PHARMACOGENOMICS

-IN CARDIOVASCULAR DISEASES

INTRODUCTION• Pharmacogenomics is the study of genetic

variations that influence individual’s response to drugs.

• Combines pharmacology and genomics.

• More personalized approaches.

• More accurate diagnoses.

• Fewer adverse side effects.

Fig: Graphical representation of deaths caused due to various reasons.

Pharmacogenomic Testing• Pharmacogenomic

tests use biomarkers.

• A biomarker is a biochemical or genetic feature that explains how your body will react to a certain drug.

• It is a very helpful tool for every doctor which will aid in treating the patient.

SNP as Biomarker in Pharmacogenomics

• SNPs are single-letter variations in DNA sequence.

• SNPs occur every 100–300 bases along the 3 billion base pairs.

• SNP Variant alleles Variable Protein & Protein Functions.

• Variation in genetic information particularly due to the SNPs has been linked with the variation in drug response.

Cardiovascular Diseases

• Heart means 'cardio' . Therefore all heart diseases belong to the category of cardiovascular diseases.

• For example Chronic Heart Disease (CHD), Cardiomyopathy, Congestive Heart Failure, are some of the types of CVDs.

Cardiovascular Disease- Scenario in India• India is the

country with maximum number of patients suffering from various cardiovascular diseases (CVDs).

• By the year 2020, more than 4.6 million people will suffer from CVDs in India.

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.

Clinical Issues Related to these Drugs

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.

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.

Pharmacogenomics for Efficient Clopidogrel Treatment

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 Gene VKORC1 GeneLocation: 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.

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 clotting factors.

CYP2C9 And VKORC1 Together Explain The Variation In Coumarin Dose

Requirement

Interplay of CYP2C9 & VKORC1

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 (Schalekamp, 2004).

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.

• 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.

• The creation of “Designer Drugs” is possible with pharmacogenomics.

CONCLUSION

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