Genetic Testing and the Prevention of Type 1 Diabetes

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

2. 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

3. Type 1 Diabetes IncidenceAllegheny County, PA

4. Type 1 Diabetes Incidence Allegheny County, PA

5. Type 1 Diabetes Incidence Allegheny County, PA

6. FIN

7. Type 1 Diabetes Incidence Worldwide

8. 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

9. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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)

21. Relative Increase In Risk 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

22. 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

23. 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

24. 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%

25. 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

26. Gene - Environment Interactions Finland • Exposure increased risk by 1/100,000 / year among susceptibles • Overall population risk would increase by 0.8%

27. Gene - Environment Interactions China • Exposure increased risk by 1/100,000 / year among susceptibles • Overall population risk would increase by 10%

28. 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

29. 0 1.8 Rate (per 100,000)

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31. 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

32. Jan Alice Lew Yang Ze