Taking Heredity to Heart and Head: Cardiovascular Disease Genetics

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Taking Heredity to Heart and Head
Cardiovascular Disease Genetics

• Amy Sturm, MS, CGC
• Heather Workman, MS, CGC

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Learning Objectives

• 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

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Chromosomes, DNA, and Genes
Adapted from Understanding Gene Testing, NIH, 1995
ASCO
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Normal Male Karyotype
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Normal Female Karyotype
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Abnormal KaryotypeDown syndrome (Trisomy 21)
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The DNA Double Helix
Base pair
ASCO
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Types of Inheritance

• Dominant
• Huntington disease
• Recessive
• Cystic fibrosis
• X-linked
• Fragile X syndrome
• Mitochondrial
• NARP, MELAS, MERFF

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What Do We Do? Genetic Risk Assessment and
Counseling

• 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

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Stroke

• Ischemic Stroke
• 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
• 10-20 of stroke
• Caused by a sudden bleeding from a brain vessel

Clinical and Experimental Hypertension 2006
Orlacchio and Bernardi
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Genetics of Stroke

• Studies in twins, families, and animal models
  provide substantial evidence for a genetic
  contribution to ischemic stroke
• Twin studies
• Concordance rates were 65 greater in identical
  versus fraternal twins
• Cohort studies
• Family history of stroke increased the odds of
  stroke by 30
• Case-control studies
• Family history of stroke increased the odds of
  stroke by 75

Lancet Neurol 2007 Dichgans Stroke 2004 Meschia
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Genetics of Stroke Age Effect

• 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
• 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
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Heritability of Ischemic Stroke in Women Versus
Men

• Oxford Vascular Study
• 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?
• Findings
• Maternal stroke was more common than paternal
  stroke in female probands (OR1.8) but not in
  males (OR1.1)
• Female probands were more likely than males to
  have an affected sister (OR3.1) but not an
  affected brother (OR1.1)
• Findings independent of traditional risk factors
  and stroke subtype
• Conclusion
• Heritability of ischemic stroke is greater in
  women than in men

Lancet Neurol 2007 Touze and Rothwell
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Monogenic versus Polygenic Disorders

• Definitions
• Monogenic
• Disorders caused by a mutation in a single gene
• Include stroke as one part of the clinical
  spectrum
• Polygenic
• Disorders caused by multiple low-penetrance
  genetic variants
• These variants predispose to multifactorial stroke

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Monogenic Stroke

• 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

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Common Causes of Monogenic Stroke

• CADASIL
• Sickle cell disease
• Fabry disease
• Homocystinuria
• MELAS
• Connective tissue disorders
• Miscellaneous
• Stroke can occur as a complication of several
  heritable cardiomyopathies, dysrhythmias,
  hemoglobinopathies, coagulopathies,
  dyslipidemias, and vasculopathies

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CADASIL

• 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
• 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

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Implications for Identifying CADASIL

• Identify at risk family members
• At risk individuals can avoid harmful agents
• Smoking
• Angiography
• Anticoagulants
• Supportive care for at risk individuals
• Uncertainty of severity of symptoms

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CADASIL- Notch3 gene

• 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

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Pedigree- CADASIL
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Polygenic Stroke

• 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

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Genetic Variants for Stroke Risk

• 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
• 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

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Hereditary Risk Factors for Stroke

• Strong evidence for a genetic component to
• Atherosclerosis
• Diabetes
• Hyperlipidemia
• Hypertension
• Obesity

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Hypertension (HTN) as an Example

• Family history as a risk factor
• First degree relative with HTN
• 2-fold increase in risk
• Two or more family members with HTN
• 4-fold increase in risk
• Race and age strongly influence 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
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Family History of Stroke as Risk Factor for
Early-Onset Coronary Heart Disease

• Scheuner et al. Genet Med 20068(8)491-501.
• Goal Further characterization of family history
  as a risk factor for CHD diagnosed
• Methods
• HealthStyles 2003 Survey Data
• Assessed associations between self-reported
  family history and personal history of
  early-onset CHD (
• ORs were calculated and adjusted for age, sex,
  ethnicity/race, marital status, education,
  income, hypercholesterolemia, hypertension, and
  obesity
• Stroke Results
• History of early-onset stroke (least one FDR 2.9 (1.7-5.0)
• 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)

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Polygenic Stroke Pedigree Example
d. 72 Stroke HTN, dx 62
75 Healthy
d. 70 MI DM, dx 60
77 Stroke, 73 HTN, dx 50
75 CABG, 64 Stroke, 75 HTN, dx 55
55 HTN, dx 55 Hyperlipidemia, dx 50
53 HTN, dx 52 DM, dx 52
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Genetic Risk Assessment and Counseling Issues and
Management

• The proband learns he is at increased risk for
  cardiovascular disease (CVD)
• This includes atherosclerosis related to stroke
  AND coronary heart disease
• He recognizes the importance of getting his
  hypertension under control
• Starts hypertension medications
• Therapeutic lifestyle changes have not been
  effective enough for this patient in reducing his
  cholesterol levels
• Starts medication for hyperlipidemia
• Patient also starts exercise program and informs
  his sister of her increased CVD risk
• At patients 3 and 6 month follow-up
  appointments, his blood pressure and cholesterol
  levels measure in the normal range

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Use of Genetic Testing for Stroke

• A valuable tool in diagnosing single-gene
  disorders associated with stroke
• Not currently recommended in patients with common
  multifactorial (polygenic) stroke
• 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

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Genetic Tests

• 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
• Laboratories may offer different types of tests
  and use different methods with varying
  sensitivities and detection rates
• Some labs will not bill a patients insurance
  directly
• Genetic tests can be costly, and may or may not
  be covered by insurance
• Letters of medical necessity
• Interpretation and implications of genetic tests
  are not always straightforward (variants of
  uncertain significance)
• Prudent to consult a genetics professional

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Types of Genetic Testing

• The identification of a gene mutation in an
  individual may
• 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)
• Testing should begin with an affected family
  member
• 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
• Price for targeted analysis typically around
  200-300

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Complexities of Genetic Testing

• Benefits and limitations vary based on
  circumstances
• Genetic testing may or may not influence medical
  management
• Psychosocial implications - for patient and
  family members
• Genetic determinism
• Anxiety
• Parental guilt
• Ethical dilemmas (e.g. revealing non-paternity,
  testing minors)
• Genetic discrimination
• Health, disability, life and long-term care
  insurance
• Employment

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Genetic Information Non-Discrimination Act (GINA)

• 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

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NSGC 3-Step Process

• To improve genetic testing outcomes
• 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.

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Genetic Counseling Is Integral to the Testing
Process
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Goals of Genetic Risk Assessment
Early Detection, Prophylactic Treatment, and
Prevention
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American Stroke Associations Family Health
History Tree
StrokeAssociation.org/power