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1、Genetics of Diabetes,Jan Dorman,PhDUniversity of PittsburghSchool of Nursing,Type 1 Diabetes(T1D),Type 1 Diabetes,Caused by the destruction of the pancreatic beta cellsInsulin is no longer producedLeads to hyperglycemia,ketoacidosis and potentially death if not treated with insulin Treatment goals f
2、or T1DMaintaining near normal levels of blood glucoseAvoidance of long-term complications,Type 1 Diabetes,2nd most common chronic childhood diseasePeak age at onset is around pubertyBut T1D can occur at any ageIncidence is increasing worldwide by 3%per yearRelated to increase in T2D?,T1D Incidence W
3、orldwide,Importance of Environmental Risk Factors in T1D,Seasonality at diagnosisMigrants assume risk of host countryRisk factors from case-control studiesInfant/childhood dietViruses exposures as early as in uteroHormonesStressImproved hygieneVitamin D,Importance of Genetic Risk Factors in T1D,Conc
4、ordance in identical twins greater in MZ versus DZ twins15-fold increased risk for 1st degree relativesRisk is 6%through age 30 yearsRisk increases in presence of susceptibility genes,MHC Region Chromosome 6p21,Predisposition to T1D is Better Determined by Haplotypes,DRB1-DQB1 haplotypes more accura
5、tely determine T1D riskTesting for both genes is more expensiveMost screening is based only on DQA1-DQB1High risk T1D haplotypesDQA1*0501-DQB1*0201DQA1*0301-DQB1*0302,Relative Increase in T1D Risk by Number of High Risk Haplotypes,Absolute T1D Risk(to age 30)by Number of High Risk Haplotypes,Absolut
6、e T1D Risk for Siblings of Affected Individuals,Genome Screens for T1D,IDDM2,Insulin(INS)geneChromosome 11p15,OMIM:176730Variable number of tandem repeats(VNTR)Class I:26-63 repeatsClass II:80 repeatsClass III:141-209 repeatsRelative increase in risk 2-fold with two class I alleles(compared to 0 cla
7、ss I alleles)Class I is associated with lower mRNA in the thymus may reduce tolerance to insulin and its precursors,IDDM12,Cytotoxic T Lymphocyte Associated-4(CTLA-4)Chromosome 2q33,OMIM:123890ICOS and CD28 flankEncodes a T cell receptor that plays are role in T cell apoptosisA49G polymorphism(Thr17
8、Ala)Relative increase in risk 1.2Dysfunction of CTLA-4 is consistent with development of T1D,PTPN22,Lymphoid specific tyrosine phosphatase(LYP)Chromosome 1p13,OMIM:600716Encodes a LPY that is important in negative T-cell activation and developmentC858T polymorphism(Arg620Trp)Relative increase in ris
9、k 1.8May alter binding of LYP to cytoplasmic tyrosine kinase,which regulates the T-cell receptor signaling kinases,Intervention Trials for T1D,StudyInterventionTarget/ScreenTRIGRAvoid CMFDR/geneticDIPPInsulin(N)GP/geneticTrialNetImmunosuppressiveFDR/antibodies agents and genetic,CM=cows milk,N=nasal
10、,FDR=first degree relatives,GP=general population,Natural History Studies for T1D,Conducted in the general populationDAISY-ColoradoPANDA-FloridaTEDDY US and EuropeBased on newborn genetic screeningConcerns about proper informed consentParents are notified of the results by mailGeneral population at
11、high risk(5-8%)recruited for follow-up50%of children who will develop T1D not eligible,Genetics and Prevention of T1D,Type 1 diabetes cannot be preventedEthical concerns regarding genetic testing for T1D,especially in childrenEducation programs are need for parents who consent to have their children
12、 involved in such studies because risk estimation isDependent on genes/autoantibodies used for assessmentIs not sensitive or specific,Type 2 Diabetes(T2D),Type 2 Diabetes,Is group of genetically heterogeneous metabolic disorders that cause glucose intoleranceInvolves impaired insulin secretion and i
13、nsulin action90%of individuals with diabetes have T2DConsiderationsMay be treated with diet/oral medications/physical activityT2D individuals may be asymptomatic for many yearsAssociated with long-term complicationsPolygenic and multifactorialCaused by multiple genes that may interactCaused by genet
14、ic and environmental risk factors,Insulin secretionand Insulin resistance,Environmental effects,Genetic effects,Fatty acid levels,Blood glucose levels,From McIntyre and Walker,2002,Thrifty Genotype,Had a selective advantageIn primitive times,individuals who were metabolically thrifty wereAble to sto
15、re a high proportion of energy as fat when food was plentifulMore likely to survive times of famineIn recent years,most populations have A continuous supply of calorie-dense processed foodsReduced physical activityThese changes likely explain the rise in T2D worldwide,Revised Classification Criteria
16、 for T2D,Fasting plasma glucose 7.0 mmol/L 126 mg/dlRandom blood glucose 11.1 mmol/L 200 mg/dl,T2D Prevalence Worldwide,Estimated Number of Adults with Diabetes Developing Countries,Estimated Number of Adults with Diabetes Developed Countries,Increase in T2D in Children,Most T2D children were female
17、s from minority populationsMean age at onset was around pubertyMany had a family history of T2D,Environmental Risk Factors in T2D,ObesityIncreases risk of developing T2DDefined as:120%of ideal body weightBody mass index(BMI)30 k/m2Likely related to the increase in T2D80%newly diagnosed cases due to
18、obesityHigher association with abdominal or central obesity Assessed by measuring the waist-to-hip ratio,Environmental Risk Factors in T2D,Physical ActivityIncreases risk of developing T2DExercise Controls weightImproves glucose and lipid metabolismIs inversely related to body mass indexLifestyle in
19、terventions decreased risk of progression of impaired glucose tolerance to T2D by 60%,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 historyRisk 40%if T2D parent;80%if 2 T2D parentsHigher concordance for MZ
20、 versus DZ twinsHas been difficult to find genes for T2DLate age at onsetPolygenic inheritanceMultifactorial inheritance,Finding Genes for T2D,Candidates selected because they are involved in Pancreatic beta cell functionInsulin action/glucose metabolismEnergy intake/expenditureLipid metabolismGenom
21、e wide screensNothing is assumed about disease etiologyGenome wide association studiesCurrent approach based on thousands of cases and controls,Challenges in Finding Genes,Inadequate sample sizesMultiplex familiesCases and controlsDifficult to define the phenotypeReduced penetranceInfluence of envir
22、onmental factorsGene-gene interactionsVariable age at onsetFailure to replicate findingsGenes identified have small effects,CAPN10 NIDDM1,Chromosome 2q37.3(OMIM 601283)Encodes an intracellular calcium-dependent cytoplasmic protease that is ubiquitously expressedMay modulate activity of enzymes and/o
23、r apoptosisLikely involves insulin secretion and resistanceStronger influence in Mexican Americans than other ethnic groupsResponsible for 40%if familial clusteringGenetic variant:A43G,Thr50Ala,Phe200ThrEstimated relative risk:2,PPAR,Peroxisome proliferator-activated receptor-(chromosome 3p25,OMIM:6
24、01487)Transcription factors that play an important role in adipocyte differentiation and functionIs associated with decreased insulin sensitivity Target for hypoglycemic drugs-thiazolidinedionesGenetic variant:Pro12Ala,Pro is risk allele(common)Estimated relative risk=1-3Variant is common May be res
25、ponsible for 25%of T2D cases,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(encod
26、ed by KCNJ11 4.5 kb apart&near INS)Part of the ATP-sensitive potassium channelInvolved in regulating insulin and glucagonMutations affect channels activity and insulin secretionSite of action of sulfonylureal drugsGenetic variants:Ser1369Ala&Glu23Lys,respectivelyEstimated relative risk=2 4,TCF7L2,Tr
27、anscription 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 dysfunctionStronger among lean versus obese T2D10%of individuals are homozygous have 2-fold increase in risk relative to those with no
28、 copy of the variantResponsive to sulfunynlureals not metforminGenetic variant:re7901695 and others in LDEstimated relative risk 1.4,GWAS New Loci Identified,FTO chr 16q12Fat mass and obesity associated geneGoverns energy balance;gene expression is regulated by feeding and fastingEstimated relative
29、risk 1.23HHEX/IDE chr 10q23-24;near TCF7L2HHEX-Haematopoietically expressed homeoboxTranscription factor in liver cellsIDE-Insulin degrading enzymeHas affinity for insulin;inhibits IDE-mediated degradation of other substancesEstimated relative risk 1.14,GWAS New Loci Identified,CDKAL1 chr 6p22Cyclin
30、-dependent kinase regulatory subunit associated protein 1-like 1Likely plays role in CDK5 inhibition and decreased insulin secretionEstimated relative risk 1.12SLC30A8 chr 8q24Solute carrier family 30 zinc transporterMay be major autoantigen for T1DEstimated relative risk 1.12,GWAS New Loci Identifi
31、ed,IGF2BP2 chr 3q28 Insulin-like growth factor 2 mRNA binding protein 2Regulates IGF2 translation;stimulates insulin actionEstimated relative risk 1.17CDKN2A/B chr 9p21Clycin dependent kinase inhibitor 2APlays role in pancreatic development and islet proliferationEstimated relative risk 1.2,T2D Gene
32、s are Drug Targets,PPAR,ABCC8 and KCNJ11 are the targets of drugs used routinely in the treatment of T2DPharmacogenetic implications Response to oral agents may be related to ones genotypeGenetic testing may Identify individuals at high risk for T2DGuide treatment regimens for T2DIndividualize thera
33、py,Genetics and Prevention of T2D,T2D is preventableMaintaining age-appropriate body weightPhysical activityNew genes will provide insight to etiologyPublic health messages may have a greater influence on genetically susceptibleWill genetic testing prevent T2D?Unclear whether knowledge of ones genet
34、ic risk will lead to behavior modifications,Genetics and Prevention of T2D,Challenges include:Predictive values of most test is lowHow to communicate risk information?Health care professionals may not be able to interpret genetic testsGenetic testing may lead to distress,etc.Insurance and employment
35、 discriminationConfidentiality and stigmatizationDirect to consumer marketing for genetic testing,Maturity Onset Diabetes of the Young(MODY),MODY,Account for 5%of type 2 diabetesSingle gene defectsAutosomal dominant inheritanceMultiple generations affectedEarly age at onset(age 25 years)Characterize
36、d by the absence of obesity,no ketosis and no evidence of beta cell autoimmunityHyperglycemia often corrected by diet,MODY Genes,MODY1 is HNF4A(hepatocyte nuclear factor 4-alpha)on 20q12-q13.1,Transcription factor Expressed in the liver,kidney,intestine and pancreatic islet cellsHas been associated
37、with T2DControls genes involved in glucose,cholesterol and fatty acid metabolismControls transcription of HNF1A(MODY3)Several mutations/splicing defects identifiedAccount for 5%of all MODY cases,MODY2is GCK(glucokinase)on 7p15-p13,Only MODY gene that is not a transcription factorRequired for glucose
38、 metabolism and insulin secretion;acts as a glucose sensorMODY2 is generally a mild form of diabetes 200 mutations have been identified VNTR,nonsense and missense mutationsAccount for 15%of all MODY cases,MODY3 is HNF1A(hepatocyte nuclear factor 1-alpha)on 12q24.2,Regulates expression of insulin and
39、 other genes involved in glucose transport/metabolismInfluences expression of HNF4A(MODY1)Results in a severe insulin secretory defectMay contribute to abnormal islet cell developmentMore than 100 genetic variants have been identifiedMutations in MODY3 are the most common cause of MODYAccount for 65
40、%of all MODY casesSensitive to sulphonylureas,MODY4is IPF1(insulin promoter factor-1)on 13q12.1,Transcription factor that regulates expression of insulin,somatostatin and other genesInvolved in the development of the pancreasIn adults,expressed only in pancreatic cellsMutations lead to decreased bin
41、ding activity to the insulin promoterReduced activation of insulin gene in response to glucoseGenetic variants include frameshift,insertions and missense mutationsAccounts for a very small proportion of MODY cases,MODY5is HNF1B(hepatocyte nuclear factor 1-beta)on 17cen-q21.3,Transcription factor req
42、uired for liver-specific expression of a variety of genesIs highly homologous to HNF1A(MODY3)Recognizes same binding site as HNF1AHNF1A and HNF1B likely interact to regulate gene expressionIndividuals have lower renal threshold to glucoseIs a rare cause of MODY,MODY6is NEUROD1(neurogenic differentia
43、tion factor 1)on 2q32,Is a transcription factor involved in the differentiation of neuronsRegulates insulin gene expression by binding to a critical motif on the insulin promoterFew genetic variants identifiedMissense and nonsense mutationsAccount for 1%of all MODY cases,Summary of MODY Genetics,All
44、 MODY genes are expressed in the pancreas,and play a role in:The metabolism of glucoseThe regulation of insulin or other genes involved in glucose transportThe development of the fetal pancreasMODY phenotype depends on the MODY genotype(on next slide)Knowing the genotype is important to determine treatment,MODY Phenotpes,D=Diet,O=Oral agents,I=Insulin,
