糖尿病的遗传学课件.ppt

1、糖尿病的遗传学Type 1 Diabetes(T1D)Type 1 DiabetesnCaused 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 nTreatment goals for T1D Maintaining near normal levels of blood glucose Avoidance of

2、long-term complicationsType 1 Diabetesn2nd most common chronic childhood diseasenPeak age at onset is around puberty But T1D can occur at any agenIncidence is increasing worldwide by 3%per year Related to increase in T2D?T1D Incidence WorldwideImportance of Environmental Risk Factors in T1DnSeasonal

3、ity at diagnosisnMigrants assume risk of host countrynRisk factors from case-control studies Infant/childhood diet Viruses exposures as early as in utero Hormones Stress Improved hygiene Vitamin DImportance of Genetic Risk Factors in T1DnConcordance in identical twins greater in MZ versus DZ twinsn1

4、5-fold increased risk for 1st degree relatives Risk is 6%through age 30 years Risk increases in presence of susceptibility genesMHC Region Chromosome 6p21Predisposition to T1D is Better Determined by HaplotypesnDRB1-DQB1 haplotypes more accurately determine T1D risknTesting for both genes is more ex

5、pensive Most screening is based only on DQA1-DQB1nHigh risk T1D haplotypes DQA1*0501-DQB1*0201 DQA1*0301-DQB1*0302Relative Increase in T1D Risk by Number of High Risk HaplotypesNumber of High Risk DQA1-DQB1 haplotypesEthnicity TwoOneCaucasians164African Americans457Asians114Absolute T1D Risk(to age

6、30)by Number of High Risk HaplotypesNumber of High Risk DQA1-DQB1 HaplotypesEthnicityTwoOneZeroCaucasians2.6%0.7%0.2%African Americans3.1%0.5%0.1%Asians0.2%0.1%0.02%Absolute T1D Risk for Siblings of Affected Individuals Number of High Risk DQA1-DQB1 HaplotypesTwoOneZeroRisk of developing T1D25%8.3%1

7、%Genome Screens for T1DIDDM16p21IDDM132q34-q35IDDM211p15IDDM156q21IDDM315q26IDDM1710q25IDDM411q13IDDM185q31-q33IDDM56q25-q27PTPN221p13IDDM618q218q24IDDM72q31VDR,INF12q12-qterIDDM86q27-qter16p11-p13IDDM93q21-q2516q22-q24IDDM1010p11-q1117q24-qterIDDM1114q24-q31TGF119p13-q13IDDM122q33Xp11IDDM2nInsulin(

8、INS)genenChromosome 11p15,OMIM:176730nVariable 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)nClass I is associated with lower mRNA in the thymus may reduce tol

9、erance to insulin and its precursorsIDDM12nCytotoxic T Lymphocyte Associated-4(CTLA-4)nChromosome 2q33,OMIM:123890 ICOS and CD28 flanknEncodes a T cell receptor that plays are role in T cell apoptosis A49G polymorphism(Thr17Ala)Relative increase in risk 1.2nDysfunction of CTLA-4 is consistent with d

10、evelopment of T1DPTPN22nLymphoid specific tyrosine phosphatase(LYP)nChromosome 1p13,OMIM:600716nEncodes a LPY that is important in negative T-cell activation and development C858T polymorphism(Arg620Trp)Relative increase in risk 1.8nMay alter binding of LYP to cytoplasmic tyrosine kinase,which regul

11、ates the T-cell receptor signaling kinasesIntervention Trials for T1DStudyInterventionTarget/ScreenTRIGRAvoid CMFDR/geneticDIPPInsulin(N)GP/geneticTrialNetImmunosuppressiveFDR/antibodies agents and geneticNatural History Studies for T1DnConducted in the general populationDAISY-ColoradoPANDA-FloridaT

12、EDDY US and EuropenBased on newborn genetic screeningConcerns about proper informed consentParents are notified of the results by mailGeneral population at high risk(5-8%)recruited for follow-up50%of children who will develop T1D not eligibleGenetics and Prevention of T1DnType 1 diabetes cannot be p

13、reventednEthical concerns regarding genetic testing for T1D,especially in childrennEducation 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 specificType 2 D

14、iabetes(T2D)Type 2 DiabetesnIs group of genetically heterogeneous metabolic disorders that cause glucose intolerance Involves impaired insulin secretion and insulin actionn90%of individuals with diabetes have T2DnConsiderations May be treated with diet/oral medications/physical activity T2D individu

15、als may be asymptomatic for many years Associated with long-term complicationsnPolygenic and multifactorial Caused by multiple genes that may interact Caused by genetic and environmental risk factors Insulin secretionand Insulin resistanceEnvironmental effectsGenetic effectsFatty acid levels Blood g

16、lucose levelsFrom McIntyre and Walker,2002Thrifty GenotypenHad a selective advantagenIn 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 faminenIn recent years,most populations hav

17、e A continuous supply of calorie-dense processed foods Reduced physical activitynThese changes likely explain the rise in T2D worldwideRevised Classification Criteria for T2DnFasting plasma glucose 7.0 mmol/L 126 mg/dlnRandom blood glucose 11.1 mmol/L 200 mg/dlT2D Prevalence WorldwideEstimated Numbe

18、r of Adults with Diabetes Developing Countrieswww.who.int/diabetes/actionnow/en/diabprev.pdfEstimated Number of Adults with Diabetes Developed Countrieswww.who.int/diabetes/actionnow/en/diabprev.pdfIncrease in T2D in ChildrennMost T2D children were females from minority populationsnMean age at onset

19、 was around pubertynMany had a family history of T2DEnvironmental Risk Factors in T2DnObesity 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 abdomin

20、al or central obesity Assessed by measuring the waist-to-hip ratioEnvironmental Risk Factors in T2DnPhysical 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 prog

21、ression of impaired glucose tolerance to T2D by 60%Genetics and T2DnIndividuals 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 parentsnHigher concordance for MZ versus DZ twinsnHas been difficu

22、lt to find genes for T2D Late age at onset Polygenic inheritance Multifactorial inheritanceFinding Genes for T2DnCandidates selected because they are involved in Pancreatic beta cell function Insulin action/glucose metabolism Energy intake/expenditure Lipid metabolismnGenome wide screens Nothing is

23、assumed about disease etiologynGenome wide association studies Current approach based on thousands of cases and controlsChallenges in Finding GenesnInadequate sample sizes Multiplex families Cases and controlsnDifficult to define the phenotypenReduced penetrance Influence of environmental factors Ge

24、ne-gene interactionsnVariable age at onsetnFailure to replicate findingsnGenes identified have small effectsCAPN10 NIDDM1nChromosome 2q37.3(OMIM 601283)Encodes an intracellular calcium-dependent cytoplasmic protease that is ubiquitously expressed May modulate activity of enzymes and/or apoptosis Lik

25、ely 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:2PPARnPeroxisome proliferator-activated receptor-(chromosome 3p25,OMIM:601487)Trans

26、cription 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

27、 for 25%of T2D casesABCC8 and KCNJ11nATP-binding cassette,subfamily C member 8(chromosome 11p15.1,OMIM 600509)nPotassium 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 KC

28、NJ11 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 4TCF7L2nTransc

29、ription factor 7-like 2(chromosome 10q25,OMIM 602228)Related to impaired insulin release of glucagon-like peptide-1(islet secretagogue),reduced-cell mass or-cell dysfunction Stronger among lean versus obese T2D 10%of individuals are homozygous have 2-fold increase in risk relative to those with no c

30、opy of the variant Responsive to sulfunynlureals not metformin Genetic variant:re7901695 and others in LD Estimated relative risk 1.4GWAS New Loci IdentifiednFTO chr 16q12 Fat mass and obesity associated gene Governs energy balance;gene expression is regulated by feeding and fasting Estimated relati

31、ve risk 1.23nHHEX/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 1.14GWAS New Loci IdentifiednCDKAL1 chr 6p

32、22 Cyclin-dependent kinase regulatory subunit associated protein 1-like 1 Likely plays role in CDK5 inhibition and decreased insulin secretion Estimated relative risk 1.12nSLC30A8 chr 8q24 Solute carrier family 30 zinc transporter May be major autoantigen for T1D Estimated relative risk 1.12GWAS New

33、 Loci IdentifiednIGF2BP2 chr 3q28 Insulin-like growth factor 2 mRNA binding protein 2 Regulates IGF2 translation;stimulates insulin action Estimated relative risk 1.17nCDKN2A/B chr 9p21 Clycin dependent kinase inhibitor 2A Plays role in pancreatic development and islet proliferation Estimated relati

34、ve risk 1.2T2D Genes are Drug TargetsnPPAR,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

35、T2D Individualize therapyGenetics and Prevention of T2DnT2D is preventable Maintaining age-appropriate body weight Physical activitynNew genes will provide insight to etiologynPublic health messages may have a greater influence on genetically susceptiblenWill genetic testing prevent T2D?Unclear whet

36、her knowledge of ones genetic risk will lead to behavior modificationsGenetics and Prevention of T2DnChallenges 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,

37、etc.Insurance and employment discrimination Confidentiality and stigmatization Direct to consumer marketing for genetic testingMaturity Onset Diabetes of the Young(MODY)MODYnAccount for 5%of type 2 diabetesnSingle gene defects Autosomal dominant inheritance Multiple generations affectednEarly age at

38、 onset(10065%MODY4IPF113q12.1Insulin promotor factor-1FewMODY5HNF1B17cen-q21.3Hepatocyte nuclear factor 1-betaFew3%MODY6NEUROD12q32Neurogenic differentiation factor 1FewMODY1 is HNF4A(hepatocyte nuclear factor 4-alpha)on 20q12-q13.1nTranscription factor Expressed in the liver,kidney,intestine and pa

39、ncreatic islet cells Has been associated with T2DnControls genes involved in glucose,cholesterol and fatty acid metabolismnControls transcription of HNF1A(MODY3)nSeveral mutations/splicing defects identified Account for 5%of all MODY casesMODY2 is GCK(glucokinase)on 7p15-p13nOnly MODY gene that is n

40、ot a transcription factornRequired for glucose metabolism and insulin secretion;acts as a glucose sensornMODY2 is generally a mild form of diabetesn 200 mutations have been identified VNTR,nonsense and missense mutations Account for 15%of all MODY casesMODY3 is HNF1A(hepatocyte nuclear factor 1-alph

41、a)on 12q24.2nRegulates expression of insulin and other genes involved in glucose transport/metabolism Influences expression of HNF4A(MODY1)nResults in a severe insulin secretory defect May contribute to abnormal islet cell developmentnMore than 100 genetic variants have been identifiednMutations in

42、MODY3 are the most common cause of MODY Account for 65%of all MODY cases Sensitive to sulphonylureasMODY4 is IPF1(insulin promoter factor-1)on 13q12.1nTranscription factor that regulates expression of insulin,somatostatin and other genes Involved in the development of the pancreas In adults,expresse

43、d only in pancreatic cellsnMutations lead to decreased binding activity to the insulin promoter Reduced activation of insulin gene in response to glucosenGenetic variants include frameshift,insertions and missense mutations Accounts for a very small proportion of MODY casesMODY5 is HNF1B(hepatocyte

44、nuclear factor 1-beta)on 17cen-q21.3nTranscription factor required for liver-specific expression of a variety of genesnIs highly homologous to HNF1A(MODY3)Recognizes same binding site as HNF1AnHNF1A and HNF1B likely interact to regulate gene expressionnIndividuals have lower renal threshold to gluco

45、senIs a rare cause of MODYMODY6 is NEUROD1(neurogenic differentiation factor 1)on 2q32nIs a transcription factor involved in the differentiation of neuronsnRegulates insulin gene expression by binding to a critical motif on the insulin promoternFew genetic variants identified Missense and nonsense m

46、utations Account for 1%of all MODY casesSummary of MODY GeneticsnAll 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 pancreasnMODY phenotype depends on the MODY genotype(on next slide)nKnowing the genotype is important to determine treatmentMODY PhenotpesTypeOnsetComplicationsTreatmentMODY1SevereFrequentD,O,IMODY2MildRareDMODY3SevereFrequentD,O,IMODY4ModerateLittle dataO,IMODY5SevereRenal diseaseO,IMODY6SevereLittle DataD,O,OD=Diet,O=Oral agents,I=Insulin