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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

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
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
clinical trials antibody screening
Clinical Trials Antibody Screening
  • DPT-1
    • Diabetes Prevention Trial - 1
    • USA - Secondary Prevention
  • ENDIT
    • European Nicotinamide Diabetes Intervention Trial
    • Europe, Canada - Secondary Prevention
genetic screening
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

genetic screening5
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
autoantibody screening
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
beta cell autoantibodies
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%
autoantibody screening8
Autoantibody Screening
  • Considered as endpoints

- TRIGR, DIPP

  • ICA positives are further tested

- DPT-1, for ICA+ individuals only

  • ICA only

- ENDIT

autoantibody screening9
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
intervention trials for type 1 diabetes
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

avoidance of cow s milk etiologic hypotheses
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
avoidance of cow s milk controversies
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
results from trigr
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

results from trigr14
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
potential impact of trigr
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

results from dipp
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

results from dipp17
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

insulin intervention etiologic hypotheses
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

insulin intervention controversies
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
insulin intervention controversies20
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
dpt 1
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
dpt 122
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
results of insulin injection arm
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

results of insulin injection arm24
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

behavioral science research conference
Behavioral Science Research Conference
  • Regarding type 1 diabetes intervention trials identified:
    • Sub-adequate methods of risk notification
    • Barriers to efficient utilization of screening information
behavioral science research conference26
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
genetic autoantibody testing for type 1 diabetes
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
plan for pittsburgh
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

current dod proposal
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
proposed sub project
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

risk status determination
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

risk status determination32
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
risk notification
Risk Notification
  • Develop and evaluate materials and processes for communicating information about genetic risks

Programs Targeted for the Internet

‘Telegenetics’

risk notification35
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
risk evaluation
Risk Evaluation
  • Evaluate psychosocial / behavioral effects of receiving type 1 diabetes risk information and being followed

Develop Strategies to Reduce Distress

risk evaluation39
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
proposed sub project40
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