Download Taking Heredity to Heart and Head: Cardiovascular Disease Genetics

Taking Heredity to Heart and Head:
Cardiovascular Disease Genetics
Amy Sturm, MS, CGC
Heather Workman, MS, CGC
Learning Objectives
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Review genetic concepts including genes,
chromosomes, inheritance patterns, genetic
counseling and genetic testing
Describe the genetics of stroke, including heritability,
relative risk with positive family history, etc.
Review hereditary risk factors such as hypertension
and hyperlipidemia that give an increased risk for
atherosclerosis as related to stroke and coronary
heart disease; pedigree examples will be included
Chromosomes, DNA, and Genes
Gene
Cell
Nucleus
Chromosomes
Protein
Adapted from Understanding Gene Testing, NIH, 1995
ASCO
Normal Male Karyotype
Normal Female Karyotype
Abnormal Karyotype
Down syndrome (Trisomy 21)
The DNA Double Helix
Sugar
phosphate
backbone
Base pair
Bases
Adenine (A)
Cytosine (C)
Thymine (T)
Guanine (G)
ASCO
Types of Inheritance
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Dominant
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Recessive
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Cystic fibrosis
X-linked
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Huntington disease
Fragile X syndrome
Mitochondrial
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NARP, MELAS, MERFF
What Do We Do?
Genetic Risk Assessment and Counseling
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Consultations last ~1-2 hours
Review and document medical history
Review and document family history
– 3-4 generation pedigree
– Documentation of all diagnoses in the family with medical records, autopsy
reports, and/or death certificates
Physical examination
Risk Assessment
– Assess familial risk of developing disease in question
– Inherited versus acquired causes
Education
– Basic genetic and medical concepts
– Differential Diagnosis
 Relevant hereditary syndromes and their associated risks
– Inheritance Pattern
 Risk for proband and their relatives
– Benefits, limitations and risks of genetic testing
– Disease management and risk reduction
Stroke
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Ischemic Stroke
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80-90% of stroke
Caused by a complete occlusion of a cerebral
artery due to an atherosclerotic process in the
brain or to an embolic or cardiogenic event
Hemorrhagic Stroke
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10-20% of stroke
Caused by a sudden bleeding from a brain vessel
Clinical and Experimental Hypertension 2006 Orlacchio and Bernardi
Genetics of Stroke
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Studies in twins, families, and animal models provide
substantial evidence for a genetic contribution to
ischemic stroke
Twin studies
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Cohort studies
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Concordance rates were ~65% greater in identical versus
fraternal twins
Family history of stroke increased the odds of stroke by ~30%
Case-control studies
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Family history of stroke increased the odds of stroke by ~75%
Lancet Neurol 2007 Dichgans
Stroke 2004 Meschia
Genetics of Stroke: Age Effect
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Both twin and family history studies suggest a stronger
genetic component in stroke patients younger than 70 y
Case-control study of Jerrard-Dunne et al
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1000 consecutive cases with ischemic stroke and 800 controls
matched for age and sex
Family history (FH) of stroke in first-degree relatives obtained
FH of stroke at any age not statistically significant
FH of stroke occurring in a relative before age 65 was a significant
risk factor
FH of stroke before age 65 increased the odds of stroke by 38%
after adjusting for age, sex, hypertension, diabetes, cholesterol,
and smoking
Lancet Neurol 2007 Dichgans
Stroke 2003 Jerrard-Dunne et al
Heritability of Ischemic Stroke in
Women Versus Men
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Oxford Vascular Study
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Findings
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What was the prevalence of stroke in the mother, father, and
other first-degree relatives in female and male probands with
ischemic stroke or TIA?
Maternal stroke was more common than paternal stroke in
female probands (OR=1.8) but not in males (OR=1.1)
Female probands were more likely than males to have an
affected sister (OR=3.1) but not an affected brother (OR=1.1)
Findings independent of traditional risk factors and stroke
subtype
Conclusion
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Heritability of ischemic stroke is greater in women than in men
Lancet Neurol 2007 Touze and Rothwell
Monogenic versus Polygenic
Disorders
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Definitions
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Monogenic
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Disorders caused by a mutation in a single gene
Include stroke as one part of the clinical spectrum
Polygenic
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Disorders caused by multiple low-penetrance genetic
variants
These variants predispose to multifactorial stroke
Monogenic Stroke
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A large number of monogenic disorders can cause
stroke
However, these disorders only account for a small
proportion of all strokes
Important cause of stroke, especially in young stroke
patients without known risk factors
In some disorders stroke is the prevailing
manifestation, whereas in others it is part of a wider
spectrum
Most monogenic disorders are associated with specific
stroke subtypes, which along with the accompanying
systemic features can lead to a diagnosis
Common Causes of Monogenic Stroke
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CADASIL
Sickle cell disease
Fabry disease
Homocystinuria
MELAS
Connective tissue disorders
Miscellaneous
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Stroke can occur as a complication of several heritable
cardiomyopathies, dysrhythmias, hemoglobinopathies,
coagulopathies, dyslipidemias, and vasculopathies
CADASIL
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Cerebral Autosomal Dominant Arteriopathy with Subcortical
Infarcts and Leukoencephalopathy
Recurrent strokes- ages 30s-60s (85%)
Migraines with aura (30-40%)
White matter and lesions and subcortical infarcts on
neuroimaging studies
Depression (30%), cognitive impairment (60%), dementia
(75%)
CADASIL should be considered
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Young person who presents with migraine with aura and white matter
changes on MRI
Family of individuals with multiple occurrences of stroke, migraines, stroke
leading to dementia and cognitive impairment
Implications for Identifying
CADASIL
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Identify at risk family members
At risk individuals can avoid harmful agents
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Smoking
Angiography
Anticoagulants
Supportive care for at risk individuals
Uncertainty of severity of symptoms
CADASIL- Notch3 gene
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Only gene associated with CADASIL
Mutation detection: 57-96%
Genetic testing should always begin with an
affected individual
Most persons with CADASIL have an
affected parent
Pedigree- CADASIL
Polygenic Stroke
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The majority of stroke cases
Complex disease caused by a wide number
of gene-gene and gene-environment
interactions
The number of genes involved is unknown
Does not follow a classic mode of inheritance
Genetic Variants for Stroke Risk
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The contribution to stroke risk of individual
genetic variants is likely to be small with odds
ratios between 1.1 and 1.5
Specific genetic variants may
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Affect intermediate phenotypes (e.g. Carotid
artery intima media thickness)
Predispose to conventional stroke risk factors
(e.g. hypertension)
Have a direct independent effect on stroke risk
Hereditary Risk Factors for Stroke
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Strong evidence for a genetic component to
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Atherosclerosis
Diabetes
Hyperlipidemia
Hypertension
Obesity
Hypertension (HTN) as an Example
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Family history as a risk factor
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First degree relative with HTN
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Two or more family members with HTN
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4-fold increase in risk
Race and age strongly influence risk
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2-fold increase in risk
In African Americans, parental history of HTN gives 9-fold
increase in risk
Having both parents with HTN before age 60 years increases
the odds of HTN to 5.3 in women and 7.8 in men
Shared genes AND shared family environment both
contribute to blood pressure level
Hypertension Primer: The Essentials of High Blood Pressure
Izzo et al (American Heart Association) 4th Edition 2007
Family History of Stroke as Risk Factor
for Early-Onset Coronary Heart Disease
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Scheuner et al. Genet Med 2006:8(8):491-501.
Goal: Further characterization of family history as a risk factor for
CHD diagnosed <60 years
Methods:
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HealthStyles 2003 Survey Data
Assessed associations between self-reported family history and
personal history of early-onset CHD (<60 years)
ORs were calculated and adjusted for age, sex, ethnicity/race, marital
status, education, income, hypercholesterolemia, hypertension, and
obesity
Stroke Results
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History of early-onset stroke (<60 years) in at least one FDR:
2.9 (1.7-5.0)
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No significant associations were observed given only SDRs with stroke
>1 sibling with stroke at any age of onset: 3.2 (1.2-8.3)
Polygenic Stroke Pedigree Example
d. 72
Stroke
HTN, dx 62
d. 70
MI
DM, dx 60
75
CABG, 64
Stroke, 75
HTN, dx 55
77
Stroke, 73
HTN, dx 50
75
Healthy
55
HTN, dx 55
Hyperlipidemia, dx 50
53
HTN, dx 52
DM, dx 52
Genetic Risk Assessment and
Counseling Issues and Management
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The proband learns he is at increased risk for cardiovascular
disease (CVD)
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He recognizes the importance of getting his hypertension under
control
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Starts hypertension medications
Therapeutic lifestyle changes have not been effective enough for
this patient in reducing his cholesterol levels
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This includes atherosclerosis related to stroke AND coronary heart
disease
Starts medication for hyperlipidemia
Patient also starts exercise program and informs his sister of her
increased CVD risk
At patient’s 3 and 6 month follow-up appointments, his blood
pressure and cholesterol levels measure in the normal range
Use of Genetic Testing for Stroke
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A valuable tool in diagnosing single-gene disorders
associated with stroke
Not currently recommended in patients with common
multifactorial (polygenic) stroke
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Family health history (FHH) remains gold standard in the
“genetic” evaluation for polygenic stroke
• Powerful tool that can identify individuals at increased disease
risk who may benefit from targeted personal health promotion
efforts and prevention therapies
• Reflects shared genetic susceptibilities, shared environment, and
common behaviors
• Both easily and inexpensively obtained on a routine health
assessment
Genetic Tests
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More than 1000 genetic tests are now available for a multitude of
conditions
Hundreds more are moving through the research pipeline to clinical
application
Determining the appropriate genetic test and testing laboratory is
critical
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Genetic tests can be costly, and may or may not be covered by
insurance
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Laboratories may offer different types of tests and use different methods
with varying sensitivities and detection rates
Some labs will not bill a patient’s insurance directly
Letters of medical necessity
Interpretation and implications of genetic tests are not always
straightforward (variants of uncertain significance)
Prudent to consult a genetics professional
Types of Genetic Testing
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The identification of a gene mutation in an individual may:
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Testing should begin with an affected family member
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Confirm the diagnosis of a genetic condition (diagnostic testing)
Identify a susceptibility to develop a condition later in life
(predictive or presymptomatic testing)
Indicate that while there are no symptoms of the condition, there
may be an increased risk to have a child with a genetic condition
(carrier testing)
Greatest likelihood of finding a mutation
Targeted mutation analysis can be conducted on at-risk family
members once a mutation has been identified in the proband
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Price for targeted analysis typically around $200-300
Complexities of Genetic Testing
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Benefits and limitations vary based on circumstances
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Psychosocial implications - for patient and family
members
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Genetic testing may or may not influence medical management
Genetic determinism
Anxiety
Parental guilt
Ethical dilemmas (e.g. revealing non-paternity, testing minors)
Genetic discrimination
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Health, disability, life and long-term care insurance
Employment
Genetic Information NonDiscrimination Act (GINA)
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Protects individuals who undergo genetic
testing against health insurance
discrimination based on their genetic status
Employment discrimination protection
There is no protection for life insurance or
disability insurance
NSGC 3-Step Process
To improve genetic testing outcomes
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Step One: Before you get tested, meet with a genetic
counselor. Discuss why you are interested in undergoing
genetic testing, if a genetic test is available and appropriate for
your situation, and what the results will actually tell you.
Step Two: Explore with the genetic counselor what emotional
and medical effects the test results could have on you and your
family.
Step Three: Once you have your test results, take time to find
out from your genetic counselor what the results mean for your
health, what next steps you will want to take, and who else in
your family may be at risk.
Genetic Counseling Is Integral
to the Testing Process
Goals of Genetic Risk Assessment
Risk Factor Modification
Early Detection, Prophylactic Treatment, and Prevention
30’s
Birth
50’s
no symptoms symptoms
Age at diagnosis with
genetic counseling
Typical age at
diagnosis
Death
American Stroke Association’s
Family Health History Tree
StrokeAssociation.org/power