Proposed guidelines on genetic screening for type 1 diabetes
Download
1 / 41

Proposed Guidelines on Genetic Screening for - PowerPoint PPT Presentation


  • 503 Views
  • Updated On :

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

Related searches for Proposed Guidelines on Genetic Screening for

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Proposed Guidelines on Genetic Screening for ' - mike_john


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.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Proposed guidelines on genetic screening for type 1 diabetes l.jpg

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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
Autoantibody Screening

  • Considered as endpoints

    - TRIGR, DIPP

  • ICA positives are further tested

    - DPT-1, for ICA+ individuals only

  • ICA only

    - ENDIT


Autoantibody screening9 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg

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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
Risk Notification

  • Develop and evaluate materials and processes for communicating information about genetic risks

    Programs Targeted for the Internet

    ‘Telegenetics’


Risk notification35 l.jpg
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 l.jpg
Risk Evaluation

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

    Develop Strategies to Reduce Distress


Risk evaluation39 l.jpg
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 l.jpg
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


ad