This document discusses how gene therapy can be used to treat cardiovascular diseases by replacing defective genes. It then focuses on three commonly prescribed cardiovascular drugs - statins, clopidogrel, and coumarin derivatives - and how patient responses to these drugs can vary due to genetic factors. Specifically, it describes genes like SLCO1B1, CYP2C19, CYP2C9, and VKORC1 that influence how effectively the body metabolizes and makes use of these drugs. Understanding a patient's genetic profile could allow doctors to select the most appropriate drug or dosage for that individual to maximize efficacy and safety.

1. GeneTherapyfor
CardiovascularDiseases

2. GENE THERAPY
Gene therapy is the insertion, alteration, or removal of genes within
individual's cells to treat diseases and hereditary diseases in which a
defective mutant gene is replaced with a functional one.
CARDIOVASCULAR DISEASES
•Involve heart or blood vessels •Leading cause of death globally
•Includes coronary artery diseases (angina and myocardial
infarction),stroke, heart failure, hypertensive heart disease, rheumatic
heart disease, cardiomyopathy, heart arrhythmia, congenital heart
disease, valvular heart disease, carditis, aortic aneurysms, peripheral
artery disease, and venous thrombosis.

3. Pharmacogenomic Interactions in
CVDs
Cardiovascular drugs are widely used for prevention or treatment
of CVDs.
The most commonly prescribed drugs in the management of
CVDs with important gene-drug interactions are:
A. Statins [HMG-CoA reductase inhibitors]
B. Clopidogrel [Platelet Inhibitors (PI)]
C. Coumarin Derivatives [Vitamin-K Antagonists]
These three drugs are candidates for pharmacogenomic testing in
everyday practice.

4. Clinical Issues Related to these Drugs

5. Statins
Statins are widely used to treat hypercholesterolemia and prevent CVD, but
the efficacy varies among patients. The effect of statins depends on the statin
concentration at the site of action- the Liver. It is carried to the liver by the
protein- OATP1B1 (organic anion transporter polypeptide 1B1), produced by
the SLCO1B1 gene (solute carrier organic anion transporter family, member
1B1). The SLCO1B1 gene is located on the short arm of Chromosome 12. It
belongs to the family of genes called SLC (solute carriers).
SNP Associated with Statin Function
The *5 SNP in the SLCO1B1 gene produces a less efficient OATP1B1 protein.
The Valine at the 174 position of OATP1B1 protein gets replaced with Alanine.
The protein thus produced is less able to transport Statins to the liver.
Pharmacogenomics for Safe Statin Therapy
Various kinds of Statin are available; some of which depend on the genetic
make up of the patients, and some don’t. Genotyping for SLCO1B1
polymorphisms before prescribing the kind of statin could be helpful.

6. Clopidogrel
Clopidogrel monotherapy is used for secondary prevention of atherosclerotic
complications. When used along with aspirin, it reduces the risk of
thrombosis, stroke, etc. Variation in response to Clopidogrel is related to
genetic variability in the Cytochrome P450- 2C19 gene (CYP2C19 gene),
located on the Chromosome 10. Presently more than 33 alleles of the
CYP2C19 gene have been identified.
SNP Related to Clopidogrel Response
The *2 SNP of the CYP2C19 gene results into an decreased efficiency of the
drug by hampering its metabolic pathway.
Clopidogrel Metabolism
Clopidogrel is administered to patients as a Prodrug, gets metabolized by
hepatic CYP450 & form the active PI metabolite. • This is done in two steps: 1.
Formation of intermediate metabolite 2- oxoclopidogrel. 2. 2-oxoclopidogrel
hydrolyzed into Thiol derivative R-130964, which block ADP P2RY12 receptors
on the platelet surface & inhibit platelet aggregation.

7. Coumarin Derivatives
Oral anticoagulants used to treat and prevent thromboembolic events. Dosage is difficult
to predict and frequent monitoring is necessary because of wide inter-patient variability.
Dosage monitored by the International Normalized Ratio (INR), which should be kept
within a certain range. This wide variability in dose requirement is caused by several
factors such as dietary intake of Vitamin K, comorbidities, sex, age, height and weight
along with genetic factors.
CYP2C9 And VKORC1 Together Explain The Variation In Coumarin Dose Requirement:
CYP2C9 Gene
Location: Chromosome 10.
Function: Produces the Cytochrome P450 2C9 (CYP2C9) enzyme, an important component
for many drug metabolic pathways.
Mutations Associated: *2 & *3 SNP in this gene results into the increased sensitivity to the
Coumarins among patients.
VKORC1 Gene
Location: Chromosomes 7 & 16.
Function: Produces the enzyme Vitamin-K epoxide reductase multi- protein complex-1
(VKORC1), which reduces Vitamin-K 2,3-epoxide to its active form.
Mutations Associated: Mutation in this gene affects the interaction of Vitamin-K with the

8. Pharmacogenomics for the Correct Dosage of
Coumarins
• Patients who are the carriers of *2 and *3 SNP require a
lower dose of Coumarins and have an increased risk of
overanticoagulation, which is associated with an increased
risk of bleeding.
• Mutations in the VKORC1 Gene prevents the conversion of
Vitamin-K into its Active (reduced) form. The inactivated
Vitamin-K cannot interact with the clotting factors which
ultimately hampers the clotting process in the body.

9. CONCLUSION
The serious problems related to CVDs can be greatly reduced using
pharmacogenomics in the treatment of the following drugs:
Statin: Carriers of a variant allele of the SLCO1B1 gene could be treated with
a SLCO1B1 independent Statin to increase the safety of the treatment.
Clopidogrel: It is less metabolized into its active form by patients carrying a
variant allele of CYP2C19, resulting in a less effective therapy.
Coumarins: VKORC1 and CYP2C9 genotype could be used to define
appropriate dose during the anticoagulation therapy with Coumarins to
enhance the efficacy and increase the safety of the treatment.
Other than CVDs, pharmacogenomics also holds a great future in curing
various chronic diseases such a neurological, psychological disorders,
cancer & even AIDS.