and Dyslipidemia in African Americans -- Sale, Michele M (VA)
  3. 1RC1TW008485-01 -- Markers of the Metabolic Syndrome Linking Type 2 Diabetes and MI in South Asia -- Danesh, John Navid; Rader, Daniel James; Saleheen, Danish (PA)
  4. 1RC1DK086474-01 -- Production of Animal Models To Define How CTLA-4 Impacts to T1D Susceptibility -- Kang, Joonsoo (MA)
  5. 1RC1HD063590-01 -- Epidemiology & Epigenetics: Maternal Diet, DNA Methylation, & Offspring Adiposity-- Gillman, Matthew W (MA)
  6. 1RC1DK086239-01-- Genome-Wide Epigenetic Control of Circadian Metabolism by Heme Receptor Rev-erb -- Lazar, Mitchell A (PA)

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