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Genetics of Diabetes

Genetics of Diabetes. Lecture 10. 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

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Genetics of Diabetes

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  1. Genetics of Diabetes Lecture 10

  2. 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

  3. 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?

  4. 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 • Insulin, PTPN22, CTLA4 and IL2RA

  5. MHC Region – Chromosome 6p21

  6. 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

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

  8. Genome Screens for T1D (36)

  9. 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 • Class I is associated with lower mRNA in the thymus – may reduce tolerance to insulin and its precursors

  10. IDDM12 • Cytotoxic T Lymphocyte Associated-4 (CTLA-4) • Chromosome 2q33 • ICOS and CD28 • 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

  11. PTPN22 • Lymphoid specific tyrosine phosphatase (LYP) • Chromosome 1p13, • Encodes a LYP 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

  12. Natural History Studies for T1D • Conducted in the general population • DAISY - Colorado • PANDA - Florida • TEDDY – US and Europe • Type 1 Diabetes Genetics Consortium (T1DGC) • Based on newborn genetic screening • General population

  13. 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

  14. Development of type 1 diabetes

  15. Type 2 Diabetes (T2D)

  16. 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

  17. Genotype • 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

  18. 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

  19. Increase in T2D in Children

  20. 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 single 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

  21. 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

  22. CAPN10 – NIDDM1 • Chromosome 2q37.3 • 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

  23. PPARγ • Peroxisome proliferator-activated receptor-γ (chromosome 3p25) • 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

  24. ABCC8 and KCNJ11 • ATP-binding cassette, subfamily C member 8 (chromosome 11p15.1) • Potassium channel, inwardly rectifying, subfamily J, member 11 (chromosome 11p15.1) • 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

  30. 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

  31. Maturity Onset Diabetes of the Young (MODY)

  32. 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

  33. MODY Genes

  34. 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

  35. 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

  36. 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

  37. 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

  38. MODY5 is HNF1B (hepatocyte nuclear factor 1-beta)on 17cen-q21.3 • Transcription factor required for liver-specific expression of a variety of genes • Is highly homologous to HNF1A (MODY3) • Recognizes same binding site as HNF1A • HNF1A and HNF1B likely interact to regulate gene expression • Individuals have lower renal threshold to glucose • Is a rare cause of MODY

  39. MODY6 is NEUROD1 (neurogenic differentiation factor 1) on2q32 • Is a transcription factor involved in the differentiation of neurons • Regulates insulin gene expression by binding to a critical motif on the insulin promoter • Few genetic variants identified • Missense and nonsense mutations • Account for ~1% of all MODY cases

  40. Summary of MODY Genetics • All MODY genes are expressed in the pancreas, and play a role in: • The metabolism of glucose • The regulation of insulin or other genes involved in glucose transport • The development of the fetal pancreas • MODY phenotype depends on the MODY genotype • Knowing the genotype is important to determine treatment

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