Cardiovascular disease and polymorphisms 06/12/22 Flashcards
What are the risk factors for cardiovascular disease?
-Hypertension (High blood pressure increases the risk of vessel disease, heart attack, and stroke. Risk is significantly reduced when b.p remains below 120/80).
-Diet (High saturated fat, sugar, and salt diets lead to increased CV risk. Mediterranean diets have been shown to protect against CV disease as shown below).
-High blood cholesterol (LDL) (Cholesterol is carried through our blood by lipoproteins: low-density lipoprotein (LDL) and high-density lipoprotein (HDL). High levels of LDL lead to atherosclerosis increasing the risk of CV events. HDL reduces the risk of cardiovascular disease as it carries cholesterol away from the bloodstream).
-Smoking (Smoking increases heart rate, and b.p., and induces vessel contraction and stiffness. Tobacco also increases clotting activity - thrombus).
-Inactivity (Exercise lowers b.p, decreases LDL, and strengthens the heart muscle. Overall CV risk is decreased through exercise, most important after (not) smoking).
What treatment is given to reduce risk factors?
Statins - Inhibit HMA-CoA reductase (the enzyme responsible for the production of excess cholesterol in the liver).
NICE recommends in patients with more than 10% risk score. Can decrease CVD risk by up to 60%. Reasonably well-tolerated and cheap.
What is a genome-wide association study?
GWAS is an approach to looking for genetic variations (SNPs) that are associated with a particular disease. Researchers compare the genetics of healthy volunteers to people with a disease to look for disease-causing mutations. There are many worldwide databases that allow the sharing and comparison of screening data.
Why is HDL good?
HDL is a good cholesterol that can mop up LDL. Higher HDL is found in people with Mediterranean diets. Therefore, ratio of LDL to HDL is the most important thing.
What discoveries were found in the GWAS obesity studies?
GWAS studies found genes linked to obesity and this could explain why some ethnicities are more inclined to have CVD.
What is the purpose of the GWAS studies?
Fine the gene and SNP responsible and create drugs that can target it to treat it.
For example, type 2 diabetes, gene is SLC3OA8/KCNJ11, drug is ZnT-8 antagonists/Glyburide.
What is leptin?
This is a hormone that is synthesised by fat cells that regulated fat storage.
What is ghrelin?
This is the hunger hormone to let the body know when you are full.
What mutation can occur in leptin to cause CVD?
Rodents identified with spontaneous mutations in the leptin gene and/or the leptin receptor genes leading to uncontrollable hunger and increased fat storage.
What is an example of leptin mutations in humans?
It is rare but in 1998 a study found a family with a recessive mutation in the leptin gene. All were obese and didn’t progress to sexual maturity. A more recent study has shown an association between a specific leptin gene polymorphism and obesity.
What is familia hypercholesterolemia?
FH is caused by mutations in the genes associated with lipid metabolism. Autosomal dominant disorder characterised by a deficiency or defective function or LDLR affects 1 in 500 people in the UK.
Clinical features are very high levels of LDL and early onset of CVD. Symptoms are usually yellow cholesterol deposits around the eyes and tendons (really rare and only in homozygous people). Around 85% if people with FH are undiagnosed. Treatment is statins for heterozygous and homozygous is statins with LDL aphaeresis.
When will someone with FH have their first CVD event?
Heterozygous - 40-60 years
Homozygous - 0-30 years
How is FH tested for?
The tepnel AMRS PCR kit is currently used in the UK to screen for the 20 most common FH causing mutations. This will detect known mutations only, as the primers are designed to amplify common FH variants.
What is cascade screening in FH?
Cascade screening is used to identify people at risk for a genetic condition by a process of family tracing. FH has a high prevalence amongst family members, with 50% of relatives of heterozygotes affected. Once a patient (the index case), has been identified as having an FH-causing mutation, their 1st and 2nd degree relatives may be called in for screening. This will consist of serum LDL measurement and genetic testing. NICE review showed that the cascade process significantly reduces morbidity and mortality in FH heterozygotes with appropriate statin treatment.
What is Prader-Willi syndrome?
Rare genetic disorder where up to 7 genes on chromosome 15 fail to be correctly expressed.
No single gene defect has been identified and the severity of symptoms depends on silencing mechanism/severity. Recent studies have also implicated epigenetics (small nucleolar RNAs).
Symptoms - growth abnormalities, cognitive impairment and chronic hunger leading to life- threatening obesity (T2D, CVD etc).
