Taking Heredity to Heart and Head: Cardiovascular Disease Genetics Amy Sturm, MS, CGC Heather Workman, MS, CGC
Dec 18, 2015
Taking Heredity to Heart and Head: Cardiovascular Disease Genetics
Amy Sturm, MS, CGC
Heather Workman, MS, CGC
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
ASCO
Chromosomes, DNA, and Genes
Adapted from Adapted from Understanding Gene TestingUnderstanding Gene Testing, NIH, 1995, NIH, 1995
CellCellNucleusNucleus
ChromosomesChromosomes
Gene
ProteinProtein
ASCO
The DNA Double Helix
Base pairBase pair
Adenine (A)Adenine (A)
Thymine (T)Thymine (T)
Cytosine (C)Cytosine (C)
Guanine (G)Guanine (G)
BasesBases
Sugar Sugar phosphate phosphate backbonebackbone
Types of Inheritance
Dominant– Huntington disease
Recessive– Cystic fibrosis
X-linked– Fragile X syndrome
Mitochondrial– NARP, MELAS, MERFF
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
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
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 DichgansStroke 2004 Meschia
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 DichgansStroke 2003 Jerrard-Dunne et al
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 (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
– Heritability of ischemic stroke is greater in women than in men
Lancet Neurol 2007 Touze and Rothwell
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
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
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
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
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
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
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
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
Hereditary Risk Factors for Stroke
Strong evidence for a genetic component to– Atherosclerosis– Diabetes– Hyperlipidemia– Hypertension– Obesity
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
Family History of Stroke as Risk Factor for Early-Onset Coronary Heart Disease
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:
– 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– History of early-onset stroke (<60 years) in at 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)
Polygenic Stroke Pedigree Example
55HTN, dx 55Hyperlipidemia, dx 50
77Stroke, 73 HTN, dx 50
53HTN, dx 52DM, dx 52
75CABG, 64Stroke, 75HTN, dx 55
75Healthy
d. 70MIDM, dx 60
d. 72StrokeHTN, dx 62
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 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
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
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 patient’s 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
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
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
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
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.
Goals of Genetic Risk Assessment
no symptoms symptoms
Typical age atdiagnosis
Risk Factor Modification
30’s 50’s
Birth Death
Age at diagnosis with genetic counseling
Early Detection, Prophylactic Treatment, and Prevention