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

Type 1 Diabetes c One of most frequent chronic diseases of children - Prevalence ~ 2 / 1000 in Allegheny County, PA c Epidemiology of type 1 diabetes has been studied at the University of Pittsburgh since Dr. Allan Drash and Dr. Lewis Kuller

Type 1 Diabetes Incidence Allegheny County, PA

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Type 1 Diabetes Incidence Worldwide

Specific Environmental Risk Factors c Case-control studies - conflicting c Possible risk factors - Infant diet or lack of breast feeding - Childhood diet - Viruses (exposure as early as in utero) - Hormones - Stress c May act as initiators or precipitators

Evidence for Genetic Risk Factors c Increased risk for 1st degree relatives of affected individuals c Concordance in MZ twins % c Recent genome wide screens have revealed 15+ possible susceptibility genes c 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 * Candidate Gene *Possible Candidate *No Candidate Gene

Interpreting Linkage Analysis for Type 1Diabetes c Need to control for effect of HLA c Some genes confer susceptibility in absence of high risk HLA haplotypes c Need model- free statistical methods c Account for gender, parent-of-origin effects and environmental risk factors c 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-1family IDDM12 2q33 CTLA4, CD28 IDDM132q34IGFBP2, IGFBP5 * 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

WHO DiaMond Molecular Epidemiology Study c Have evaluated HLA DQ Best single genetic marker c 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

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 c Hypothesis Geographic differences in type 1 diabetes incidence reflect population variation in the frequencies of disease susceptibility genes c 20+ countries participating c Focus on 2, 1, or 0 high risk HLA-DQ haplotypes (SS, SP, PP)

Relative Increase In Risk Population SS SPPP Caucasian † * Af Americans † * Asian ‡ * * 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? c Increased risk for individuals with SS and SP genotypes, relative to PP, with a significant dose response c Cumulative risk for SS individuals in high-moderate incidence countries approaches rates for first degree relatives; 3 - 6%

What do these data tell us? c Contribution of the highest risk HLA- DQ genotypes to type 1 diabetes incidence varied from 19% - 43% across populations c More than 50% of the incidence of type 1 diabetes is NOT explained by the highest risk HLA-DQ genotypes

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

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

Molecular Epidemiology of Type 1 Diabetes in China c What is contributing to the low overall incidence and large variation in risk within China? - Etiological heterogeneity - Susceptibility genes - Environmental risk factors c Project based on DiaMond registry network c Model study for molecular epidemiology

Rate (per 100,000) 01.8

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Molecular Epidemiology of Type 1 Diabetes in China c Data collection completed in Dr. Yang Ze c 296 cases, 528 controls; 18 centers c Molecular analyses - Beijing - HLA DRB1, DQB1 typing c Serological analyses - Pittsburgh - GAD, IA-2, TPOAb, TGAb, C-pep c Environmental data - Pittsburgh - Nutrition, infections, pollution c Dissertation for Dr. Elsa Strotmeyer

Jan AliceLewYang Ze