1. health and fitness
2. disease

What does it mean to unlock the
secrets of your DNA?
Ethical, social and clinical Challenges
of personalized genomics
Holly K. Tabor, Ph.D.
Treuman Katz Center for Pediatric Bioethics
Seattle Children’s Hospital
Division of Bioethics, Department of Pediatrics
University of Washington
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Where do we go from here?
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What do genetic susceptibility results really
mean?
Is there such a thing as personalized genomic
medicine?
How will access to more genetic information
affect the way people feel about genes, disease
and identity?
How does this affect research?
Outline
1.
There are substantial challenges to translating genetics results
about disease susceptibility into practice.
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2.
Studies on genetic susceptibility produce large volumes of data
on a wide range of phenotypes: what are the potential risks?
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3.
example: Craig Venter
The impact of genetic data can extend beyond clinical utility.
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4.
example: Type II Diabetes
example: presymptomatic ApoE4 testing
Where should we go from here?
Definitions
Genetic Profiling
 Using technology that interrogates the whole genome
to develop a “profile” of a large set of genetic
information that provides information about complex
phenotypes
Personalized Medicine
 Using information to tailor health interventions
specifically to individuals
Point 1:
There are substantial challenges to
translating results about disease
susceptibility into practice.
The example of Type 2 Diabetes.
What do we do when we identify
genes for Mendelian disease?
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Provide clinical testing in regulated approved
labs
Identify therapies/interventions/drugs that may
be more effective for subsets of disease
Create a different diagnostic, risk and treatment
pathways for at-risk individuals
Huntington’s Disease
“What does seem absolutely clear is that testing for
Huntington’s is never innocuous, it is always a
profoundly life-changing event, not only to the
individual going through the testing, but to his or her
family, and often to wider circles as well. Gene testing,
in the case of Huntington’s disease, can never be taken
lightly, it can never be routine.”
-Alice Wexler, “Mapping Fate”
What do we do when we identify
genes for complex disease?
“Whole genome information, when combined with
clinical and other phenotypic data, offers the potential
for increased understanding of basic biological
processes affecting human health, improvement in the
prediction of disease and patient care, and ultimately
the realization of the promise of personalized
medicine.”
-NIH Statement on GWAS
But how well can we predict disease and improve patient
care?
The Current Realities
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Results from genome wide association studies are being
published for complex traits
These results will be reported/interpreted as identifying
genetic profiles for disease risk/susceptibility
Some results will be replicated, some not
Consumers will be able to get genetic profile data from:
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Direct-to-Consumer Genetic Testing (e.g. 23andme)
Whole genome/targeted sequencing
Who will have this information?
Near Future:
 Participants in GWAS/Sequencing Studies
 People who order Direct-to-Consumer products (23andme,
DNA Direct, others)
More Distant Future:
 Patients with specific disorders may possibly obtain data through
clinical tests
Who will not have this information?
 Low-income patients/patients without insurance
 Individuals in the developing world
What could we do with results for
Type 2 Diabetes?
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Design a test:
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Quantify the risk:
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Assign risk of disease to each SNP/combination of
SNPs/haplotypes.
Describe the scientific validity:
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conduct whole genome testing, or
create a panel testing just 8-500 SNPs.
Replication results, populations studied, technologies used,
how much risk is explained.
Describe the clinical validity:
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what added information comes from this profile and how
does this impact health care decisions?
Type 2 Diabetes
Scott et al, Science, June 2007
 Population Attributable Risk of 5-27% at each locus
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95-63% of population risk of diabetes is NOT explained by each loci
All 8 loci combined contribute only 2.3% to the overall variance
in diabetes risk
Conclusion:
 Most of diabetes risk in a subset of individuals is explained by
other genetic and environmental factors
It is difficult to translate even this kind of well-replicated data
into a genetic profile with clinical validity.
Point 2:
Whole Genome Sequencing
What if you could “unlock the secrets
of your DNA?”
What does that mean?
HuRef: September 2007
What is the difference?
Associated Common Traits
•Blue eye/fair skin color
•Evening preference
•Novelty seeking
•Alcohol
•Tobacco Addiction
Confidence of Genotype
HuRef Variants and Phenotypes
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Cardiovascular Disease
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Cancer
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heterozygous for GSTM1
unclear “if this variant contributes to the reported health status events
experienced by the donor, such as skin cancer.”
Unknown data:
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family history
several genotypes associated with CVD, but conflict in direction of
risk/protection
novel deletion causing protein truncation for an enzyme associated with
lipid metabolism
Inconsistencies:
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Genotype should confer adult lactose tolerance, but does not match with
self-reported phenotype
Tracking/understanding
potential “adverse events”
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Paternity/genealogy
Issues of identity/profiling
“Right not to know” genetic information
Communicating genetic information to minors/relatives
Lack of insurability (health or life)
Employment discrimination
Forensic uses/abuses
“Claim relatedness of the volunteer to infamous villains”
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Perceived stigma
Therapeutic misconception: “suggestion for diagnostic tests”
Reproductive decision-making
Example 3:
How do patients use genetic
information about susceptibility?
The example of ApoE4 testing.
ApoE4 Testing: Study Design
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Gooding et al, Patient Education and
Counseling, 2006
60 adult children of individuals with AD
Tested for ApoE4, interviewed about the testing
process
ApoE4 neither necessary nor sufficient for
development of AD
No therapeutic or preventive course of action
ACMG recommends against ApoE4
testing…but you can order it online!
ApoE4 Testing: Results
“Even though the development of Alzheimer’s disease was seen as
uncontrollable by most individuals, for some the act of acquiring genetic
information was seen as a way to confront their risk and therefore exert
control.”
“Even without prevention or treatment options, genetic testing may be a useful
coping strategy for some at risk individuals.”
“The ApoE genotype is more memorable than a numeric risk estimate for
Alzheimer’s disease. Health professionals testing for complex disorders like
Alzheimer’s disease must find an appropriate balance between communicating
risk in an understandable format and addressing the probabilistic nature of
the information.”
Implications for Genomic Profiling
and Personalized Medicine
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There may emotional, rather than practical benefits and risks of
genetic risk information.
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The emotional meaning may be more relevant for very large
amounts of genetic information and information on
susceptibility and risk, rather than prediction/diagnosis.
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People may react very differently to this kind of data, based on
personality/coping strategy and the context of the information.
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Patients should be encouraged to consider the range of results,
how they might cope, and the range of possible
actions/reactions before testing.
Where should we go from here?
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As genetic studies on susceptibility to disease proliferate, we
need to demand replication and understanding of population
attributable risks of significant findings.
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As patients/consumers seek out genetic profiling, physicians
need to understand the clinical validity and limitations of the
data for making health-related decisions.
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We need well-designed studies about how patients/consumers
are affected by genetic data, especially large amounts of data, in
order to understand the risk and benefits.
There Is Nothing New
Under the Sun
“Personalized medicine has always been a component of
good medical practice. Genetic tests may provide new
tools, but they do not change the fundamental goals of
clinicians to adapt available medical tests and
technologies to the individual circumstances of their
patients. . . When genetic testing is used, the
personalized nature of the care will extend well beyond
the patient’s base pair sequence.”
-Wylie Burke and Bruce Pstay
JAMA, October 10, 2007
There is Nothing Good or Bad
But Thinking Makes it So
“My guest Craig Venter has
successfully decoded his own
genome, which has been
hailed as a breakthrough in
the field of medicine . . . for
Craig Venter.”
Stephen Colbert
The Colbert Report,
October 30, 2007
Acknowledgements
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Benjamin Wilfond
Mildred Cho
David Magnus
Sandra Lee
Jennifer McCormick
Martine Lappé
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Funding from NHGRI
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1 K99 HG004316-01
5 P50 HG003389-04
My Research
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Ethical and Social Issues in the Study of Genetics of
Complex Traits
Focus groups
Goal: explore the attitudes of adolescents towards
genetic research on complex traits and the risks and
benefits of participation
Examine perspectives on risk of genetics for complex
behavioral traits, like smoking, and perspectives on
consent/assent in participation in large genomic and
health databases
My Research
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Other Research Settings
Disease Context: Studies of autism
 Health Care Setting Context: Genome Wide
Association Studies at Group Health Cooperative
 Prospective Cohort Study Context: The National
Children’s Study
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