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Genetics of Diabetes

Genetics of Diabetes. Jan Dorman, PhD University of Pittsburgh School of Nursing jsd@pitt.edu. Type 1 Diabetes (T1D). Type 1 Diabetes. Caused by the destruction of the pancreatic beta cells Insulin is no longer produced

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Genetics of Diabetes

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  1. Genetics of Diabetes Jan Dorman, PhD University of Pittsburgh School of Nursing jsd@pitt.edu

  2. Type 1 Diabetes (T1D)

  3. Type 1 Diabetes • Caused by the destruction of the pancreatic beta cells • Insulin is no longer produced • Leads to hyperglycemia, ketoacidosis and potentially death if not treated with insulin • Treatment goals for T1D • Maintaining near normal levels of blood glucose • Avoidance of long-term complications

  4. Type 1 Diabetes • 2nd most common chronic childhood disease • Peak age at onset is around puberty • But T1D can occur at any age • Incidence is increasing worldwide by ~3% per year • Related to increase in T2D?

  5. T1D Incidence Worldwide

  6. Importance of Environmental Risk Factors in T1D • Seasonality at diagnosis • Migrants assume risk of host country • Risk factors from case-control studies • Infant/childhood diet • Viruses – exposures as early as in utero • Hormones • Stress • Improved hygiene • Vitamin D

  7. Importance of Genetic Risk Factors in T1D • Concordance in identical twins greater in MZ versus DZ twins • 15-fold increased risk for 1st degree relatives • Risk is ~6% through age 30 years • Risk increases in presence of susceptibility genes

  8. MHC Region – Chromosome 6p21

  9. Predisposition to T1D is Better Determined by Haplotypes • DRB1-DQB1 haplotypes more accurately determine T1D risk • Testing for both genes is more expensive • Most screening is based only on DQA1-DQB1 • High risk T1D haplotypes • DQA1*0501-DQB1*0201 • DQA1*0301-DQB1*0302

  10. Relative Increase in T1D Risk by Number of High Risk Haplotypes

  11. Absolute T1D Risk (to age 30) by Number of High Risk Haplotypes

  12. Absolute T1D Risk for Siblings of Affected Individuals

  13. Genome Screens for T1D

  14. IDDM2 • Insulin (INS) gene • Chromosome 11p15, OMIM: 176730 • Variable number of tandem repeats (VNTR) • Class I: 26-63 repeats • Class II: ~80 repeats • Class III: 141-209 repeats • Relative increase in risk ~2-fold with two class I alleles (compared to 0 class I alleles) • Class I is associated with lower mRNA in the thymus – may reduce tolerance to insulin and its precursors

  15. IDDM12 • Cytotoxic T Lymphocyte Associated-4 (CTLA-4) • Chromosome 2q33, OMIM: 123890 • ICOS and CD28 flank • Encodes a T cell receptor that plays are role in T cell apoptosis • A49G polymorphism (Thr17Ala) • Relative increase in risk ~ 1.2 • Dysfunction of CTLA-4 is consistent with development of T1D

  16. PTPN22 • Lymphoid specific tyrosine phosphatase (LYP) • Chromosome 1p13, OMIM: 600716 • Encodes a LPY that is important in negative T-cell activation and development • C858T polymorphism (Arg620Trp) • Relative increase in risk ~ 1.8 • May alter binding of LYP to cytoplasmic tyrosine kinase, which regulates the T-cell receptor signaling kinases

  17. Intervention Trials for T1D StudyIntervention Target /Screen TRIGR Avoid CM FDR / genetic DIPP Insulin (N) GP / genetic TrialNet Immunosuppressive FDR / antibodies agents and genetic CM = cows milk, N = nasal, FDR = first degree relatives, GP = general population

  18. Natural History Studies for T1D • Conducted in the general population • DAISY - Colorado • PANDA - Florida • TEDDY – US and Europe • Based on newborn genetic screening • Concerns about proper informed consent • Parents are notified of the results by mail • General population at ‘high’ risk (5-8%) recruited for follow-up >50% of children who will develop T1D not eligible

  19. Genetics and Prevention of T1D • Type 1 diabetes cannot be prevented • Ethical concerns regarding genetic testing for T1D, especially in children • Education programs are need for parents who consent to have their children involved in such studies because risk estimation is • Dependent on genes/autoantibodies used for assessment • Is not sensitive or specific

  20. Type 2 Diabetes (T2D)

  21. Type 2 Diabetes • Is group of genetically heterogeneous metabolic disorders that cause glucose intolerance • Involves impaired insulin secretion and insulin action • ~90% of individuals with diabetes have T2D • Considerations • May be treated with diet / oral medications / physical activity • T2D individuals may be asymptomatic for many years • Associated with long-term complications • Polygenic and multifactorial • Caused by multiple genes that may interact • Caused by genetic and environmental risk factors

  22. Blood glucose levels Genetic effects Insulin secretion and Insulin resistance Environmental effects Fatty acid levels From McIntyre and Walker, 2002

  23. Thrifty Genotype • Had a selective advantage • In primitive times, individuals who were ‘metabolically thrifty’ were • Able to store a high proportion of energy as fat when food was plentiful • More likely to survive times of famine • In recent years, most populations have • A continuous supply of calorie-dense processed foods • Reduced physical activity • These changes likely explain the rise in T2D worldwide

  24. Revised Classification Criteria for T2D • Fasting plasma glucose • > 7.0 mmol/L • > 126 mg/dl • Random blood glucose • > 11.1 mmol/L • > 200 mg/dl

  25. T2D Prevalence Worldwide

  26. Estimated Number of Adults with Diabetes – Developing Countries www.who.int/diabetes/actionnow/en/diabprev.pdf

  27. Estimated Number of Adults with Diabetes – Developed Countries www.who.int/diabetes/actionnow/en/diabprev.pdf

  28. Increase in T2D in Children • Most T2D children were females from minority populations • Mean age at onset was around puberty • Many had a family history of T2D

  29. Environmental Risk Factors in T2D • Obesity • Increases risk of developing T2D • Defined as: • > 120% of ideal body weight • Body mass index (BMI) > 30 k / m2 • Likely related to the increase in T2D • ~80% newly diagnosed cases due to obesity • Higher association with abdominal or central obesity • Assessed by measuring the waist-to- hip ratio

  30. Environmental Risk Factors in T2D • Physical Activity • Increases risk of developing T2D • Exercise • Controls weight • Improves glucose and lipid metabolism • Is inversely related to body mass index • Lifestyle interventions decreased risk of progression of impaired glucose tolerance to T2D by ~60%

  31. Genetics and T2D • Individuals with a positive family history are about 2-6 times more likely to develop T2D than those with a negative family history • Risk ~40% if T2D parent; ~80% if 2 T2D parents • Higher concordance for MZ versus DZ twins • Has been difficult to find genes for T2D • Late age at onset • Polygenic inheritance • Multifactorial inheritance

  32. Finding Genes for T2D • Candidates selected because they are involved in • Pancreatic beta cell function • Insulin action / glucose metabolism • Energy intake / expenditure • Lipid metabolism • Genome wide screens • Nothing is assumed about disease etiology • Genome wide association studies • Current approach based on thousands of cases and controls

  33. Challenges in Finding Genes • Inadequate sample sizes • Multiplex families • Cases and controls • Difficult to define the phenotype • Reduced penetrance • Influence of environmental factors • Gene-gene interactions • Variable age at onset • Failure to replicate findings • Genes identified have small effects

  34. CAPN10 – NIDDM1 • Chromosome 2q37.3 (OMIM 601283) • Encodes an intracellular calcium-dependent cytoplasmic protease that is ubiquitously expressed • May modulate activity of enzymes and/or apoptosis • Likely involves insulin secretion and resistance • Stronger influence in Mexican Americans than other ethnic groups • Responsible for ~40% if familial clustering • Genetic variant: A43G, Thr50Ala, Phe200Thr • Estimated relative risk: ~2

  35. PPARγ • Peroxisome proliferator-activated receptor-γ (chromosome 3p25, OMIM: 601487) • Transcription factors that play an important role in adipocyte differentiation and function • Is associated with decreased insulin sensitivity • Target for hypoglycemic drugs -thiazolidinediones • Genetic variant: Pro12Ala, Pro is risk allele (common) • Estimated relative risk = 1 - 3 • Variant is common • May be responsible for ~25% of T2D cases

  36. ABCC8 and KCNJ11 • ATP-binding cassette, subfamily C member 8 (chromosome 11p15.1, OMIM 600509) • Potassium channel, inwardly rectifying, subfamily J, member 11 (chromosome 11p15.1, OMIM 600937) • ABCC8 encodes the sulfonylurea receptor (drug target ) • Is coupled to the Kir6.2 subunit (encoded by KCNJ11 – 4.5 kb apart & near INS ) • Part of the ATP-sensitive potassium channel • Involved in regulating insulin and glucagon • Mutations affect channel’s activity and insulin secretion • Site of action of sulfonylureal drugs • Genetic variants: Ser1369Ala & Glu23Lys, respectively • Estimated relative risk = 2 – 4

  37. TCF7L2 • Transcription factor 7-like 2 (chromosome 10q25, OMIM 602228) • Related to impaired insulin release of glucagon-like peptide-1 (islet secretagogue), reduced β-cell mass or β-cell dysfunction • Stronger among lean versus obese T2D • 10% of individuals are homozygous have 2-fold increase in risk relative to those with no copy of the variant • Responsive to sulfunynlureals not metformin • Genetic variant: re7901695 and others in LD • Estimated relative risk ~ 1.4

  38. GWAS New Loci Identified • FTO – chr 16q12 • Fat mass and obesity associated gene • Governs energy balance; gene expression is regulated by feeding and fasting • Estimated relative risk ~ 1.23 • HHEX/IDE – chr 10q23-24; near TCF7L2 • HHEX - Haematopoietically expressed homeobox • Transcription factor in liver cells • IDE - Insulin degrading enzyme • Has affinity for insulin; inhibits IDE-mediated degradation of other substances • Estimated relative risk ~ 1.14

  39. GWAS New Loci Identified • CDKAL1 – chr 6p22 • Cyclin-dependent kinase regulatory subunit associated protein 1-like 1 • Likely plays role in CDK5 inhibition and decreased insulin secretion • Estimated relative risk ~ 1.12 • SLC30A8 – chr 8q24 • Solute carrier family 30 zinc transporter • May be major autoantigen for T1D • Estimated relative risk ~ 1.12

  40. GWAS New Loci Identified • IGF2BP2 – chr 3q28 • Insulin-like growth factor 2 mRNA binding protein 2 • Regulates IGF2 translation; stimulates insulin action • Estimated relative risk ~ 1.17 • CDKN2A/B – chr 9p21 • Clycin dependent kinase inhibitor 2A • Plays role in pancreatic development and islet proliferation • Estimated relative risk ~ 1.2

  41. T2D Genes are Drug Targets • PPARγ, ABCC8 and KCNJ11 are the targets of drugs used routinely in the treatment of T2D • Pharmacogenetic implications • Response to oral agents may be related to one’s genotype • Genetic testing may • Identify individuals at high risk for T2D • Guide treatment regimens for T2D • Individualize therapy

  42. Genetics and Prevention of T2D • T2D is preventable • Maintaining age-appropriate body weight • Physical activity • New genes will provide insight to etiology • Public health messages may have a greater influence on genetically susceptible • Will genetic testing prevent T2D? • Unclear whether knowledge of one’s genetic risk will lead to behavior modifications

  43. Genetics and Prevention of T2D • Challenges include: • Predictive values of most test is low • How to communicate risk information? • Health care professionals may not be able to interpret genetic tests • Genetic testing may lead to distress, etc. • Insurance and employment discrimination • Confidentiality and stigmatization • Direct to consumer marketing for genetic testing

  44. Maturity Onset Diabetes of the Young (MODY)

  45. MODY • Account for ~ 5% of type 2 diabetes • Single gene defects • Autosomal dominant inheritance • Multiple generations affected • Early age at onset (< age 25 years) • Characterized by the absence of obesity, no ketosis and no evidence of beta cell autoimmunity • Hyperglycemia often corrected by diet

  46. MODY Genes

  47. MODY1 is HNF4A (hepatocyte nuclear factor 4-alpha) on 20q12-q13.1 • Transcription factor • Expressed in the liver, kidney, intestine and pancreatic islet cells • Has been associated with T2D • Controls genes involved in glucose, cholesterol and fatty acid metabolism • Controls transcription of HNF1A (MODY3) • Several mutations/splicing defects identified • Account for ~5% of all MODY cases

  48. MODY2 is GCK (glucokinase) on7p15-p13 • Only MODY gene that is not a transcription factor • Required for glucose metabolism and insulin secretion; acts as a glucose ‘sensor’ • MODY2 is generally a mild form of diabetes • ~ 200 mutations have been identified • VNTR, nonsense and missense mutations • Account for ~15% of all MODY cases

  49. MODY3 is HNF1A (hepatocyte nuclear factor 1-alpha) on 12q24.2 • Regulates expression of insulin and other genes involved in glucose transport / metabolism • Influences expression of HNF4A (MODY1) • Results in a severe insulin secretory defect • May contribute to abnormal islet cell development • More than 100 genetic variants have been identified • Mutations in MODY3 are the most common cause of MODY • Account for ~65% of all MODY cases • Sensitive to sulphonylureas

  50. MODY4is IPF1 (insulin promoter factor-1) on13q12.1 • Transcription factor that regulates expression of insulin, somatostatin and other genes • Involved in the development of the pancreas • In adults, expressed only in pancreatic cells • Mutations lead to decreased binding activity to the insulin promoter • Reduced activation of insulin gene in response to glucose • Genetic variants include frameshift, insertions and missense mutations • Accounts for a very small proportion of MODY cases

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