proposed guidelines on genetic screening for type 1 diabetes screening by determining hla type is...
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Proposed Guidelines on Proposed Guidelines on Genetic Screening for Genetic Screening for
Type 1 DiabetesType 1 Diabetes
Screening by determining HLA Screening by determining HLA type is not currently warranted type is not currently warranted outside the context of defined outside the context of defined research studiesresearch studies
American Diabetes AssociationAmerican Diabetes Association
Clinical Trials Clinical Trials Genetic ScreeningGenetic Screening
TRIGRTRIGR Trial to Reduce Type 1 Diabetes in Trial to Reduce Type 1 Diabetes in
Genetically At RiskGenetically At RiskFinland - Primary PreventionFinland - Primary Prevention
DIPPDIPP Diabetes Prediction and Prevention TrialDiabetes Prediction and Prevention TrialFinland - Primary PreventionFinland - Primary Prevention
Clinical Trials Clinical Trials Antibody ScreeningAntibody Screening
DPT-1DPT-1 Diabetes Prevention Trial - 1Diabetes Prevention Trial - 1
USA - Secondary PreventionUSA - Secondary Prevention
ENDITENDITEuropean Nicotinamide Diabetes European Nicotinamide Diabetes Intervention TrialIntervention TrialEurope, Canada - Secondary Europe, Canada - Secondary PreventionPrevention
Genetic ScreeningGenetic Screening DQB1*0302 and / or *0201DQB1*0302 and / or *0201
- TRIGR, DIPP- TRIGR, DIPP
Not DQB1*0602/3 or *301 (exclusion)Not DQB1*0602/3 or *301 (exclusion)- DPT-1, for ICA+ individuals only- DPT-1, for ICA+ individuals only
No genetic screeningNo genetic screening- ENDIT- ENDIT
Genetic ScreeningGenetic Screening Genetic counseling Genetic counseling is not providedis not provided
- Except DIPP- Except DIPP Psychological consequencesPsychological consequences of of
genetic screening and follow-up are genetic screening and follow-up are likely to significantlikely to significant
Excludes Excludes >1/2 future cases>1/2 future cases Potential Potential benefitbenefit for reducing for reducing
incidence is incidence is lowlow
Autoantibody ScreeningAutoantibody Screening
Beta cell autoantibodies (BCA)Beta cell autoantibodies (BCA)- - Islet cell antigens (ICA)Islet cell antigens (ICA)- Glutamic acid decarboxylase (GAD)- Glutamic acid decarboxylase (GAD)- Islet tyrosine phosphatase (IA-2)- Islet tyrosine phosphatase (IA-2)- Insulin- Insulin (IAA)(IAA)
Utilized as pre-clinical markersUtilized as pre-clinical markers
Beta Cell AutoantibodiesBeta Cell Autoantibodies Most type 1 cases (~90%) are Most type 1 cases (~90%) are
positive at onset for 1+ BCApositive at onset for 1+ BCA Prevalence decreases with durationPrevalence decreases with duration General population prevalence ~1%General population prevalence ~1% Risk of type 1 diabetes increases Risk of type 1 diabetes increases
with number of BCAwith number of BCA2 BCA - Risk ~ 65%2 BCA - Risk ~ 65%3 BCA - Risk > 90%3 BCA - Risk > 90%
Autoantibody ScreeningAutoantibody Screening Considered as endpointsConsidered as endpoints
- TRIGR, DIPP- TRIGR, DIPP
ICA positives are further testedICA positives are further tested- DPT-1, for ICA+ individuals only- DPT-1, for ICA+ individuals only
ICA onlyICA only- ENDIT- ENDIT
Autoantibody ScreeningAutoantibody Screening ICA negative individuals ICA negative individuals (excluded from (excluded from
clinical trials)clinical trials) develop type 1 diabetes develop type 1 diabetes
ICA negative first degree relatives with ICA negative first degree relatives with high risk DQ alleles - Pittsburghhigh risk DQ alleles - Pittsburgh
Risk >30% after 12 years follow-upRisk >30% after 12 years follow-up
Pietropaolo, 2000Pietropaolo, 2000
Intervention Trials forIntervention Trials for Type 1 Diabetes Type 1 Diabetes
StudyStudy InterventionIntervention Target /ScreenTarget /ScreenTRIGRTRIGR Avoid CMAvoid CM FDR / geneticFDR / geneticDIPPDIPP Insulin (N)Insulin (N) GP / geneticGP / geneticDPT-1DPT-1 Insulin (P,0)Insulin (P,0) FDR / ICA / exFDR / ICA / exENDITENDIT NicotinamideNicotinamide FDR / ICAFDR / ICA
CM = cows milk, FDR = first degree realtives, CM = cows milk, FDR = first degree realtives, ICA = islet cell antibodies, P=parenteral,ICA = islet cell antibodies, P=parenteral,O=oral, N = nasal, GP = general populationO=oral, N = nasal, GP = general population
Avoidance of Cow’s Milk Avoidance of Cow’s Milk Etiologic HypothesesEtiologic Hypotheses
Molecular mimicryMolecular mimicryExposure to CM proteins very early in Exposure to CM proteins very early in life, when the infant gut is extremely life, when the infant gut is extremely permeability, may trigger humoral and permeability, may trigger humoral and cellular responses that later become cellular responses that later become autoreactiveautoreactive
Disturbance in oral toleranceDisturbance in oral toleranceExposure to bovine insulin in CM Exposure to bovine insulin in CM disturbs oral tolerance to insulin and disturbs oral tolerance to insulin and leads to the development of IAAleads to the development of IAA
Avoidance of Cow’s Milk Avoidance of Cow’s Milk ControversiesControversies
Evidence for molecular mimicry is Evidence for molecular mimicry is inconsistent and lacks specificity inconsistent and lacks specificity
Natural history studies show no Natural history studies show no association between CM and BCAassociation between CM and BCA
Exposure to other nutrients in Exposure to other nutrients in breast milk or later during childhood breast milk or later during childhood are likely importantare likely important
Results From TRIGRResults From TRIGR N = 173 high risk infants from Finland N = 173 high risk infants from Finland
were randomizedwere randomized Treatment was for 6-8 monthsTreatment was for 6-8 months % with ICA in treatment vs. control % with ICA in treatment vs. control
group:group: 3.6% vs. 11.2% , p = 0.06 3.6% vs. 11.2% , p = 0.06 Abstract: Abstract: 1.9% vs. 12.5%, p < 0.041.9% vs. 12.5%, p < 0.04
American Diabetes Association, 1999American Diabetes Association, 1999
Results From TRIGRResults From TRIGRCM CM HCHC BFBF
Total NumberTotal Number n = 58n = 58 n = 61n = 61Age enrolledAge enrolled1.9 mo1.9 mo 3.0 mo 3.0 mo **ExposureExposure 4.8 mo4.8 mo 3.6 mo 3.6 mo **IAAIAA 22 11At 3 moAt 3 mo n = 14n = 14 n = 9n = 9 n = 17n = 17
SI to BISI to BI 2.22.2 1.81.8 1.6 1.6 **IgG to BIIgG to BI 0.210.21 0.13 0.13 **
No differences after 3 moNo differences after 3 mo* p < 0.05* p < 0.05 Diabetes 49:1657-65, 2000Diabetes 49:1657-65, 2000
Potential Impact of TRIGRPotential Impact of TRIGR
If avoidance of cow’s milk was the If avoidance of cow’s milk was the only potential diabetogenic exposure only potential diabetogenic exposure ANDAND prevented prevented ALL ALL susceptible susceptible cases, AT MOSTcases, AT MOST::
~ 30% of cases prevented~ 30% of cases prevented~ 70% of cases NOT prevented~ 70% of cases NOT prevented
Results From DIPPResults From DIPP Study ongoing for 4 yearsStudy ongoing for 4 years Genetic screening is accepted Genetic screening is accepted Adherence to follow-up ~70%Adherence to follow-up ~70% Results published relate to onset of Results published relate to onset of
BCA positivity / type 1 diabetesBCA positivity / type 1 diabetes No information on enrollment or No information on enrollment or
acceptance of nasal insulin acceptance of nasal insulin interventionintervention
Diabetologia 44:290-7, 2001Diabetologia 44:290-7, 2001
Results From DIPPResults From DIPP 22 infants developed type 1 diabetes22 infants developed type 1 diabetes 12 participated in DIPP12 participated in DIPP
3 refused3 refused7 not susceptible and excluded (32%)7 not susceptible and excluded (32%)
Revised genetic screening strategy Revised genetic screening strategy would have missed 5 (23%)would have missed 5 (23%)
Diabetologia 44:290-7, 2001Diabetologia 44:290-7, 2001
Insulin Intervention Insulin Intervention Etiologic HypothesesEtiologic Hypotheses
Animal studies show that prophylactic Animal studies show that prophylactic insulin therapy can delay the onset of insulin therapy can delay the onset of type 1 diabetestype 1 diabetes
Possible mechanisms involve:Possible mechanisms involve:- Beta cell rest- Beta cell rest- Immune modulation - Immune modulation - Tolerance- Tolerance
Insulin Intervention Insulin Intervention ControversiesControversies
Mechanisms of action via any route of Mechanisms of action via any route of administration are unclearadministration are unclear
Animal studies show that insulin therapy Animal studies show that insulin therapy can can induce type 1 diabetesinduce type 1 diabetes
Initial results of human pilot studies are Initial results of human pilot studies are based on very small samples and short-based on very small samples and short-term follow-upterm follow-up
Insulin Intervention Insulin Intervention ControversiesControversies
Concerns about the potential for Concerns about the potential for severe hypoglycemia in the severe hypoglycemia in the treatment grouptreatment group
Long-term physiological and Long-term physiological and psychological consequences of daily psychological consequences of daily insulin therapy are unknowninsulin therapy are unknown
DPT-1DPT-1
Hypothesis for high risk group Hypothesis for high risk group (>50%):(>50%): Daily insulin injections will Daily insulin injections will reduce the incidence of type 1 reduce the incidence of type 1 diabetes by 35% in 5 yrsdiabetes by 35% in 5 yrs
Population: Population: 1 & 21 & 2o o relatives relatives >> 3 yrs 3 yrs Screening: Screening: ICA, IV/OGTT, IAA, DQICA, IV/OGTT, IAA, DQ Treatment: Treatment: Insulin 2x/day, IV 1x/yrInsulin 2x/day, IV 1x/yr Control: Control: PlaceboPlacebo
DPT-1DPT-1 Hypothesis for moderate risk group (25-Hypothesis for moderate risk group (25-
50%): 50%): Oral insulin will reduce the Oral insulin will reduce the incidence of type 1 diabetes by 35% in 5 incidence of type 1 diabetes by 35% in 5 yearsyears
Population: Population: 1 & 21 & 2o o relatives relatives >> 3 yrs 3 yrs Screening: Screening: ICA, IV/OGTT, IAA, DQICA, IV/OGTT, IAA, DQ Treatment: Treatment: Daily oral insulin Daily oral insulin Control: Control: PlaceboPlacebo
Results of Insulin Results of Insulin Injection ArmInjection Arm
Screened > 89,000 relativesScreened > 89,000 relatives 3.5% had ICA3.5% had ICA Enrolled 339 high risk individualsEnrolled 339 high risk individuals Age range: 4 - 45; mean age = 11 yrsAge range: 4 - 45; mean age = 11 yrs After 5 yearsAfter 5 years
~ 60% of the intervention and control ~ 60% of the intervention and control groups developed type 1 diabetesgroups developed type 1 diabetes
American Diabetes Association, 2001American Diabetes Association, 2001
Results of InsulinResults of InsulinInjection ArmInjection Arm
No adverse events reportedNo adverse events reported Enrolled subjects are still followedEnrolled subjects are still followed Questions remainingQuestions remaining
- Disease had progressed to far- Disease had progressed to far- Incorrect dose- Incorrect dose- Could be effective in adults- Could be effective in adults
Oral insulin arm is still recruitingOral insulin arm is still recruitingAmerican Diabetes Association, 2001American Diabetes Association, 2001
Behavioral Science Behavioral Science Research ConferenceResearch Conference
Regarding type 1 diabetes Regarding type 1 diabetes intervention trials identified:intervention trials identified:
Sub-adequate methods of risk Sub-adequate methods of risk notificationnotification
Barriers to efficient utilization of Barriers to efficient utilization of screening informationscreening information
Behavioral Science Behavioral Science Research ConferenceResearch Conference
Emphasized the need to:Emphasized the need to:Maximize benefits of determining riskMaximize benefits of determining risk
Minimize distress of risk notificationMinimize distress of risk notification
Provide accurate risk informationProvide accurate risk information
Educate children, families and health Educate children, families and health professionals regarding genetic testingprofessionals regarding genetic testing
Genetic / Autoantibody Genetic / Autoantibody Testing for Type 1 DiabetesTesting for Type 1 Diabetes
Being done in high risk families as Being done in high risk families as well as in the general populationwell as in the general population
- For research purposes now- For research purposes now- For clinical purposes in the future- For clinical purposes in the future
Critical need to:Critical need to:- Consider risks and benefits- Consider risks and benefits- Develop appropriate strategies for risk - Develop appropriate strategies for risk identification, notification and identification, notification and evaluationevaluation
Plan for PittsburghPlan for Pittsburgh
““New Advanced Technology to New Advanced Technology to Improve Prediction and Prevention of Improve Prediction and Prevention of Type 1 Diabetes”Type 1 Diabetes”
M. Trucco, PIM. Trucco, PI
Previous funding from the DOD to Previous funding from the DOD to develop suspension microarrays for develop suspension microarrays for
HLA molecular typingHLA molecular typing
Current DOD ProposalCurrent DOD Proposal
Molecular technology developed by Dr. Molecular technology developed by Dr. Trucco is now available for screening Trucco is now available for screening for type 1 diabetesfor type 1 diabetes
Suspension microarraysSuspension microarraysGenetic:Genetic: HLA DR-DQHLA DR-DQImmunologic:Immunologic: BCA, TCR VBCA, TCR V77Environmental:Environmental: Coxsackie virusesCoxsackie viruses
Proposed Sub-ProjectProposed Sub-Project
““Genetic Testing for Type 1 Diabetes in Genetic Testing for Type 1 Diabetes in Families of Military Dependents: Families of Military Dependents: Translating the Results from the Translating the Results from the Laboratory to the Community”Laboratory to the Community”
J DormanJ Dorman GSPHGSPH D Charron-Prochownik School of Nursing D Charron-Prochownik School of Nursing
L SiminerioL Siminerio UPMCUPMC
Risk Status DeterminationRisk Status Determination Risk algorithm based on population-Risk algorithm based on population-
based molecular epidemiologic data based molecular epidemiologic data Genetic / Environment-Specific RiskGenetic / Environment-Specific Risk
Available from the WHO DiaMond Available from the WHO DiaMond Molecular Epidemiology Project, Molecular Epidemiology Project,
including Chinaincluding China
Risk Status DeterminationRisk Status Determination Evaluate epidemiologic Evaluate epidemiologic
associations / interactions between associations / interactions between type 1 diabetes and:type 1 diabetes and:- HLA DR-DQ- HLA DR-DQ - TCR V- TCR V77- BCA, other AA- BCA, other AA - Coxsackie viruses- Coxsackie viruses
Develop and validate risk algorithm Develop and validate risk algorithm for type 1 diabetesfor type 1 diabetes
Permits ‘personalized’ approach to Permits ‘personalized’ approach to risk estimationrisk estimation
Photo of Risk Calculator
Risk NotificationRisk Notification Develop and evaluate materials and Develop and evaluate materials and
processes for communicating processes for communicating information about genetic risksinformation about genetic risks
Programs Targeted for the InternetPrograms Targeted for the Internet‘‘Telegenetics’Telegenetics’
Risk NotificationRisk Notification Consider ethical issues associated Consider ethical issues associated
with genetic testingwith genetic testing
Develop, implement and evaluate Develop, implement and evaluate highly interactive, culturally highly interactive, culturally sensitive, internet-based education sensitive, internet-based education programs for programs for - Military and their dependents Military and their dependents - Health-care professionalsHealth-care professionals
Risk EvaluationRisk Evaluation
Evaluate psychosocial / behavioral Evaluate psychosocial / behavioral effects of receiving type 1 diabetes effects of receiving type 1 diabetes risk information and being followedrisk information and being followed
Develop Strategies to Reduce DistressDevelop Strategies to Reduce Distress
Risk EvaluationRisk Evaluation
Explore possible medical, behavioral Explore possible medical, behavioral and psychological factors that may and psychological factors that may be important in risk perception be important in risk perception
Develop and disseminate information Develop and disseminate information on interventions for informed on interventions for informed decision makingdecision making
Proposed Sub-ProjectProposed Sub-Project Opportunity to develop standards for Opportunity to develop standards for
genetic translation based on genetic translation based on molecular epidemiology researchmolecular epidemiology research
As per guidelines from the Task As per guidelines from the Task Force on Genetic Testing at NHGRIForce on Genetic Testing at NHGRI
Essential as Human Genome Project Essential as Human Genome Project comes to completioncomes to completion
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