Proposed Guidelines on Genetic Screening for Type 1 Diabetes

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

• DQB10302 and / or 0201
• - TRIGR, DIPP
• Not DQB10602/3 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 gt1/2 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 gt 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 gt30 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, Pparenteral,
• Ooral, N nasal, GP general population

11
Avoidance of Cows 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 Cows 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 lt 0.04
• American Diabetes Association, 1999

14
Results From TRIGR

• 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 lt 0.05 Diabetes 491657-65, 2000

15
Potential Impact of TRIGR

• If avoidance of cows 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 44290-7, 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 44290-7, 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 (gt50) Daily
  insulin injections will reduce the incidence of
  type 1 diabetes by 35 in 5 yrs
• Population 1 2o relatives gt 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 gt 3 yrs
• Screening ICA, IV/OGTT, IAA, DQ
• Treatment Daily oral insulin
• Control Placebo

23
Results of Insulin Injection Arm

• Screened gt 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
(No Transcript)
37
(No Transcript)
38
Risk Evaluation

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

39
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

40
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

41
(No Transcript)