cap.15 la genetica del diabete di tipo i

La genetica del diabete La genetica del diabete mellito di tipo 1mellito di tipo 1

• La storia di Paolo• il Diabete Mellito di tipo 1• La genetica delle Malattie

Multifattoriali• La genetica del diabete di tipo 1

Il caso di Paolo• Nato a termine, nulla da segnalare in

anamnesi fino a 6 anni• A 6 anni episodio chetoacidosico,

ricovero in ospedale e diagnosi di DMT1.

• E’ in terapia insulinica, è seguito dall’ambulatorio dell’ospedale

• La madre desidera conoscere i rischi di malattia nella seconda figlia

IL DIABETEIL DIABETE

• MELLITO– tipo I (o giovanile o

insulino-dipendente)– tipo 2 (o dell’adulto o

non insulinodipendente)

– altri tipi...

• INSIPIDOII:5 II:6 II:7 II:8

III:6

IV:1

V:9

III:

IV:10 IV:

V:12 V:13

III:18

IV:15 IV:16 IV:17IV:18 IV:19

V:17 V:18

IV:20

V:19

II:1 II:2 II:3 II:4II:10

III:1III:9

IV:2 IV:3

V:1 V:2 V:3V:4

VI:1 VI:2

V:5

VI:3

V:6

VI:4

V:10

III:21

IV:14

V:15 V:16

III:23

IV:21IV:25 IV:26

V:20 V:21 V:22

IV:27

V:23 V:24 V:25V:26

VI:5

IV:44

I:1 I:2

II:5 II:6 II:7 II:8 II:9

III:3 III:6 III:8

IV:1IV:4

V:7 V:8 V:9

IV:5

III:14

IV:10 IV:11 IV:12IV:13

V:12 V:13 V:14

III:18

IV:15 IV:16 IV:17IV:18 IV:19

V:17 V:18

IV:20

V:19

III:24

IV:32 IV:33 IV:34IV:35 IV:36 IV:37IV:38

V:32 V:33 V:34V:35

VI:63

V:36

VI:72

IV:39

V:37 V:38 V:39

IV:40

V:40 V:41

IV:41IV:42

V:42

IV:43

V:43 V:44

III:26III:27

IV:48 IV:49 IV:50 IV:51 IV:52IV:53

V:45 V:46 V:47

IV:54

V:45 V:46 V:47

IV:55

V:48 V:49

IV:56

V:50 V:51

IV:57

V:52

II:1 II:2 II:3 II:4II:10

III:1 III:7III:9

IV:2 IV:3

V:1 V:2 V:3V:4

VI:1 VI:2

V:5

VI:3

V:6

VI:4

V:10

III:21

IV:14

V:15 V:16

III:23

IV:21IV:22 IV:24 IV:25 IV:26

V:20 V:21 V:22

IV:27

V:23 V:24 V:25V:26

VI:5

IV:28

V:273

IV:29IV:30

V:28

IV:31

V:29 V:30 V:31

III:25

IV:44 IV:45 IV:46 IV:47

TWO MAIN FORMS OF DIABETESType 1 diabetes

• Primarily due to autoimmune-mediated destruction of pancreatic β-cell islets resulting in absolute insulin deficiency

• Patients must take exogenous insulin for survival to prevent ketoacidosis

• Its frequency is low relative to type 2 diabetes, which accounts for over 90% of cases globally

Type 2 diabetes• Characterized by insulin resistance and/or abnormal

insulin secretion• Patients are not dependent an exogenous insulin, but

may require it for control of blood glucose levels if this is not achieved with diet alone or with oral hypoglycemic agents

Diabetes mellitus, long considered a disease of minor significance to world health, is now taking its place as one of the main threats to human health in the 21st century

Pronounced changes in the human environment, and in human behavior and life style, have accompanied globalization, and these have resulted in escalating rates of both obesity and diabetes

THE GLOBAL BURDEN OF DIABETES (2000-2025)

16.724.5

39.3

18.2

38.430.7

21.89.1

57.2

22.8

37.5

18.6

0.4 0.7

20002025

* In million subjects

47%

116%

25%

140%

150%

102%

64%

Developed DevelopingWorld

99 m228 m

20002025

154 m300 m

55 m72 m

King et al., Diabetes Care, 1998

Although type 2 diabetes is numerically more prevalent in the general population, type 1 diabetes is the most common chronic disease of children

With increasing prevalence of type 2 diabetes in children and adolescents, the order may be reversed within one to two decades

Zimmet et al., Nature, 2001

ENVIRONMENTAL FACTORS HAVE A PARTICULARY POWERFUL INFLUENCE ON THE APPEARANCE OF TYPE 1 DIABETES

Very low rates of type 1 diabetes has been found in Asian populations

Finland shows the world’s highest incidence of 35 cases per 100,000

Other Baltic States, particularly Estonia, whose population is linguistically and ethnically very similar to that of Finland, suffer only a third the incidence

Karvonen et al., Diabetologia, 1993

Tuomilehto et al., Diabetologia, 1992

Tuomilehto et al., Int J Epidemiol, 1992

POSSIBLE ETIOLOGICAL FACTORS IN TYPE 1 DIABETES

Non-genetic * Genetic °

Human leukocyte antigen (HLA) associated

Non-HLA associated

Viral infections(for example, coxsackie, cytomegalovirus)

Early infant diet(early cessation of breast feeding/early introduction of cow’s milk)

Perinatal infections

Toxins (for example, dietary nitrosamines, bafilomycin, concanamycin A)

Vaccine administration

* No clear evidence for the role of any of these agents has been established°Consistent evidence for both HLA-and non-HLA associated genes has been established

Zimmel et al., Nature, 2001

Normal islets of Langerhans, on the right withimmunoperoxidase staining for insulin to identify beta cells and on the left with immunoperoxidase stainingfor glucagon to identify alpha cells, are shown here.

An islet of Langerhans demonstrates insulitis withlymphocytic infiltrates in a patient developing typeI diabetes mellitus. This lesion precedes clinicalonset of diabetes mellitus and is rarely observed.

HOW TO ACHIEVE EXCELLENT GLUCOSE CONTROL?

Whole-pancreas transplantation is the only treatment for type 1 diabetes mellitus that can induce an insulin-independent normoglycemic state

MORE THAN 15,000 PANCREAS TRANSPLANTS HAVE BEEN REPORTED WORLDWIDE (1987-2000)

11,495

39

2

3,234

114

182

International Pancreas Transplant Registry, 2000

Ma torniamo a Paolo e alla sua famigliaI

II

III

IV

V

1 individuo ogni 2000 circa si ammala di IDDM

1 fratello di diabetico giovanammala anche lui della stessa malattia

ComplexComplexdiseasesdiseases

• frequent• Etiology

unknown• multifactorial

–genetics–environmental

Complex or multifactorial inheritance - disease occurrences in families that do not match one of the simple Mendelian patterns of inheritance.

Discrete/qualitative trait - traits that are present or absent.

Continuous/quantitative trait - traits that have measurable characteristics across a range of values.

1. A; 2. D; 3. 10, 12; 4. 3, 6; 5. 3, 7; 6. 5, 25; 7. B; 8. D

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6deviazione dalla media

0

500

1000

1500

2000

2500nu

mer

o di

bam

bini

bambini:

difetto mentalenormali

distribuzione per

l'intelligenza dei bambini delle scuole elementari

Frequency of Different Types of Genetic Disease

~600~50~50Disease with multifactorialinheritance

203.610Disease due to single gene mutations

3.81.86Diseases due to genome/chromosome mutations

Population Prevalence (per

1,000)

Prevalence at Age 25 Years (per 1,000)

Incidence at Birth

(per 1,000)Type

Familial Clustering of Diseases

Relatives share a greater proportion of their alleles than with unrelated individuals in the population.

A primary characteristic of disease with complex inheritance is that affected individuals tend to cluster in families (familial aggregation).

The reverse is not necessarily true - familial aggregation of a disease does not mean that a disease must have a genetic contribution. Non-genetic factors could have the same effect - besides sharing alleles, families share culture, behavior, diet, and environmental exposure.

Relative RiskFamilial aggregation can be measured by comparing the frequency of the disease in the relatives of an affected proband with its frequency (prevalence) in the general population.

Relative risk ratio (λr) is defined as:

prevalence of disease in arelative “r” of an affected person

λr = population prevalence of the disease

λr = 1 indicates that a relative of an affected is no more likely to develop a disease than any individual in the population.

Risk Ratios for Relatives of Probands with Diseases Showing Familial Aggregation

80024

MZ twinsSiblings

Multiple sclerosis

84025

MZ twinsSiblings

Crohn’s disease

8012

MZ twinsSiblings

Type I diabetes mellitus

607

MZ twinsSiblings

Manic-depressive (bipolar) disorder

2000150

MZ twinsSiblings

Autism

4812

MZ twinsSiblings

Schizophrenia

λrRelationshipDisease

Empirical Risks for Cleft Lip with/without Cleft Palate in Relatives of Affected Probands

30.3Third-degree relatives

70.7Second-degree relatives

404.0First-degree relatives

-----0.1General population

λrelativeIncidence Cleft

LipPopulation

Affected




Trieste 10 gennaio 2003

Genetica dell'IDDMfattori

ambientali

Genetica dell'IDDMfattori

ambientali

genetici

The concept of a normal range for traits is fundamental to clinical medicine. However, the distance a measurement is from the mean before it is considered abnormal is somewhat arbitrary. In general, a trait is considered abnormal (out of the range of normal values) if the value of the trait is greater than 2 standard deviations away from the population mean.

Family studies can also be used to determine the role of genetics versus environment in the expression of complex traits. With families,the coefficient of correlation (r) provides a measure of correlation of particular traits among relatives compared to thegeneral population.

r can range from 0, no correlation, to +1 for perfect positive correlation and to -1 for perfect negative correlation.

r = ~0.6

Heritability (h2) - developed to quantify the role of genetic differences in determining variability of quantitative traits

Defined as the fraction of the total phenotypic variance of a quantitative trait that is caused by genes and is, therefore, a measure of the extent of to which different alleles at various loci are responsible for the variability in a given trait across a population.

The higher the heritability, the greater is the contribution of genetic differences among people in causing variability of the trait.

CHARACTERISTICS OF ‘COMPLEX’ TRAITS

Highly variable phenotypesAggregate but may not segregate in familiesAppear to be caused by multiple factors,

including environmentsVarious types:

‘normal’ traits like weightdiseases like heart diseaserare or severe cases at tails of risk distribution

Includes many chronic, gradual or late onset diseases

DISEASE EXAMPLESAlzheimer’s Disease AutismArthritisAsthmaCancerDiabetes: adult onset (type 2) Diabetes: juvenile (type 1) Hearing disorders Heart disease, lipid disordersHypertension (blood pressure)Obesity related disordersSchizophreniaRetinal degeneration (vision)

SOME QUESTIONSWHEN IS A CASE OF A COMPLEX TRAIT‘GENETIC’?

HOW CAN WE APPLY SINGLE-LOCUS IDEASTO MULTILOCUS TRAITS?

HOW CAN WE RELATE ENVIRONMENTAL AND GENETIC RISK?

HOW CAN GENES PRODUCE A QUANTITATIVETRAIT?

HOW DISCRETE MENDELIAN ALLELES CAN GENERATE CONTINUOUS VARIATION (and a ‘normal’ – bell-shaped -- trait distribution )

The line is the distribution of the trait in the population. It is smooth because (as in previous slide) there is variation in trait for any given genotype

Maroni 2-3

GENETIC BASIS OF QUANTITATIVE TRAITS

(This is just another view of the same point as previous slide)

QUANTITATIVE TRAITS ACROSS GENERATIONS

(Assumes Random Mating)

Note ‘regression to the mean’

Parental contributions to the offspring classes

These parents produce these offspring

FINDING THE GENE(S)

1. Linkage mapping in families to find ‘new’ (previously unknown)genes (based on complex specification of the mean associatedwith AA, Aa, and aa genotypes at each point in the genome)

2. Association mapping studies to find marker locations associated with mean trait differences (e.g., between cases and controls for hypertension)

3. Association mapping studies to search for variant alleles or haplotypes incandidate genes that you have reason to think may be involved)

4. Expression studies comparing normal and abnormalcandidate tissue, or EST searches from the tissue at risk

THE GENETICS OF COMPLEX HUMAN

TRAITS

Nature or Nurture ?

COMPLEX TRAITS INVOLVE MANY GENES, & EACH MAY HAVE MANY MUTATIONS

SOME ‘COMPLEX’ TRAITS ARE QUANTITATIVE, LIKE BLOOD PRESSURE

OTHER ‘COMPLEX’ TRAITS

ARE QUALITATIVE, SUCH AS

HEART DISEASE

DIABETES

HEREDITARY HEARING LOSS

Patient’s related

GeneticsGenetics of of complexcomplex diseasesdiseases

Wild Wild typetype

VariationVariation 1:1:mutationmutation

VariationVariation 2: 2: polymorphismpolymorphism

healthyhealthyMonofactorialMonofactorialdisease disease with some with some defectdefect

healthy, but the healthy, but the protein could protein could have different have different functional or functional or biophysical biophysical properties: properties: genetic genetic susceptibilitysusceptibility

HOW WELL CAN A COMPLEX TRAIT BE DISSECTED BETWEEN GENETICS AND ENVIRONMENT?

A) MONOZIGOTICI

DIZIGOTICI

B) MONOZIGOTICI

DIZIGOTICI

C) MONOZIGOTICI

DIZIGOTICI

Nessuna differenzanessuna ereditabilità

Poca differenzapoca ereditabilità

maggiore differenzamaggiore ereditabilità




Trieste 10 gennaio 2003

concordanza di IDDM in gemelli

54

14

46

86

monozigotici dizigotici

gemelli

0

20

40

60

80

100

% d

i cop

pie

concordanti discordanti

concordant discordant

Type 2 DM 47 (89%) 6

Type 1 DM 73 (55%) 59

Pyke et al., 1979

ConcordanceConcordance ratesrates forfordiabetesdiabetes among pairsamong pairs of of

monozygousmonozygous twinstwins

Ereditabilità del diabemisura dei fattori genetici: 2):

Conc. monozigotici - Conc. dizigotici 1 - concordanza dizigotici

(.54 - .14) /(1 - .14) = 46%

rischi empirici di IDDM per consanguinei di malati

familiari malati età di insorgenza della malattia

rischio (%) di ammalarsi

madre 1.3%padre 6.1%

padre e madre 39%1 fratello <10 anni 8.5%

1 fratello e 1 genitore <10 anni 12.5%1 fratello >10 anni 4.6%

1 fratello e 1 genitore >10 anni 5.2%2 fratelli 15.3%1 figlio 4.5%2 figli 9.5%

Quali geni sono implicati nella suscettibilità al diabete di tipo 1?

• Una volta riconosciuta la base genetica di una malattia complessa si pone il problema di comprendere quali siano i geni coinvolti

• 2 metodi principali

Per cercare quali siano i fattori Per cercare quali siano i fattori genetici coinvolti nella suscettibilità a genetici coinvolti nella suscettibilità a

malattie complessemalattie complesse• Si confrontano le caratteristiche

genetiche dei malati e quelle della popolazione sana

studi di associazione• si confrontano le caratteristiche

genetiche famigliari malatistudi di "linkage"

The human Major HistocompatibilityComplex (MHC) spans 3.6 Mbp at the chromosome 6p21.31. The complete sequence revealed that:

-it contains 264 identified loci (genes or pseudogenes), 52 of which are related with the immune response,

-it is the most gene-dense region of the human genome discovered so far,

- it encodes the most polymorphic humanproteins known to date: the HLA Class I and II molecules

FUNCTION OF HLA MOLECULES

HLA molecules are receptors which carry peptide

fragments of antigen and present them on the

cell surface, where they can be recognised by

appropriate T cells.

In fact peptide antigens alter the HLA molecule

by occupying the pocket and changing the

molecular display scrutinised by T cells.

HLA-A HLA-B HLA-C HLA-E HLA-F HLA-G

Full List of HLA Class I alleles assigned as of July 2002

A*01011 B*07021 Cw*0102 E*0101 F*0101 G*01011

A*01012 B*07022 Cw*0103 E*0102 G*01012

A*0102 B*07023 Cw*0104 E*01031 G*01013

A*0103 B*0703 Cw*0105 E*01032 G*01014

A*0104N B*0704 Cw*0106 E*01033 G*01015

A*0106 B*0705 Cw*02021 E*0104 G*01016

A*0107 B*0706 Cw*02022 G*01017

A*0108 B*0707 Cw*02023 G*01018

A*0109 B*0708 Cw*02024 G*0102

A*02011 B*0709 Cw*02025 G*0103

A*02012 B*0710 Cw*0203 G*01041

A*02013 B*0711 Cw*0204 G*01042

A*02014 B*0712 Cw*0205 G*01043

A*02015 B*0713 Cw*03021 G*0105N

A*02016 B*0714 Cw*03022 G*0106

A*0202 B*0715 Cw*03031

A*0203 B*0716 Cw*03032

A*0204 B*0717 Cw*03033

250 487 118 6 1 15

Full List of HLA Class II alleles assigned as of July 2002

HLA-DRA

HLA-DRB1

HLA-DRB2-9

HLA-DQA1

HLA-DQB1

HLA-DPA1

HLA-DPB1

HLA-DMA

HLA-DMB

HLA-DOA

HLA-DOB

DRA*0101

DRB1*01011

DRB2*0101

DQA1*01011

DQB1*0201

DPA1*01031

DPB1*01011

DMA*0101

DMB*0101

DOA*01011

DOB*0101101

DRA*01021

DRB1*01012

DRB3*01011

DQA1*01012

DQB1*0202

DPA1*01032

DPB1*01012

DMA*0102

DMB*0102

DOA*0101201

DOB*0101102

3 316 75 22 53 20 101 4 6 8 8

• Picture of an HLA-DQ moleculepresentingan antigenicpeptide for a T-cellreceptor

segregazione degli aplotipi HLA

ricorrenza di IDDM in fratelli ed H

2 1 0numero di aplotipi condivisi dai fratelli

0

10

20

30

40

50

60

70

% d

i cop

pie

osservatiattesi

HLA e risfratelli sani di pazienti

88

2311

9,8

2,34

0,31

2 1 0numero di aplotipi in comune tra fratelli

0

20

40

60

80

100

risch

io re

lativ

o

0

2

4

6

8

10

12

rischio empirico

DQA1 Protein Sequences1 10 20 30 40 50 60 70 80 90 100 . . . . . . . . . . .

DQA1*0101 EDIVADHVASCGVNLYQFYGPSGQYTHEFDGDEEFYVDLERKETAWRWPEFSKFGGFDPQGALRNMAVAKHNLNIMIKRYNSTAATNEVPEVTVFSKSPVTLDQA1*0102 ---------------------------------Q--------------------------------------------------------------------DQA1*0103 ------------------------F--------Q------K---------------------------------------------****************DQA1*0104 -G------------------------------------------------------------------------------------****************DQA1*0201 ----------Y------S------F-------------------V-KL-L-HRL R----F--T-I--L------L---S----------------------DQA1*03011 ----------Y------S-------S------------------V-QL-L-RR-RR----F--T-I--L------V---S----------------------DQA1*03012 ----------Y------S-------S------------------V-QL-L-RR-RR----F--T-I--L------V---S-------***************DQA1*0302 ****------Y------S-------S------------------V-QL-L-RR-RR----F--T-I--L------V---S----------------------DQA1*0401 ----------Y------S---------------Q-----G----V-CL-VLRQ- R----F--T-I--T------L---S----------------------DQA1*05011 ----------Y------S---------------Q-----G----V-CL-VLRQ- R----F--T-I--L-----SL---S----------------------DQA1*05012 ----------Y------S---------------Q-----G----V-CL-VLRQ- R----F--T-I--L-----SL---S-------***************DQA1*05013 ************-----S---------------Q-----G----V-CL-VLRQ- R----F--T-I--L-----SL---S----------------------DQA1*0601 *****************S------F--------Q-----G----V-CL-VLRQ- R----F--T-I--T------L---S**********************

DQB1 Protein SequencesDQB1*0501 RDSPEDFVYQFKGLCYFTNGTERVRGVTRHIYNREEYVRFDSDVGVYRAVTPQGRPVAEYWNSQKEVLEGARASVDRVCRHNYEVAYRGILQRRVEPTVTISDQB1*0502 --------------------------------------------------------S---------------------------------------------DQB1*05031 --------------------------------------------------------D---------------------------------------------DQB1*05032 ********************------------------------------------D------------*********************************DQB1*0504 ********---------------------Y--------------------------S--------DI--ED-----------********************DQB1*06011 --P-----L---AM-----------Y---Y------D-------------------D--------DI--RT--EL-T---------F---------------DQB1*06012 ************AM-----------Y---Y------D-------------------D--------DI--RT--EL-T---**********************DQB1*0602 --------F----M-----------L---Y-------A------------------D-------------T--EL-T---------F---------------DQB1*0603 -------------M-----------L-----------A------------------D-------------T--EL-T---------F---------------DQB1*0604 -------------M-----------L-----------A-------------------------------RT--EL-T--------G----------------DQB1*0605 -------------------------L---Y-------A-------------------------------RT--EL-T--------G----------------DQB1*0606 ********************-----L---Y-------A-------------------------------RT--A----************************DQB1*0607 ********-----M-----------L-----------A------------------D------------RT--EL-T-----********************DQB1*0608 ********-----M-----------L-----------A--------------------------------T--EL-T-----********************DQB1*0201 -------------M-----------L-S-S------I--------EF----LL-L-A--------DI--RK--A---------QLEL-TT------------DQB1*0301 *****-------AM-----------Y---Y-------A------E-------L-P-D------------RT--EL-T------QLEL-TT------------DQB1*0302 -------------M-----------L---Y-------A--------------L-P-A------------RT--EL-T------QLEL-TT------------DQB1*03031 -------------M-----------L---Y-------A--------------L-P-D------------RT--EL-T------QLEL-TT----********DQB1*03032 -------------M-----------L---Y-------A--------------L-P-D------------RT--EL-T------QLEL-TT------------DQB1*0304 ------------AM-----------Y---Y-------A------E-------L-P-A------------RT--EL-T------QLEL-TT----********DQB1*0305 ****---------M---------------Y-------A--------------L-P-A------------RT--EL-T--***********************DQB1*0401 --------F----M--------L------Y-------A--------------L--LD--------DI--ED-----T------QLEL-TT----********DQB1*0402 --------F----M---------------Y-------A--------------L--LD--------DI--ED-----T------QLEL-TT------------

Aspartic acid at position 57 of DQB and IDDM

Asp-/Asp- Asp-/Asp+ Asp+/Asp+0

102030405060708090

100

perc

enta

ge o

f pos

itive

indi

vidu

als Individuals examined:

Patients (n=47)Controls (n=47)

Patients (n=47) 78,7 17 4,3Controls (n=47) 23,4 53,2 33,4

*

**

°

** p:1x10-7; * p: .0002; ° p:.0071

arginine at position 52 of DQA and IDDM

Arg+/Arg+ Arg+/Arg- Arg-/Arg-0

1020304050607080

perc

enta

ge o

f pos

itive

indi

vidu

als Individuals examined:

Patients (n=48)Controls (n=49)

Patients (n=48) 70 22,9 0Controls (n=49) 22,4 48,9 28,6

*

**

°

** p<1x10-7; * p: .0075; ° p<.0001

The Structure of the Peptide-Binding Groove of HLA-DQ8 (Panel A), I-Ag7 (Panel B), and I-Ad (Panel C).

Panel A shows a bound insulin peptide, indicated by its -carbon backbone, in the peptide-binding groove.

Panel B shows the "right-hand" end of the peptide-binding grooveof I-Ag7

Panel C shows the samesegment of I-Ad.

Blue indicates a positive surface charge, and reda negative surfacecharge. P denotesposition.

KNOWN MUTATIONS IN DIABETES RELATED GENESJuvenile Adult MODYs OTHER

AIRE 21 ADRB3

1 RPS6KA3

GCK 22 AQP2 17

CTLA1 1 CACNA1D

SLC2A1

10 HNF4 AVPR2 86

IDDM GCGR 1 SLC2A2

3 INS 1 CP 4

IDDM2 GCK 24 SLC2A4

2 TCF1 62 HK1 2

PTPRN2

GIPR 2 TCF1 2 TCF2 2 SUR 29

TCF1 3 HK2 7 UCP3 3 HNF3B 1 KCNJ11

2

HLA IAPP 1 WRN 21 AVP 29

INSR 37 CD38 1 GCK 11

IRS1 8 KCNJ11

1 TCF2 1

MTND1

GPD2 1 INS 6

PCSK1 2 IPF1 4

PON2 1

Sources: 2002 OMIM & HGMD

Quali le applicazioni?conoscenze ulteriori sulla patogenesi della malattia

valutazione del rischio di ricorrenza di malatdi diabetici

screening nella popolazione?

IDDM è simile a

popolazione (0.1%)

2 fratelli

2 fratelli

IDDM è simile a quello dei gemelli monozigoti (45%)

cap.15 la genetica del diabete di tipo i

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