Genetics Of Cardiovascular Disease Flashcards
Broad types of cardiovascular diseases
1) Coronary heart disease
2) cerebrovascular disease
3) peripheral arterial disease
4) rheumatic heart disease
5) deep vein thrombosis and PEs
6) congenital heart disease
* NOTE: 17.9 million people die every year from cardiovascular diseases (31% of all global deaths)*
Multifactorial disorders
Disorders that do not follow a clear inheritance pattern
Symptoms from the diseases themselves are caused by caused by the interplay between two things
1) multiple genes (polygenic)
2) exogenous (environmental) factors
Possible exogenous factors
Lifestyle
- diet
- physical activity
- smoking
- drug abuse
- sun exposure
- sleep habits
- technology use
Medications
Chemicals
The threshold model
Assumes there is an underlying liability distribution in a population of a certain disease, but a threshold of total liabilities must be reached before the disease expresses itself individually
- people are predisposed to all diseases, however people who actually express the disease have crossed the set threshold for liabilities possessed.
Examples of diseases
- pyloric stenosis
- heart diseases
- congenital malformations
most of these diseases, males at more of a risk
Difference between calculating risks for diseases that are single gene disorders vs polygenic
Single gene = calculate w/ math and punnet squares
- have reduced penetrance and variable expression
Polygenic = empirical risks that are based on direct observations from pro bands (children) Usually are specified as ranges since specific populations have their own risks for the disease.
Criteria required to define multifactorial inheritance risks to a disease
1) the risks for the disease increase if more than one family member is affected
2) increases if the expression of the disease in children are more severe than in adults
3) increases if a child of the less commonly affected sex is affected (only if there is a difference between sexes).
4) decreases if generations have gone without seeing the disease
5) increases as the overall prevalence of the disease increases in the overall population
Twin studies w/ concordance and discordance
Using twins (either monozygotic or dizygotic) to determine how much a disease is genetically based.
Concordance = twins share the same trait
Discordance - twins do not share the same trait
Heritability statistic= chance that the disease inheritance is due to genetics vs environmental
- genetic = H is closer to 1.0
- environment = H is closer to 0
Formula to calculate heritability
- H = ((Cmz)- Cdz))/ (1-Cdz)
Mz = monozygotic (identical)
Dz - dizygotic (faternal)
the further apart the mz statistic concordance is from the dz statistic concordance, the more genetic based the disease is
Adoption studies
A second means of determining gene effect on certain multifactorial diseases
- requires comparing disease rates among adopted offspring of affected parents and adopted offspring of unaffected parents
Really looks more into environmental influence of a disease w/ genetics being indirectly looked at.
4 types of genetic diseases w/ subtypes
Single gene disorders
- autosomal
- sex-linked
Mitochondrial diseases
- only inherited by mother
Chromosomal abnormalities
- number
- structure
Multifactorial disorders
- congenital malformations
- adulthood diseases
Chromosomes that affect congenital heart defects
Trisomy in chromosomes 13/18/21
note exact genes and genetic factors are not known
Liddell syndrome
Severe HTN, low renin and suppressed aldosterone levels
- caused by mutations in renal epithelial sodium channels
gene is SCNN1B/SCNN1G
Gordon syndrome
Chronically high serum potassium levels w/ increased renal salt reabsorption
- caused by mutations in WNK1/WNK4 kinase genes
Aldosteronism
Early HTN w/ suppressed plasma renin w/ elevated aldosterone levels
- caused by a fusion of aldosterone genres and 11B-hydroxylase genes
Mineralocorticoid excess syndrome
Early onset HTN w/ low potassium, renin and aldosterone levels
- caused by direct mutation in the 11 B-hydroxylase gene
Possible gene mutations in familial dilated cardiomyopathy and the results of the mutations
TNNT2 and MYH7 genes (cardiac troponin and B-myosin genes respectively)
- both reduces natural inotropy in sarcomeres
TTN gene (titin gene) - naturally destabilizes the sarcomeres
B-sarcoglycan, D-sarcoglycan and dystrophin genes
- all three destabilize the sarcolemma inside cardiac cells
Possible gene mutations in familial hypertrophic cardiomyopathy and the results of the mutations
TNNT2 and MYH7 genes (cardiac troponin and B-myosin genes respectively)
- both reduces natural inotropy in sarcomeres
MYBPC gene (myosin-binding protein C) - results in sarcomere damage
Possible gene mutations in long QT syndrome and the results of the mutations
Cardiac potassium channel (a) mutations
(LQT1/2 and KCNQ1/H2)
Cardiac sodium channel mutations
(LQT3 and SCN5A)
Ankyrin B anchoring proteins
(LQT4 and ANK2)
Cardiac potassium channel (b) subunits
(LQT5/6 and KCNE1/2)
ALL MUTATIONS result in prolonged QT intervals and arrhythmias
How does smoking cause atherosclerosis?
Smoke inhaled causes LDLs to become oxidized due to the presence of ROS from smoking
- (NOTE: vitamin E, vitamin C and B-carotene and other antioxidants can combat this)
1) endothelial injury occurs due to oxidized LDLs. Produces macrophages
2) macrophages eat the oxidized LDLs and become foam cells
3) foam cells accumulate releasing growth factors and cytokines that stimulate SMCs to produce collagen around the foam cells
Familial hyperchylomicronemia (Burger-Grutz syndrome)
Caused by deficiency of lipoprotein Lipase (LPLs)
Autosomal recessive diseases and more common in Quebec
Symptoms:
- elevated plasma TAGs
- pancreatitis
- Xanthomas
Types of Hypercholesterolemia
Familial hypercholesterolemia:
- defect LDL receptors
- autosomal dominant w/incomplete dominance and 1:500 rates
Familial defective apoB-100 (FDB)
- defect in ApoB-100 proteins (prevent binding fo s to LDL receptors)
- autosomal dominant w/ frequency rates of 1:200-1200
Hypercholesterolemia
- defect in PCSK9 proteins (more active so they degrade LDL receptors quicker)
- autosomal dominant w/ frequency rates of 1:2500
Hyperlipoproteinemia type 3 (broad beta disease)
Three common isoforms of ApoE in humans
- ApoEe2, ApoEe3, ApoEe4
All three variants prevent lipoproteins from binding to hepatic lipoprotein receptors, just at varying rates.
Symptoms
- high levels of chylomicrons in blood
- IDLs in blood
- high levels of TAGs and cholesterol in blood
- often shows cardiovascular diseases
Tangier disease
Very rare disease that is caused by a defect in ABCA1 proteins
- autosomal recessive and approximately 100 cases worldwide
Symptoms:
- significantly reduced HDL levels
- widespread neuropathy
- enlarged orange-colored tonsils
Abetalipoproteinemia (Bassein-kornzweig syndrome)
Defects in microsomes TAG-transfer protein (MTTP or MTP)
- very rare and autosomal recessive
- affects absorption of dietary fats, cholesterol, and vitamins A/D/E/K
Symptoms:
- complete absence of Apo-B containing lipoproteins
- failure to gain weight and grow
- diarrhea that smells foul*
- star shaped RBCs*
- will progress to retina degeneration and near blindness
According to twin studies, what is the genetic base for MI predisposition?
H= 0.24 for males
H =0.26 for females
- not much genetic basis for males but for females there is a genetic link*
According to twin studies, what is the genetic base for both BP and measles
Meseals = (H = 0.16)
- not much genetic basis for measles, more environmental
BP
-Roughly 6.0 for both males and females, strong genetic predisposition for BP issues
