Genetic Testing and the Prevention of Type 1 Diabetes Janice S. Dorman, Ph.D. September 4, 2001 mnb

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 Incidence Allegheny County, PA

Type 1 Diabetes Incidence Allegheny County, PA

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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

Genome Screens for Type 1 Diabetes IDDM1 6p21.3 IDDM2 11p15.5 IDDM3 15q26 IDDM4 11q13.3 IDDM5 6q15 IDDM6 18q12-q21 IDDM7 2q31-33 IDDM8 6q25-27 IDDM9 3q21-25 IDDM10 10p11-q11 IDDM11 14q24-q31 IDDM12 2q33 IDDM13 2q34 IDDM14 ND IDDM15 6q21 * 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

Genome Screens for Type 1 Diabetes Chromosome 6 IDDM8 6q25-27 IDDM15 6q21 Chromosome 2 IDDM7 2q31-33 HOX8, IL-1 family IDDM12 2q33 CTLA4, CD28 IDDM13 2q34 IGFBP2, IGFBP5 * 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

WHO DiaMond Molecular Epidemiology Study Have evaluated HLA DQ Best single genetic marker Evaluate other candidate genes IDDM1 HLA DR, DP IDDM2 INS-VNTR IDDM12 CTLA4 Others VDR, 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

University of Pittsburgh 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 SP PP Caucasian† 15.9 4.0 1.0* 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 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 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

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 Alice Lew Yang Ze