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  • 1. Murugu Manickam, MD discloses no significant financial interests or other relationships with commercial interests. Presentation will not include discussion of commercial products or services and will not include unapproved or off-label usage of a commercial product or device. Genetics of Diabetes: An Overview Murugu Manickam, MD Clinical Assistant Professor Division of Human Genetics
  • 2. Diabetes Mellitus
    • Increasingly common disease consisting for multiple forms
      • Type 1: insulin deficiency
      • Type 2: insulin resistance
      • Gestational diabetes: only pregnancy-associated
    • Overlap is considerable
      • Insulin resistance to insulin deficiency over time
      • Gestational diabetes to insulin resistance
  • 3. Diabetes
    • Well recognized risk factors
      • Obesity
      • Metabolic syndrome
      • Chronic pancreatitis/pancreatic injury
      • Autoimmune disease
  • 4. Genetic Risk Factors
    • Rare diseases associated with development of diabetes
      • Cystic fibrosis
      • Hemochromatosis
      • Pheochromocytoma
      • Insulin receptor defects
      • Proinsulin cleavage enzyme defect
    Autosomal recessive
  • 5. Genetic Risk Factors
    • Rarer disease associated with development of diabetes
      • MODY: maturity onset diabetes of the young
        • Appears acutely like insulin dependent at older age
        • Multiple genes involved (but all appear to transmit autosomal dominant manner)
    Autosomal dominant
  • 6. Genetic Risk Factors
    • Very rare diseases associated with development of diabetes
      • Mitochondrial disorders: both autosomal recessive inheritance and mitochondrial inheritance (maternal transmission to all children)
      • MELAS: mitochondrial encephalopathy, lactic acidosis, stroke like symptoms
      • MNGIE, Kearns-Sayre also associated
  • 7. Genomics and Diabetes
    • There is clear evidence that diabetes as a strong genetic component
    • Type II
    • 1 parent affected: 1 in 10
    • 2 parents affected: 1 in 2
    • monozygotic twin studies: 2 in 3
      • Last is important that it is independent of diet
    • Type I
    • smaller risk with an affected relative
  • 8.
    • Diabetes has been one of the most investigated areas in genome wide association studies by single nucleotide polymorphisms
      • Over 40 to this point have been identified
      • Most have small relative risk and replication studies are variable
      • Individually likely small effect but combination of risks is not well defined
      • Some have identified previously unrealized genes associated with diabetes including regulatory genes and enzyme controls
  • 9.
    • Still some the findings have been very revealing
      • On chromosome 9,several SNPs have been independently associated with obesity, diabetes, heart disease
      • variant in  PPARG  and a variant in  KCNJ11  are located in genes that encode drug targets (thiazolidinediones and sulfonylureas, respectively)
        • But to date no difference in dosing
  • 10. Pharmacogenomics
    • Patients with maturity onset diabetes of the young type 3 (due to mutations in  HNF1A ) seem to respond better to sulfonylureas than to metformin
  • 11. Summary
    • There are some rare causes to diabetes that are inherited in an autosomal dominant manner- MODY most significantly
    • Most SNP associated risks for diabetes only confer a small risk to the individual
    • Diabetes SNPs have proven valuable for insight into disease mechanism but not for prediction of disease