This document summarizes recent updates on genetics and type 1 diabetes. It discusses the role of HLA genes, other genetic loci linked to diabetes risk, and studies looking at disease progression based on the number of islet autoantibodies present. Intervention trials aiming to prevent type 1 diabetes by targeting at-risk family members or the general population are also summarized.

1. GENETICA E DIABETE TIPO 1: AN UPDATE Rosa Anna Rabini U.O. Malattie Metaboliche e Diabetologia INRCA - Ancona

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

7. DQB1*0402 Asp57  Leu56   -chain  -chain BDC BDC

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

12. Inherited Susceptibility Loci LOCUS CHROMOSOME CANDIDATE GENES or MICROSATELLITES IDDM1 6p21 HLA-DQR 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

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

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

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

17. We can now predict type 1 diabetes. We cannot now prevent type 1 diabetes.

20. BabyDiab and DAISY Age introduction gluten (Ziegler) or cereal (Norris) greatly increases development of anti-islet autoantibodies in infants followed from birth.

26. GRAZIE DELL’ATTENZIONE