Download Free Medical Genetics Of Diabetes PowerPoint Presentation

Genetics Of Diabetes PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : Download Free Genetics Of Diabetes Professional PowerPoint Presentation for your presentation

Tags : genetics of diabetes

Published on : Jul 06, 2017 | Views : 3600 | Downloads : 18

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

Genetics of Diabetes Jan Dorman, PhD University of Pittsburgh School of Nursing jsd@pitt.edu
Slide 2-

Type 1 Diabetes (T1D)
Slide 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
Slide 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?
Slide 5-

T1D Incidence Worldwide
Slide 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
Slide 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
Slide 8-

MHC Region – Chromosome 6p21
Slide 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
Slide 10-

Relative Increase in T1D Risk by Number of High Risk Haplotypes
Slide 11-

Absolute T1D Risk (to age 30) by Number of High Risk Haplotypes
Slide 12-

Absolute T1D Risk for Siblings of Affected Individuals
Slide 13-

Genome Screens for T1D
Slide 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
Slide 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
Slide 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
Slide 17-

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
Slide 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
Slide 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
Slide 20-

Type 2 Diabetes (T2D)
Slide 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
Slide 22-

Insulin secretion and Insulin resistance Environmental effects Genetic effects Fatty acid levels Blood glucose levels From McIntyre and Walker, 2002
Slide 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
Slide 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
Slide 25-

T2D Prevalence Worldwide
Slide 26-

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

Estimated Number of Adults with Diabetes – Developed Countries www.who.int/diabetes/actionnow/en/diabprev.pdf
Slide 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
Slide 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
Slide 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%
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 44-

Maturity Onset Diabetes of the Young (MODY)
Slide 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
Slide 46-

MODY Genes
Slide 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
Slide 48-

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
Slide 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
Slide 50-

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
Slide 51-

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
Slide 52-

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
Slide 53-

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
Slide 54-

MODY Phenotpes D = Diet, O = Oral agents, I = Insulin
Slide 55-

Thank You