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Genetic Testing and the Prevention of Type 1 Diabetes. Janice S. Dorman, Ph.D. September 4, 2001. Type 1 Diabetes. One of most frequent chronic diseases of children - Prevalence ~ 2 / 1000 in Allegheny County, PA

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Genetic testing and the prevention of type 1 diabetes

Genetic Testing and the Prevention of Type 1 Diabetes

Janice S. Dorman, Ph.D.

September 4, 2001


Type 1 diabetes
Type 1 Diabetes

  • One of most frequent chronic diseases of children

    • - Prevalence ~ 2 / 1000 in Allegheny County, PA

  • Epidemiology of type 1 diabetes has been studied at the University of Pittsburgh since 1979

    • - Dr. Allan Drash and Dr. Lewis Kuller


Type 1 diabetes incidence allegheny county pa
Type 1 Diabetes IncidenceAllegheny County, PA






Specific environmental risk factors
Specific Environmental Risk Factors

  • Case-control studies - conflicting

  • Possible risk factors

    • - Infant diet or lack of breast feeding

    • - Childhood diet

    • - Viruses (exposure as early as in utero)

    • - Hormones

    • - Stress

  • May act as initiators or precipitators


Evidence for genetic risk factors
Evidence for Genetic Risk Factors

  • Increased risk for 1st degree relatives of affected individuals

  • Concordance in MZ twins 20 - 50%

  • Recent genome wide screens have revealed 15+ possible susceptibility genes

  • Associations with HLA class II alleles in all populations


Genome screens for type 1 diabetes

IDDM16p21.3

IDDM211p15.5

IDDM315q26

IDDM4 11q13.3

IDDM5 6q15

IDDM6 18q12-q21

IDDM7 2q31-33

IDDM86q25-27

IDDM93q21-25

IDDM1010p11-q11

IDDM1114q24-q31

IDDM122q33

IDDM13 2q34

IDDM14ND

IDDM156q21

Genome Screens for Type 1 Diabetes

* Candidate Gene *Possible Candidate *No Candidate Gene


Interpreting linkage analysis for type 1diabetes
Interpreting Linkage Analysis for Type 1Diabetes

  • Need to control for effect of HLA

  • Some genes confer susceptibility in absence of high risk HLA haplotypes

  • Need model- free statistical methods

  • Account for gender, parent-of-origin effects and environmental risk factors

  • May not be appropriate phenotype


Genome screens for type 1 diabetes1

Chromosome 6

IDDM8 6q25-27

IDDM15 6q21

Chromosome 2

IDDM7 2q31-33 HOX8, IL-1 family IDDM12 2q33CTLA4, CD28 IDDM13 2q34 IGFBP2, IGFBP5

Genome Screens for Type 1 Diabetes

* Candidate Gene *Possible Candidate *No Candidate Gene


Genome screens for autoimmune diseases

Candidate Genes - Type 1 Diabetes

IDDM1 6p21.3 DR-DQ, 2nd loci - TNF?

IDDM2 11p15.5 INS-VNTR

IDDM12 2q33 CTLA4, CD28

Candidate Genes - Other Disorders

IDDM1 ATD, CD, RA, MS, SLE

IDDM2 SLE, ankylosing spondylitis

IDDM12 ATD

Genome Screens for Autoimmune Diseases


Who diamond molecular epidemiology study
WHO DiaMond Molecular Epidemiology Study

  • Have evaluated HLA DQ

    • Best single genetic marker

  • Evaluate other candidate genes

    IDDM1HLA DR, DP

    IDDM2 INS-VNTR

    IDDM12CTLA4

    Others VDR, HLA class I


Who multinational project for childhood diabetes diamond

WHO Multinational Project for Childhood Diabetes (DiaMond)

What is Causing the Tremendous Geographic Variation in Incidence of Type 1 Diabetes?

Monitored Incidence Worldwide

1990 - 2000


Who collaborating center for diabetes registries research and training

WHO Collaborating Center for Diabetes Registries, Research and Training

Ron LaPorte, Ph.D. Disease Monitoring & Telecommunications

Jan Dorman,Ph.D. Molecular Epidemiology

University of Pittsburgh


Who diamond molecular epidemiology study1
WHO DiaMond Molecular Epidemiology Study and Training

  • Hypothesis

    Geographic differences in type 1 diabetes incidence reflect population variation in the frequencies of disease susceptibility genes

  • 20+ countries participating

  • Focus on 2, 1, or 0 high risk HLA-DQ haplotypes (SS, SP, PP)


Relative increase in risk
Relative Increase In Risk and Training

Population SS SP PP

Caucasian† 15.9 4.01.0*

Af Americans† 44.8 7.3 1.0*

Asian‡ 10.7 3.6 1.0*

* p < 0.05, test for trend

†Allegheny Co, PA and Jefferson Co, AL

‡Hokkaido, Japan and Seoul, Korea


Cumulative risk through age 30 years
Cumulative Risk Through and TrainingAge 30 Years

Population SS SP PP

Caucasian† 2.6% 0.7% 0.2%

Af Americans† 3.1% 0.5% 0.1%

Asian‡ 0.2% 0.1% 0.02%

†Allegheny Co, PA and Jefferson Co, AL

‡Hokkaido, Japan and Seoul, Korea


Population attributable fraction
Population Attributable Fraction and Training

Population SS SS or SP

Caucasian† 36.2% 66.6%

Af Americans† 43.5% 74.9%

Asian‡ 18.8% 53.3%

†Allegheny Co, PA and Jefferson Co, AL

‡Hokkaido, Japan and Seoul, Korea


What do these data tell us
What do these data tell us? and Training

  • Increased risk for individuals with SS and SP genotypes, relative to PP, with a significant dose response

  • Cumulative risk for SS individuals in high-moderate incidence countries approaches rates for first degree relatives; 3 - 6%


What do these data tell us1
What do these data tell us? and Training

  • Contribution of the highest risk HLA-DQ genotypes to type 1 diabetes incidence varied from 19% - 43% across populations

  • More than 50% of the incidence of type 1 diabetes is NOT explained by the highest risk HLA-DQ genotypes


Gene environment interactions
Gene - Environment Interactions and Training

Finland

  • Exposure increased risk by 1/100,000 / year among susceptibles

  • Overall population risk would increase by 0.8%


Gene environment interactions1
Gene - Environment Interactions and Training

China

  • Exposure increased risk by 1/100,000 / year among susceptibles

  • Overall population risk would increase by 10%


Molecular epidemiology of type 1 diabetes in china
Molecular Epidemiology of Type 1 Diabetes in China and Training

  • What is contributing to the low overall incidence and large variation in risk within China?

    - Etiological heterogeneity

    - Susceptibility genes

    - Environmental risk factors

  • Project based on DiaMond registry network

  • Model study for molecular epidemiology


0 and Training

1.8

Rate (per 100,000)


* and Training

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*


Molecular epidemiology of type 1 diabetes in china1
Molecular Epidemiology of Type 1 Diabetes in China and Training

  • Data collection completed in 1999 - Dr. Yang Ze

  • 296 cases, 528 controls; 18 centers

  • Molecular analyses - Beijing

    - HLA DRB1, DQB1 typing

  • Serological analyses - Pittsburgh

    - GAD, IA-2, TPOAb, TGAb, C-pep

  • Environmental data - Pittsburgh

    - Nutrition, infections, pollution

  • Dissertation for Dr. Elsa Strotmeyer


Jan Alice Lew Yang Ze and Training


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