糖尿病的遺傳學(xué)ppt課件

1、Genetics of DiabetesJan Dorman, PhDUniversity of PittsburghSchool of NType 1 Diabetes (T1D)Type 1 DiabetesnCaused by the destruction of the pancreatic beta cellsnInsulin is no longer producednLeads to hyperglycemia, ketoacidosis and potentially death if not treated with insulin nTre

2、atment goals for T1DnMaintaining near normal levels of blood glucosenAvoidance of long-term complicationsType 1 Diabetesn2nd most common chronic childhood diseasenPeak age at onset is around pubertynBut T1D can occur at any agenIncidence is increasing worldwide by 3% per yearnRelated to increase in

3、T2D?T1D Incidence WorldwideImportance of Environmental Risk Factors in T1DnSeasonality at diagnosisnMigrants assume risk of host countrynRisk factors from case-control studiesnInfant/childhood dietnViruses exposures as early as in uteronHormonesnStressnImproved hygienenVitamin DImportance of Genetic

4、 Risk Factors in T1DnConcordance in identical twins greater in MZ versus DZ twinsn15-fold increased risk for 1st degree relativesnRisk is 6% through age 30 yearsnRisk increases in presence of susceptibility genesMHC Region Chromosome 6p21Predisposition to T1D is Better Determined by HaplotypesnDRB1-

5、DQB1 haplotypes more accurately determine T1D risknTesting for both genes is more expensivenMost screening is based only on DQA1-DQB1nHigh risk T1D haplotypesnDQA1*0501-DQB1*0201nDQA1*0301-DQB1*0302Relative Increase in T1D Risk by Number of High Risk HaplotypesNumber of High Risk DQA1-DQB1 haplotype

6、sEthnicity TwoOneCaucasians164African Americans457Asians114Absolute T1D Risk (to age 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 Indivi

7、duals Number of High Risk DQA1-DQB1 HaplotypesTwoOneZeroRisk of developing T1D25%8.3%1%Genome Screens for T1DIDDM16p21IDDM132q34-q35IDDM211p15IDDM156q21IDDM315q26IDDM1710q25IDDM411q13IDDM185q31-q33IDDM56q25-q27PTPN221p13IDDM618q218q24IDDM72q31VDR, INF12q12-qterIDDM86q27-qter16p11-p13IDDM93q21-q2516q

8、22-q24IDDM1010p11-q1117q24-qterIDDM1114q24-q31TGF119p13-q13IDDM122q33Xp11IDDM2nInsulin (INS) genenChromosome 11p15, OMIM: 176730nVariable number of tandem repeats (VNTR)nClass I: 26-63 repeatsnClass II: 80 repeatsnClass III: 141-209 repeatsnRelative increase in risk 2-fold with two class I alleles (

9、compared to 0 class I alleles)nClass I is associated with lower mRNA in the thymus may reduce tolerance to insulin and its precursorsIDDM12nCytotoxic T Lymphocyte Associated-4 (CTLA-4)nChromosome 2q33, OMIM: 123890nICOS and CD28 flanknEncodes a T cell receptor that plays are role in T cell apoptosis

10、nA49G polymorphism (Thr17Ala)nRelative increase in risk 1.2nDysfunction of CTLA-4 is consistent with development of T1DPTPN22nLymphoid specific tyrosine phosphatase (LYP)nChromosome 1p13, OMIM: 600716nEncodes a LPY that is important in negative T-cell activation and developmentnC858T polymorphism (A

11、rg620Trp)nRelative increase in risk 1.8nMay alter binding of LYP to cytoplasmic tyrosine kinase, which regulates the T-cell receptor signaling kinasesIntervention Trials for T1DStudyInterventionTarget /ScreenTRIGRAvoid CMFDR / geneticDIPPInsulin (N)GP / geneticTrialNetImmunosuppressiveFDR / antibodi

12、es agents and geneticNatural History Studies for T1DnConducted in the general populationnDAISY - ColoradonPANDA - FloridanTEDDY US and EuropenBased on newborn genetic screeningnConcerns about proper informed consentnParents are notified of the results by mailnGeneral population at high risk (5-8%) r

13、ecruited for follow-upn50% of children who will develop T1D not eligibleGenetics and Prevention of T1DnType 1 diabetes cannot be preventednEthical concerns regarding genetic testing for T1D, especially in childrennEducation programs are need for parents who consent to have their children involved in

14、 such studies because risk estimation isnDependent on genes/autoantibodies used for assessmentnIs not sensitive or specificType 2 Diabetes (T2D)Type 2 DiabetesnIs group of genetically heterogeneous metabolic disorders that cause glucose intolerancenInvolves impaired insulin secretion and insulin act

15、ionn90% of individuals with diabetes have T2DnConsiderationsnMay be treated with diet / oral medications / physical activitynT2D individuals may be asymptomatic for many yearsnAssociated with long-term complicationsnPolygenic and multifactorialnCaused by multiple genes that may interactnCaused by ge

16、netic and environmental risk factors Insulin secretionand Insulin resistanceEnvironmental effectsGenetic effectsFatty acid levels Blood glucose levelsFrom McIntyre and Walker, 2002Thrifty GenotypenHad a selective advantagenIn primitive times, individuals who were metabolically thrifty werenAble to s

17、tore a high proportion of energy as fat when food was plentifulnMore likely to survive times of faminenIn recent years, most populations have nA continuous supply of calorie-dense processed foodsnReduced physical activitynThese changes likely explain the rise in T2D worldwideRevised Classification C

18、riteria for T2DnFasting plasma glucosen 7.0 mmol/Ln 126 mg/dlnRandom blood glucose n 11.1 mmol/Ln 200 mg/dlT2D Prevalence WorldwideEstimated Number of Adults with Diabetes Developing C/diabetes/actionnow/en/diabprev.pdfEstimated Number of Adults with Diabetes Developed Countrieswho.in

19、t/diabetes/actionnow/en/diabprev.pdfIncrease in T2D in ChildrennMost T2D children were females from minority populationsnMean age at onset was around pubertynMany had a family history of T2DEnvironmental Risk Factors in T2DnObesitynIncreases risk of developing T2DnDefined as:n 120% of ideal body wei

20、ghtnBody mass index (BMI) 30 k / m2nLikely related to the increase in T2Dn80% newly diagnosed cases due to obesitynHigher association with abdominal or central obesity nAssessed by measuring the waist-to- hip ratioEnvironmental Risk Factors in T2DnPhysical ActivitynIncreases risk of developing T2DnE

21、xercise nControls weightnImproves glucose and lipid metabolismnIs inversely related to body mass indexnLifestyle interventions decreased risk of progression of impaired glucose tolerance to T2D by 60%Genetics and T2DnIndividuals with a positive family history are about 2-6 times more likely to devel

22、op T2D than those with a negative family historynRisk 40% if T2D parent; 80% if 2 T2D parentsnHigher concordance for MZ versus DZ twinsnHas been difficult to find genes for T2DnLate age at onsetnPolygenic inheritancenMultifactorial inheritanceFinding Genes for T2DnCandidates selected because they ar

23、e involved in nPancreatic beta cell functionnInsulin action / glucose metabolismnEnergy intake / expenditurenLipid metabolismnGenome wide screensnNothing is assumed about disease etiologynGenome wide association studiesnCurrent approach based on thousands of cases and controlsChallenges in Finding G

24、enesnInadequate sample sizesnMultiplex familiesnCases and controlsnDifficult to define the phenotypenReduced penetrancenInfluence of environmental factorsnGene-gene interactionsnVariable age at onsetnFailure to replicate findingsnGenes identified have small effectsCAPN10 NIDDM1nChromosome 2q37.3 (OM

25、IM 601283)nEncodes an intracellular calcium-dependent cytoplasmic protease that is ubiquitously expressednMay modulate activity of enzymes and/or apoptosisnLikely involves insulin secretion and resistancenStronger influence in Mexican Americans than other ethnic groupsnResponsible for 40% if familia

26、l clusteringnGenetic variant: A43G, Thr50Ala, Phe200ThrnEstimated relative risk: 2PPARnPeroxisome proliferator-activated receptor- (chromosome 3p25, OMIM: 601487)nTranscription factors that play an important role in adipocyte differentiation and functionnIs associated with decreased insulin sensitiv

27、ity nTarget for hypoglycemic drugs -thiazolidinedionesnGenetic variant: Pro12Ala, Pro is risk allele (common)nEstimated relative risk = 1 - 3nVariant is common nMay be responsible for 25% of T2D casesABCC8 and KCNJ11nATP-binding cassette, subfamily C member 8 (chromosome 11p15.1, OMIM 600509)nPotass

28、ium channel, inwardly rectifying, subfamily J, member 11 (chromosome 11p15.1, OMIM 600937)nABCC8 encodes the sulfonylurea receptor (drug target )nIs coupled to the Kir6.2 subunit (encoded by KCNJ11 4.5 kb apart & near INS )nPart of the ATP-sensitive potassium channelnInvolved in regulating insul

29、in and glucagonnMutations affect channels activity and insulin secretionnSite of action of sulfonylureal drugsnGenetic variants: Ser9Ala & Glu23Lys, respectivelynEstimated relative risk = 2 4TCF7L2nTranscription factor 7-like 2 (chromosome 10q25, OMIM 602228)nRelated to impaired insulin release

30、of glucagon-like peptide-1 (islet secretagogue), reduced -cell mass or -cell dysfunctionnStronger among lean versus obese T2Dn10% of individuals are homozygous have 2-fold increase in risk relative to those with no copy of the variantnResponsive to sulfunynlureals not metforminnGenetic variant: re79

31、01695 and others in LDnEstimated relative risk 1.4GWAS New Loci IdentifiednFTO chr 16q12nFat mass and obesity associated genenGoverns energy balance; gene expression is regulated by feeding and fastingnEstimated relative risk 1.23nHHEX/IDE chr 10q23-24; near TCF7L2nHHEX - Haematopoietically expresse

32、d homeoboxnTranscription factor in liver cellsnIDE - Insulin degrading enzymenHas affinity for insulin; inhibits IDE-mediated degradation of other substancesnEstimated relative risk 1.14GWAS New Loci IdentifiednCDKAL1 chr 6p22nCyclin-dependent kinase regulatory subunit associated protein 1-like 1nLi

33、kely plays role in CDK5 inhibition and decreased insulin secretionnEstimated relative risk 1.12nSLC30A8 chr 8q24nSolute carrier family 30 zinc transporternMay be major autoantigen for T1DnEstimated relative risk 1.12GWAS New Loci IdentifiednIGF2BP2 chr 3q28 nInsulin-like growth factor 2 mRNA binding

34、 protein 2nRegulates IGF2 translation; stimulates insulin actionnEstimated relative risk 1.17nCDKN2A/B chr 9p21nClycin dependent kinase inhibitor 2AnPlays role in pancreatic development and islet proliferationnEstimated relative risk 1.2T2D Genes are Drug TargetsnPPAR, ABCC8 and KCNJ11 are the targe

35、ts of drugs used routinely in the treatment of T2DnPharmacogenetic implications nResponse to oral agents may be related to ones genotypenGenetic testing may nIdentify individuals at high risk for T2DnGuide treatment regimens for T2DnIndividualize therapyGenetics and Prevention of T2DnT2D is preventa

36、blenMaintaining age-appropriate body weightnPhysical activitynNew genes will provide insight to etiologynPublic health messages may have a greater influence on genetically susceptiblenWill genetic testing prevent T2D?nUnclear whether knowledge of ones genetic risk will lead to behavior modifications

37、Genetics and Prevention of T2DnChallenges include:nPredictive values of most test is lownHow to communicate risk information?nHealth care professionals may not be able to interpret genetic testsnGenetic testing may lead to distress, etc.nInsurance and employment discriminationnConfidentiality and st

38、igmatizationnDirect to consumer marketing for genetic testingMaturity Onset Diabetes of the Young (MODY)MODYnAccount for 5% of type 2 diabetesnSingle gene defectsnAutosomal dominant inheritancenMultiple generations affectednEarly age at onset (10065%MODY4IPF113q12.1Insulin promotor factor-1FewMODY5H

39、NF1B17cen-q21.3Hepatocyte nuclear factor 1-betaFew3%MODY6NEUROD12q32Neurogenic differentiation factor 1FewMODY1 is HNF4A (hepatocyte nuclear factor 4-alpha) on 20q12-q13.1nTranscription factor nExpressed in the liver, kidney, intestine and pancreatic islet cellsnHas been associated with T2DnControls

40、 genes involved in glucose, cholesterol and fatty acid metabolismnControls transcription of HNF1A (MODY3)nSeveral mutations/splicing defects identifiednAccount for 5% of all MODY casesMODY2 is GCK (glucokinase) on 7p15-p13nOnly MODY gene that is not a transcription factornRequired for glucose metabo

41、lism and insulin secretion; acts as a glucose sensornMODY2 is generally a mild form of diabetesn 200 mutations have been identified nVNTR, nonsense and missense mutationsnAccount for 15% of all MODY casesMODY3 is HNF1A (hepatocyte nuclear factor 1-alpha) on 12q24.2nRegulates expression of insulin an

42、d other genes involved in glucose transport / metabolismnInfluences expression of HNF4A (MODY1)nResults in a severe insulin secretory defectnMay contribute to abnormal islet cell developmentnMore than 100 genetic variants have been identifiednMutations in MODY3 are the most common cause of MODYnAcco

43、unt for 65% of all MODY casesnSensitive to sulphonylureasMODY4 is IPF1 (insulin promoter factor-1) on 13q12.1nTranscription factor that regulates expression of insulin, somatostatin and other genesnInvolved in the development of the pancreasnIn adults, expressed only in pancreatic cellsnMutations lead to decreased binding activity to the insulin