genetica e diabete di tipo 1: an update - dott rosa anna rabini
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GENETICA E DIABETE TIPO 1: AN UPDATE
Rosa Anna RabiniU.O. Malattie Metaboliche e
DiabetologiaINRCA - Ancona
Human Leukocyte Antigen
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
HLAJ. Noble
DQB1*0402
Asp57
Leu56
-chain
-chain
BDC BDC
Major DR/DQ Associations• Type 1 Diabetes
DR3: DRB1*0301/DQA1*0501/DQB1*0201DR4: DRB1*0401/DQA1*0301/DQb1*0302
• Celiac DiseaseThe same as Type 1 DM plusDR5/DR7 = DQA1*0501/DQB1*0201 in trans
• Addison’s DiseaseThe same as Type 1 DM but DRB1*0404 preference (Yu, JCEM 84:328,1999)
BDC
Insulin Gene (INS)
Class I VNTR26-63 repeats
21 alleles
Predisposing
IDDM2
Insulin Gene (INS)
Class III VNTR140-200 repeats
15 alleles
IDDM2Protective
The IDDM2 Locus
VNTR = Variable Number of Tandem Repeats
Inherited Susceptibility LociLOCUS CHROMOSOME CANDIDATE GENES or MICROSATELLITESIDDM1 6p21 HLA-DQ\DRIDDM2 11p15 INS VNTRIDDM3 15q26 D15s107IDDM4 11q13 MDU1, ZFM1, RT6, FADD/MORT1, LRP5 IDDM5 6q24-27 ESR, MnSODIDDM6 18q12-q21 D18s487, D18s64, JK (Kidd locus)IDDM7 2q31 D2s152, IL-1, NEUROD, GALNT3IDDM8 6q25-27 D6s264, D6s446, D6s281IDDM9 3q21-25 D3s1303IDDM10 10p11-q11 D10s193, D10s208, D10s588IDDM11 14q24.3-q31 D14s67IDDM12 2q33 CTLA-4, CD28IDDM13 2q34 D2s137, D2s164, IGFBP2, IGFBP5IDDM14 ? NCBI # 3413IDDM15 6q21 D6s283, D6s434, D6s1580IDDM16 ? NCBI # 3415IDDM17 10q25 D10s1750-D10s1773OTHERS
Genome Screens for T1DIDDM1 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, INFγ 12q12-qter
IDDM8 6q27-qter 16p11-p13
IDDM9 3q21-q25 16q22-q24
IDDM10 10p11-q11 17q24-qter
IDDM11 14q24-q31 TGFβ1 19p13-q13
IDDM12 2q33 Xp11
T1D Risk AlgorithmA 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
0
20
40
60
80
100
0 2,5 5 7,5 10 12,5 15
3 Abs2 Abs1 Ab
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 11 Abs n = 93 23 14 10 6 4
We can now predict type 1 diabetes.
We cannot now prevent type 1
diabetes.
Intervention Trials for T1DStudy Intervention Target /ScreenTRIGR Avoid CM FDR / geneticDIPP Insulin (N) GP / geneticTrial Net Immunosuppr FDR / antibodies
and genetic
CM = cows milk, FDR = first degree relatives, CM = cows milk, FDR = first degree relatives, N = nasal, GP = general populationN = nasal, GP = general population
Natural History Studies for T1D• Conducted in the general population
– DAISY - Colorado– PANDA - Florida– DEW-IT - Washington
• Based on newborn genetic screening– Concerns about proper informed consent– Parents are notified of the results by mail– Newborns at ‘high’ risk (~6%) recruited for
follow-up
Ziegler, JAMA 2003: 290:721
0
5
10
15
20
25
30
0 2 4 6 8
Age (years)
Isle
t au
toim
mu
nit
y, %
<=3 mo.
>6 mo.
>3 to6 mo.
DR3/4 DQ8: Norris JAMA 290:1713
0
5
10
15
20
25
0 2 4 6 8
Age (years)
Isle
t A
uto
imm
un
ity,
%
<=3 mo.
4 o 6 mo.
>=7 mo.
BabyDiab and DAISY
Age introduction gluten (Ziegler) or cereal (Norris) greatly increases development of anti-islet autoantibodies in infants followed from birth.
GRAZIE DELL’ATTENZIONE