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

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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

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Age (years)

Isle

t au

toim

mu

nit

y, %

<=3 mo.

>6 mo.

>3 to6 mo.

DR3/4 DQ8: Norris JAMA 290:1713

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Age (years)

Isle

t A

uto

imm

un

ity,

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<=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.

http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=An%20external%20file%20that%20holds%20a%20picture%2C%20illustration%2C%20etc.%0AObject%20name%20is%20zdb0120855250001.jpg%20%5BObject%20name%20is%20zdb0120855250001.jpg%5D&p=PMC3&id=2584121_zdb0120855250001.jpg

GRAZIE DELL’ATTENZIONE