1 / 41

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

mike_john
Download Presentation

Proposed Guidelines on Genetic Screening for Type 1 Diabetes

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related