Genetics of Diabetes

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Genetics of Diabetes

• Jan Dorman, PhD
• University of Pittsburgh
• School of Nursing
• jsd_at_pitt.edu

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Type 1 Diabetes (T1D)
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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

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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?

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T1D Incidence Worldwide
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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

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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

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MHC Region Chromosome 6p21
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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
• DQA10501-DQB10201
• DQA10301-DQB10302

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Relative Increase in T1D Risk by Number of High
Risk Haplotypes
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Absolute T1D Risk (to age 30) by Number of High
Risk Haplotypes
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Absolute T1D Risk for Siblings of Affected
Individuals
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Genome Screens for T1D
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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

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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

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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

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Intervention Trials for T1D

• Study Intervention 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

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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

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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

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Type 2 Diabetes (T2D)
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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

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

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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

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T2D Prevalence Worldwide
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Estimated Number of Adults with Diabetes
Developing Countries
www.who.int/diabetes/actionnow/en/diabprev.pdf
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Estimated Number of Adults with Diabetes
Developed Countries
www.who.int/diabetes/actionnow/en/diabprev.pdf
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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

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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

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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

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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

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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

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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

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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

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PPAR?

• Peroxisome proliferator-activated receptor-?
  (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

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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 channels activity and insulin
  secretion
• Site of action of sulfonylureal drugs
• Genetic variants Ser1369Ala Glu23Lys,
  respectively
• Estimated relative risk 2 4

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TCF7L2

• Transcription factor 7-like 2 (chromosome 10q25,
  OMIM 602228)
• Related to impaired insulin release of
  glucagon-like peptide-1 (islet secretagogue),
  reduced ß-cell mass or ß-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

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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

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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

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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

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T2D Genes are Drug Targets

• PPAR?, 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 ones
  genotype
• Genetic testing may
• Identify individuals at high risk for T2D
• Guide treatment regimens for T2D
• Individualize therapy

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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 ones genetic risk
  will lead to behavior modifications

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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

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Maturity Onset Diabetes of the Young (MODY)
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MODY

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

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MODY Genes
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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

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MODY2 is GCK (glucokinase) on 7p15-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

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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

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MODY4 is IPF1 (insulin promoter factor-1) on
13q12.1

• 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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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

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MODY6 is NEUROD1 (neurogenic differentiation
factor 1) on 2q32

• 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

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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 (on
  next slide)
• Knowing the genotype is important to determine
  treatment

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MODY Phenotpes
D Diet, O Oral agents, I Insulin