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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

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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

  • 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 IncidenceAllegheny County, PA


Type 1 Diabetes Incidence Allegheny County, PA


Type 1 Diabetes Incidence Allegheny County, PA


FIN


Type 1 Diabetes Incidence Worldwide


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

  • 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


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

  • 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


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


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

  • 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)

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

Ron LaPorte, Ph.D.Disease Monitoring &Telecommunications

Jan Dorman,Ph.D.Molecular Epidemiology

University of Pittsburgh


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

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

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 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?

  • 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 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

Finland

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

  • Overall population risk would increase by 0.8%


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

  • 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

1.8

Rate (per 100,000)


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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


Jan AliceLewYang Ze


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