# Presentation: 155442

## Determine the Feasibility of Establishing a US National Twin Registry and Three Disease Specific Twin Registries

- Type 1 diabetes
- 13-70% concordance in MZ twins, 0-14% in DZ twins
- US prevalence is ~1.3 million
- Systemic lupus erythematosus
- 24-69% concordance in MZ twins, 1-2% for DZ twins
- US prevalence is ~1.4 million
- Multiple Sclerosis
- 25-30% concordance in MZ twins, 2-5% in DZ twins
- US prevalence is ~300,000

## Background

- Powerful tool for investigating the relative contributions of genetic susceptibility and environmental influences to complex traits and disease
- Advantages
- Increase study power due to sharing between co-twins
- MZ pairs - eliminate genetic confounders
- MZ/DZ pairs - eliminate environmental and age confounders
- Twin pairs needed for estimating genetic contribution
-        Martin, Boomsa, and Machin. Nature Genetics 1997;17:387-392.
- 200 pairs for traits of high heritability
- Several thousand pairs for traits of low to moderate heritability
- International (national population-based) Twin Registries
- Limited access
- Not representative of US population

## Polycystic Ovary Syndrome (PCOS) Twin Study

- Major cause of infertility
- Type 2 diabetes, high blood pressure, dyslipidemias, CVD, and CA
- Mid-Atlantic Twin Registry
- Cohort of MZ and DZ twins with PCOS
- Concordance rates and heritability estimates
- Identify environmental risk factors
- Monitor discordant pairs for incident cases
- Monitor discordant MZ twins over time to see whether concordance rates approach 100%
- Investigating other twin resources for the study

## Maternofetomicrochimerism as a Risk Factor for Type 1 Diabetes

- Persistence of maternal cells in the child’s circulation after birth
- British Diabetic Twins Study – Dr. David Leslie, St. Bartholomew’s Hospital, London, UK
- Discordant MZ twins and their mothers
- Nonshared HLA genotypes between mothers and their MZ twins (offspring)
- Genotype CD3+ cells in the offspring to determine if there are any cells of maternal origin
- Quantitate maternal DNA in offspring using standard real-time PCR techniques

## Tasks 1 and 2 – Describe the Current US Twin Populations

**Task 1** – Analyze and describe the current overall US twin population
- No systematic attempt to estimate and analyze the US twin population to date
- Total numbers of twins
- Zygosity, age, gender, race/ethnicity, SES, region, etc.
- Five year projection
**Task 2** – Analyze and describe US twin populations with type 1 diabetes, SLE, and MS
- Define phenotype(s) of each condition
- Totals and demographics
- Numbers justify the effort - cost/benefit point of view?
- Estimate numbers of twins that are currently enrolled in existing twin registries and/or research programs
- Literature review
- Survey existing twin registries, disease foundations, etc.

## Survey of Existing Twin Registries

- Registry characteristics
- Registry experience
- Demographics of twin population
- Human Subjects Protections
- Data collection
- Tissue collection
- Retention
- Data sharing policies
- Survey for disease specific registries and disease foundations
- Estimate the willingness of twins to participate in registries and research programs

## Task 3 – Ethical, Legal, and Social Issues

**Explore the ethical, legal and social issues (ELSI) that could impact establishing and operating a national US twin registry and the three disease-specific registries**
- Separate panel of ELSI experts (twin research, minorities/underrepresented populations, privacy, genetic issues, other areas)
- Hold a special ELSI workshop (November 2005)
- Privacy and confidentiality
- Informed consent
- Participation and recruitment – overall, children, minorities, underrepresented subgroups
- Ethics review
- Research
- Genetics
- Focus groups of representative populations
- Literature reviews

## Task 4 – Potential Size and Composition of the Proposed National Twin Registries

- Estimates from tasks 1 and 2
- Surveys of existing twin registries, foundations, studies, etc.
- Literature reviews
- Take current ELSI issues into account
- Methods for twin ascertainment, tracing, recruitment and retention
- Overall twin population
- Twins with disease
- Minorities, children, underrepresented groups, etc.

## Tasks 5, 6 and 7

**Task 5**** - Alternatives to a National US Twin Registry**
- Consortium of already existing registries
- One or more smaller population-based registries
- Pilot registry
**Task 6**** - Alternatives to the disease-specific twin registries**
- Expand existing resource
- Subgroup twins within the National US Twin Registry
**Task 7**** - Compare alternatives with national registries**
- Advantages and disadvantages of the various options
- Draft summary report
- Convene second panel expert meeting (June 2006)
- Make recommendation to NIEHS Directors

## Tasks 8, 9, and 10

**Tasks 8 and 9**** - **Devise final methods and implementation plans for establishing the Twin Registries or their alternatives.
- Ascertainment, tracing, recruitment and retention methods
- Surveillance methods (disease specific registries)
- Database development
- Data and sample collection from twins
- Registry policies
- Timelines
**Task 10**** -**Estimate infrastructure and costs
- Final Expert Panel Meeting (Oct 2006)
- Final report and recommendations

## Project Team

_**NIEHS**_** - ****Co-Project Officers/ NIEHS Co-PIs **
- Patricia C. Chulada, PhD, MHS
- Perry Blackshear, MD, DPhil
- _Virgina Commonwealth University_
- Linda Corey, PhD - Major PI
- _Phillip Morris USA_
-  Lenn Murrelle, MSPH, PhD – Consultant
- _Alpha-Gamma Technologies, Inc._
- Vani Vannappagari, PhD, MBBS – Lead Epidemiologist
- Teji Rakhra-Burris, MA - Project manager
- Reese Howle, BA – Project director
- Atif Hasan, MS – Database specialist
- Tom Bensman, BA – Logistical support

_**Research Triangle Institute**_
- Nedra Whitehead, PhD, MS – Medical Geneticist
- Paul Levy, MA, Sc.D. –Biostatistician
- Fengyu Zhang, PhD – Demographer, Statistician
- Paul Pulliam, BS – Survey specialist
- Ariana N. Napier, MA – Survey specialists
- David Rein, PhD – Research economist
_**UNC School of Public Health**_
- Robert C. Millikan, DVM, MPH, PhD – Consultant
- _University of Virginia_
- Paul Lombardo, JD, PhD, MA – Medical Bioethics

## Twins Beget Twins