Genetica e Diabete di tipo 1: an update - Dott Rosa Anna Rabini

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  • Lists the loci linked to diabetes, will mention green loci
  • Genetica e Diabete di tipo 1: an update - Dott Rosa Anna Rabini

    1. 1. GENETICA E DIABETE TIPO 1: AN UPDATE Rosa Anna Rabini U.O. Malattie Metaboliche e Diabetologia INRCA - Ancona
    2. 5. HLA H uman L eukocyte A ntigen human MHC cell-surface proteins important in self vs. nonself distinction present peptide antigens to T cells CLASS I: A,B,C CLASS II: DR,DQ,DP J. Noble
    3. 7. DQB1*0402 Asp57  Leu56   -chain  -chain BDC BDC
    4. 8. Major DR/DQ Associations <ul><li>Type 1 Diabetes DR3: DRB1*0301/DQA1*0501/DQB1*0201 DR4: DRB1*0401/DQA1*0301/DQb1*0302 </li></ul><ul><li>Celiac Disease The same as Type 1 DM plus DR5/DR7 = DQA1*0501/DQB1*0201 in trans </li></ul><ul><li>Addison’s Disease The same as Type 1 DM but DRB1*0404 preference (Yu, JCEM 84:328,1999) </li></ul>BDC
    5. 10. Insulin Gene (INS) Class I VNTR 26-63 repeats 21 alleles Predisposing IDDM2 Insulin Gene (INS) Class III VNTR 140-200 repeats 15 alleles IDDM2 Protective The IDDM2 Locus VNTR = Variable Number of Tandem Repeats
    6. 12. Inherited Susceptibility Loci LOCUS CHROMOSOME CANDIDATE GENES or MICROSATELLITES IDDM1 6p21 HLA-DQDR IDDM2 11p15 INS VNTR IDDM3 15q26 D15s107 IDDM4 11q13 MDU1 , ZFM1 , RT6 , FADD/MORT1, LRP5 IDDM5 6q24-27 ESR , MnSOD IDDM6 18q12-q21 D18s487 , D18s64, JK (Kidd locus) IDDM7 2q31 D2s152, IL-1, NEUROD, GALNT3 IDDM8 6q25-27 D6s264, D6s446, D6s281 IDDM9 3q21-25 D3s1303 IDDM10 10p11-q11 D10s193, D10s208, D10s588 IDDM11 14q24.3-q31 D14s67 IDDM12 2q33 CTLA -4, CD28 IDDM13 2q34 D2s137, D2s164, IGFBP2, IGFBP5 IDDM14 ? NCBI # 3413 IDDM15 6q21 D6s283, D6s434, D6s1580 IDDM16 ? NCBI # 3415 IDDM17 10q25 D10s1750-D10s1773 OTHERS
    7. 13. Genome Screens for T1D IDDM1 6p21 IDDM13 2q34-q35 IDDM2 11p15 IDDM15 6q21 IDDM3 15q26 IDDM17 10q25 IDDM4 11q13 IDDM18 5q31-q33 IDDM5 6q25-q27 1q42-qter IDDM6 18q21 8q24 IDDM7 2q31 VDR, INF γ 12q12-qter IDDM8 6q27-qter 16p11-p13 IDDM9 3q21-q25 16q22-q24 IDDM10 10p11-q11 17q24-qter IDDM11 14q24-q31 TGF β 1 19p13-q13 IDDM12 2q33 Xp11
    8. 15. T1D Risk Algorithm A 12 year old child who shares both DQ haplotypes with her T1D sister has a ~7% chance of developing T1D by age 30 years if neither parent has T1D Risk increases to ~38% if both parents have T1D
    9. 16. Progression to Diabetes vs Number of Autoantibodies (GAD, ICA512, Insulin) Percent not Diabetic Years of Follow-up 3 Ab n = 41 17 8 1 2 Abs n = 44 27 15 4 2 1 1 Abs n = 93 23 14 10 6 4
    10. 17. We can now predict type 1 diabetes. We cannot now prevent type 1 diabetes.
    11. 18. Intervention Trials for T1D <ul><li>Study Intervention Target /Screen </li></ul><ul><li>TRIGR Avoid CM FDR / genetic </li></ul><ul><li>DIPP Insulin (N) GP / genetic </li></ul><ul><li>Trial Net Immunosuppr FDR / antibodies </li></ul><ul><li>and genetic </li></ul>CM = cows milk, FDR = first degree relatives, N = nasal, GP = general population
    12. 19. Natural History Studies for T1D <ul><li>Conducted in the general population </li></ul><ul><ul><li>DAISY - Colorado </li></ul></ul><ul><ul><li>PANDA - Florida </li></ul></ul><ul><ul><li>DEW-IT - Washington </li></ul></ul><ul><li>Based on newborn genetic screening </li></ul><ul><ul><li>Concerns about proper informed consent </li></ul></ul><ul><ul><li>Parents are notified of the results by mail </li></ul></ul><ul><ul><li>Newborns at ‘high’ risk (~6%) recruited for follow-up </li></ul></ul>
    13. 20. BabyDiab and DAISY Age introduction gluten (Ziegler) or cereal (Norris) greatly increases development of anti-islet autoantibodies in infants followed from birth.
    14. 26. GRAZIE DELL’ATTENZIONE

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