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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


Type 1 diabetes incidence allegheny county pa1

Type 1 Diabetes Incidence Allegheny County, PA


Type 1 diabetes incidence allegheny county pa2

Type 1 Diabetes Incidence Allegheny County, PA


Genetic testing and the prevention of type 1 diabetes

FIN


Type 1 diabetes incidence worldwide

Type 1 Diabetes Incidence Worldwide


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

IDDM411q13.3

IDDM56q15

IDDM618q12-q21

IDDM72q31-33

IDDM86q25-27

IDDM93q21-25

IDDM1010p11-q11

IDDM1114q24-q31

IDDM122q33

IDDM132q34

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-1family IDDM12 2q33CTLA4, CD28 IDDM132q34IGFBP2, IGFBP5

Genome Screens for Type 1 Diabetes

* Candidate Gene *Possible Candidate *No Candidate Gene


Genome screens for autoimmune diseases

Candidate Genes - Type 1 Diabetes

IDDM16p21.3DR-DQ, 2nd loci - TNF?

IDDM211p15.5INS-VNTR

IDDM122q33CTLA4, CD28

Candidate Genes - Other Disorders

IDDM1ATD, CD, RA, MS, SLE

IDDM2SLE, ankylosing spondylitis

IDDM12ATD

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

    OthersVDR, 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

  • 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

Population SS SPPP

Caucasian† 15.94.01.0*

Af Americans†44.87.31.0*

Asian‡ 10.73.61.0*

* 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 Age 30 Years

Population SS SPPP

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

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?

  • 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?

  • 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

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

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

  • 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


Genetic testing and the prevention of type 1 diabetes

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Molecular epidemiology of type 1 diabetes in china1

Molecular Epidemiology of Type 1 Diabetes in China

  • 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


Genetic testing and the prevention of type 1 diabetes

Jan AliceLewYang Ze


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