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1、Genetics of Diabetes,Jan Dorman, PhD University of Pittsburgh School of Nursing jsdpitt.edu,Type 1 Diabetes (T1D),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 insuli
2、n Treatment goals for T1D Maintaining near normal levels of blood glucose Avoidance of long-term complications,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 increa
3、se in T2D?,T1D Incidence Worldwide,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,Importance o
4、f 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,MHC Region Chromosome 6p21,Predisposition to T1D is Better Determined by Haplo
5、types,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,Relative Increase in T1D Risk by Number of High Risk Haplotypes,Absolute T1D Risk (to age
6、30) by Number of High Risk Haplotypes,Absolute T1D Risk for Siblings of Affected Individuals,Genome Screens for T1D,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 increas
7、e 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,IDDM12,Cytotoxic T Lymphocyte Associated-4 (CTLA-4) Chromosome 2q33, OMIM: 123890 ICOS and CD28 flank Encodes a T cell rece
8、ptor 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,PTPN22,Lymphoid specific tyrosine phosphatase (LYP) Chromosome 1p13, OMIM: 600716 Encodes a LPY that is important in negative T-cell act
9、ivation 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,Intervention Trials for T1D,Study Intervention Target /Screen TRIGR Avoid CM FDR / genetic DIPP Insulin
10、(N) GP / genetic TrialNet Immunosuppressive FDR / antibodies agents and genetic,CM = cows milk, N = nasal, FDR = first degree relatives, GP = general population,Natural History Studies for T1D,Conducted in the general population DAISY - Colorado PANDA - Florida TEDDY US and Europe Based on newborn g
11、enetic 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,Genetics and Prevention of T1D,Type 1 diabetes cannot be prevented Ethical concerns reg
12、arding 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,Type 2 Diabetes (T2D),Type 2 Diabet
13、es,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 asymptoma
14、tic 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,Insulin secretion and Insulin resistance,Environmental effects,Genetic effects,Fatty acid levels,Blood glucose levels,Fr
15、om McIntyre and Walker, 2002,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 continu
16、ous supply of calorie-dense processed foods Reduced physical activity These changes likely explain the rise in T2D worldwide,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,T2D Prevalence Worldwide,Estimated Number of Adu
17、lts with Diabetes Developing Countries,www.who.int/diabetes/actionnow/en/diabprev.pdf,Estimated Number of Adults with Diabetes Developed Countries,www.who.int/diabetes/actionnow/en/diabprev.pdf,Increase in T2D in Children,Most T2D children were females from minority populations Mean age at onset was
18、 around puberty Many had a family history of T2D,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 abd
19、ominal or central obesity Assessed by measuring the waist-to- hip ratio,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 o
20、f 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 history Risk 40% if T2D parent; 80% if 2 T2D parents Higher concordance for MZ versus DZ twins Has be
21、en difficult to find genes for T2D Late age at onset Polygenic inheritance Multifactorial inheritance,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 scre
22、ens Nothing is assumed about disease etiology Genome wide association studies Current approach based on thousands of cases and controls,Challenges in Finding Genes,Inadequate sample sizes Multiplex families Cases and controls Difficult to define the phenotype Reduced penetrance Influence of environm
23、ental factors Gene-gene interactions Variable age at onset Failure to replicate findings Genes identified have small effects,CAPN10 NIDDM1,Chromosome 2q37.3 (OMIM 601283) Encodes an intracellular calcium-dependent cytoplasmic protease that is ubiquitously expressed May modulate activity of enzymes a
24、nd/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,PPAR,Peroxisome proliferator-activated receptor- (chromos
25、ome 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 -
26、3 Variant is common May be responsible 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 tar
27、get ) 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 & Gl
28、u23Lys, respectively Estimated relative risk = 2 4,TCF7L2,Transcription 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
29、 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,GWAS New Loci Identified,FTO chr 16q12 Fat mass and obesity associated gene Governs energy ba
30、lance; 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 ot
31、her substances Estimated relative risk 1.14,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
32、 transporter May be major autoantigen for T1D Estimated relative risk 1.12,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 inhibi
33、tor 2A Plays role in pancreatic development and islet proliferation Estimated relative risk 1.2,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 Genet
34、ic testing may Identify individuals at high risk for T2D Guide treatment regimens for T2D Individualize therapy,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 gre
35、ater influence on genetically susceptible Will genetic testing prevent T2D? Unclear whether knowledge of ones genetic risk will lead to behavior modifications,Genetics and Prevention of T2D,Challenges include: Predictive values of most test is low How to communicate risk information? Health care pro
36、fessionals 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,Maturity Onset Diabetes of the Young (MODY),MODY,Account for 5% of type 2 diabe
37、tes 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,MODY Genes,MODY1 is HNF4A (hepatocyte nuclear fa
38、ctor 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 ide
39、ntified Account for 5% of all MODY cases,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, nonsen
40、se and missense mutations Account for 15% of all MODY cases,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
41、 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,MODY4 is IPF1 (insulin promoter factor-1) on 13q12.1,Transcription factor that regulat
42、es 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 fra
43、meshift, insertions and missense mutations Accounts for a very small proportion of MODY cases,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 bindi
44、ng 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,MODY6 is NEUROD1 (neurogenic differentiation factor 1) on 2q32,Is a transcription factor involved in the differentiation of neurons Regulates insulin
45、 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,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,MODY Phenotpes,D = Diet, O = Oral agents, I = Insulin,