Proposed Guidelines on Genetic Screening for Type 1 Diabetes

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 Trial

Finland - 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 Intervention European Nicotinamide Diabetes Intervention TrialTrial

Europe, 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 (excluded from clinical trials)from clinical trials) develop type 1 develop type 1 diabetesdiabetes

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 TRIGR

CM CM HCHC BFBFTotal 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 refused

7 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 Animal studies show that prophylactic insulin therapy can delay prophylactic insulin therapy can delay the onset of type 1 diabetesthe onset of type 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 Animal studies show that insulin therapy can therapy can induce type 1 diabetesinduce type 1 diabetes

Initial results of human pilot studies Initial results of human pilot studies are based on very small samples and are based on very small samples and short-term follow-upshort-term 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 Hypothesis for moderate risk group (25-50%): (25-50%): Oral insulin will reduce the Oral insulin will reduce the incidence of type 1 diabetes by 35% in incidence of type 1 diabetes by 35% in 5 years5 years

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 recruiting

American 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 Molecular technology developed by Dr. Trucco is now available for Dr. Trucco is now available for screening for type 1 diabetesscreening for type 1 diabetes

Suspension microarraysSuspension microarraysGenetic:Genetic: HLA DR-DQHLA DR-DQ

Immunologic:Immunologic: BCA, TCR VBCA, TCR V77

Environmental: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