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Proposed Guidelines on Genetic Screening for Type 1 Diabetes

Proposed Guidelines on Genetic Screening for Type 1 Diabetes. Screening by determining HLA type is not currently warranted outside the context of defined research studies American Diabetes Association. Clinical Trials Genetic Screening. TRIGR

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Proposed Guidelines on Genetic Screening for Type 1 Diabetes

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  1. Proposed Guidelines on Genetic Screening for Type 1 Diabetes Screening by determining HLA type is not currently warranted outside the context of defined research studies American Diabetes Association

  2. Clinical Trials Genetic Screening • TRIGR • Trial to Reduce Type 1 Diabetes in Genetically At Risk • Finland - Primary Prevention • DIPP • Diabetes Prediction and Prevention Trial • Finland - Primary Prevention

  3. Clinical Trials Antibody Screening • DPT-1 • Diabetes Prevention Trial - 1 • USA - Secondary Prevention • ENDIT • European Nicotinamide Diabetes Intervention Trial • Europe, Canada - Secondary Prevention

  4. Genetic Screening • DQB1*0302 and / or *0201 - TRIGR, DIPP • Not DQB1*0602/3 or *301 (exclusion) - DPT-1, for ICA+ individuals only • No genetic screening - ENDIT

  5. Genetic Screening • Genetic counseling is not provided • - Except DIPP • Psychological consequences of genetic screening and follow-up are likely to significant • Excludes >1/2 future cases • Potential benefit for reducing incidence is low

  6. Autoantibody Screening • Beta cell autoantibodies (BCA) • - Islet cell antigens (ICA) • - Glutamic acid decarboxylase (GAD) • - Islet tyrosine phosphatase (IA-2) • - Insulin(IAA) • Utilized as pre-clinical markers

  7. Beta Cell Autoantibodies • Most type 1 cases (~90%) are positive at onset for 1+ BCA • Prevalence decreases with duration • General population prevalence ~1% • Risk of type 1 diabetes increases with number of BCA • 2 BCA - Risk ~ 65% • 3 BCA - Risk > 90%

  8. Autoantibody Screening • Considered as endpoints - TRIGR, DIPP • ICA positives are further tested - DPT-1, for ICA+ individuals only • ICA only - ENDIT

  9. Autoantibody Screening • ICA negative individuals (excluded from clinical trials) develop type 1 diabetes • ICA negative first degree relatives with high risk DQ alleles - Pittsburgh • Risk >30% after 12 years follow-up • Pietropaolo, 2000

  10. Intervention Trials for Type 1 Diabetes Study Intervention Target /Screen TRIGR Avoid CM FDR / genetic DIPP Insulin (N) GP / genetic DPT-1 Insulin (P,0) FDR / ICA / ex ENDIT Nicotinamide FDR / ICA CM = cows milk, FDR = first degree realtives, ICA = islet cell antibodies, P=parenteral, O=oral, N = nasal, GP = general population

  11. Avoidance of Cow’s Milk Etiologic Hypotheses • Molecular mimicry • Exposure to CM proteins very early in life, when the infant gut is extremely permeability, may trigger humoral and cellular responses that later become autoreactive • Disturbance in oral tolerance • Exposure to bovine insulin in CM disturbs oral tolerance to insulin and leads to the development of IAA

  12. Avoidance of Cow’s Milk Controversies • Evidence for molecular mimicry is inconsistent and lacks specificity • Natural history studies show no association between CM and BCA • Exposure to other nutrients in breast milk or later during childhood are likely important

  13. Results From TRIGR • N = 173 high risk infants from Finland were randomized • Treatment was for 6-8 months • % with ICA in treatment vs. control group: 3.6% vs. 11.2% , p = 0.06 • Abstract: 1.9% vs. 12.5%, p < 0.04 American Diabetes Association, 1999

  14. CM HC BF Total Number n = 58 n = 61 Age enrolled 1.9 mo 3.0 mo * Exposure 4.8 mo 3.6 mo * IAA 2 1 At 3 mo n = 14 n = 9 n = 17 SI to BI 2.2 1.8 1.6 * IgG to BI 0.21 0.13 * No differences after 3 mo * p < 0.05Diabetes 49:1657-65, 2000 Results From TRIGR

  15. Potential Impact of TRIGR • If avoidance of cow’s milk was the only potential diabetogenic exposure AND prevented ALL susceptible cases, AT MOST: ~ 30% of cases prevented ~ 70% of cases NOT prevented

  16. Results From DIPP • Study ongoing for 4 years • Genetic screening is accepted • Adherence to follow-up ~70% • Results published relate to onset of BCA positivity / type 1 diabetes • No information on enrollment or acceptance of nasal insulin intervention Diabetologia 44:290-7, 2001

  17. Results From DIPP • 22 infants developed type 1 diabetes • 12 participated in DIPP • 3 refused • 7 not susceptible and excluded (32%) • Revised genetic screening strategy would have missed 5 (23%) Diabetologia 44:290-7, 2001

  18. Insulin Intervention Etiologic Hypotheses • Animal studies show that prophylactic insulin therapy can delay the onset of type 1 diabetes • Possible mechanisms involve: - Beta cell rest - Immune modulation - Tolerance

  19. Insulin Intervention Controversies • Mechanisms of action via any route of administration are unclear • Animal studies show that insulin therapy can induce type 1 diabetes • Initial results of human pilot studies are based on very small samples and short-term follow-up

  20. Insulin Intervention Controversies • Concerns about the potential for severe hypoglycemia in the treatment group • Long-term physiological and psychological consequences of daily insulin therapy are unknown

  21. DPT-1 • Hypothesis for high risk group (>50%): Daily insulin injections will reduce the incidence of type 1 diabetes by 35% in 5 yrs • Population: 1 & 2o relatives > 3 yrs • Screening: ICA, IV/OGTT, IAA, DQ • Treatment: Insulin 2x/day, IV 1x/yr • Control: Placebo

  22. DPT-1 • Hypothesis for moderate risk group (25-50%): Oral insulin will reduce the incidence of type 1 diabetes by 35% in 5 years • Population: 1 & 2o relatives > 3 yrs • Screening: ICA, IV/OGTT, IAA, DQ • Treatment: Daily oral insulin • Control: Placebo

  23. Results of Insulin Injection Arm • Screened > 89,000 relatives • 3.5% had ICA • Enrolled 339 high risk individuals • Age range: 4 - 45; mean age = 11 yrs • After 5 years • ~ 60% of the intervention and control groups developed type 1 diabetes American Diabetes Association, 2001

  24. Results of InsulinInjection Arm • No adverse events reported • Enrolled subjects are still followed • Questions remaining • - Disease had progressed to far • - Incorrect dose • - Could be effective in adults • Oral insulin arm is still recruiting American Diabetes Association, 2001

  25. Behavioral Science Research Conference • Regarding type 1 diabetes intervention trials identified: • Sub-adequate methods of risk notification • Barriers to efficient utilization of screening information

  26. Behavioral Science Research Conference • Emphasized the need to: • Maximize benefits of determining risk • Minimize distress of risk notification • Provide accurate risk information • Educate children, families and health professionals regarding genetic testing

  27. Genetic / Autoantibody Testing for Type 1 Diabetes • Being done in high risk families as well as in the general population • - For research purposes now • - For clinical purposes in the future • Critical need to: • - Consider risks and benefits • - Develop appropriate strategies for risk identification, notification and evaluation

  28. Plan for Pittsburgh “New Advanced Technology to Improve Prediction and Prevention of Type 1 Diabetes” M. Trucco, PI Previous funding from the DOD to develop suspension microarrays for HLA molecular typing

  29. Current DOD Proposal • Molecular technology developed by Dr. Trucco is now available for screening for type 1 diabetes • Suspension microarrays • Genetic: HLA DR-DQ • Immunologic: BCA, TCR V7 • Environmental: Coxsackie viruses

  30. Proposed Sub-Project “Genetic Testing for Type 1 Diabetes in Families of Military Dependents: Translating the Results from the Laboratory to the Community” J Dorman GSPH D Charron-Prochownik School of Nursing L Siminerio UPMC

  31. Risk Status Determination • Risk algorithm based on population-based molecular epidemiologic data Genetic / Environment-Specific Risk Available from the WHO DiaMond Molecular Epidemiology Project, including China

  32. Risk Status Determination • Evaluate epidemiologic associations / interactions between type 1 diabetes and: • - HLA DR-DQ - TCR V7 • - BCA, other AA - Coxsackie viruses • Develop and validate risk algorithm for type 1 diabetes • Permits ‘personalized’ approach to risk estimation

  33. Photo of Risk Calculator

  34. Risk Notification • Develop and evaluate materials and processes for communicating information about genetic risks Programs Targeted for the Internet ‘Telegenetics’

  35. Risk Notification • Consider ethical issues associated with genetic testing • Develop, implement and evaluate highly interactive, culturally sensitive, internet-based education programs for • Military and their dependents • Health-care professionals

  36. Risk Evaluation • Evaluate psychosocial / behavioral effects of receiving type 1 diabetes risk information and being followed Develop Strategies to Reduce Distress

  37. Risk Evaluation • Explore possible medical, behavioral and psychological factors that may be important in risk perception • Develop and disseminate information on interventions for informed decision making

  38. Proposed Sub-Project • Opportunity to develop standards for genetic translation based on molecular epidemiology research • As per guidelines from the Task Force on Genetic Testing at NHGRI • Essential as Human Genome Project comes to completion

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