J a v a d J a m s h i d i

F a s a U n i v e r s i t y o f M e d i c a l S c i e n c e s , D e c e m b e r 2 0 1 4

S e s s i o n 8Medical Genetics

Pharmacogenetics

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What is Pharmacogenetics?

The sensitivity to drugs is different among people

Individual differences in response to drugs in humans are, often genetically determined

study of genetically determined variations that are revealed solely by the effects of drugs

Pharmacogenetics is now used to describe the influence of genes on the efficacy and side effects of drugs

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Stages of Metabolism of a Drug

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Various types of response to different drugs

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N-Acetyltransferase Activity

The metabolism of isoniazid shows two: rapid and slow inactivators.

To avoid side effects and also efficient treatment dose should be controlled

Slow inactivators are homozygous for an AR allele of the liver enzyme N-acetyltransferase, with lower activity levels

Metabolize several other drugs include hydralazine which is an antihypertensive, and sulfasalazine ,used to treat Crohn

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N-Acetyltransferase Activity

N-acetyltransferase activity varies in different populations.

There are three genes for N -acetyltransferase in Humans:

NATP: pseudogene , is not expressed

NAT1: No differences in activity between individuals

NAT2: Responsible for the inherited polymorphic variation

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Glucose 6-Phosphate Dehydrogenase Variants

Some people are sensitive to primaquine

Defective X-linked, glucose 6-phosphate dehydrogenase (G6PD).

Sensitive to many other compounds, including phenacetin, and certain sulfonamides

The first recognized Pharmacogenetic disorder, having been described by Pythagoras around 500 Be.

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Coumarin Metabolism

Coumarin anticoagulant drugs, such as warfarin, are used to prevent the blood from clotting

Warfarin is metabolized by the cytochrome P450 enzyme encoded by the CYP2C9 gene

(CYP2C9*2 and CYP2C9*3) result in decreased metabolism

Require a lower warfarin dose to maintain their target INR range and may be at increased risk of bleeding

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Debrisoquine Metabolism

There is a bimodal distribution in the response to the drug in the general population.

Approximately 5% to 10% of persons of European origin are poor metabolizers

One of the P450 family of genes on chromosome 22, known as CYP2D6.

This enzyme is involved in the metabolism of more than 20% of prescribed drugs including:

β-blockers metoprolol and carvedilolThe antidepressants fluoxetine and imipramineThe painkiller codeineThe anti-cancer drug tamoxifen

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Pharmacogenetics & Pharmacogenomics

Personalized or individualized medicine, where the treatment is dependent on the individual's genotype

Pharmacogenomics is the study of the interaction of an individual's genetic makeup and response to a drug.

Inherited variation at the DNA level play an essential role in determining the variability in responses to a drug

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Avoid Adverse Events

The objective is to identify a genetic profile that characterizes patients who are more likely to suffer an adverse event.

The best example is abacavir, used to treat HIV. About 5% of patients show fatal hypersensitivity to abacavir and this limited its use

A strong association with the HLA allele B*5701 was proven in 2002. Today testing for B*5701 is routine practice before abacavir is prescribed.

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Improve Efficacy

Drug should be prescribed only to those patients likely to respond to them.

Herceptin is an antibody that targets overexpression of HER2/neu protein observed in approximately one-third of patients with breast cancer.

Patients are prescribed herceptin only if their tumor has been shown to overexpress HER2/neu.

J a v a d J a m s h i d i

F a s a U n i v e r s i t y o f M e d i c a l S c i e n c e s , D e c e m b e r 2 0 1 4

Cancer Genetics

What is Cancer?Uncontrolled growth of cells

Not all tumors are cancerous

Six characteristics of cancer cells:

Self-sufficiency in growth signalingInsensitivity to anti-growth signalsEvasion of apoptosisEnabling of a limitless replicative potentialInduction and sustainment of angiogenesisMetastasis and invasion of tissue

Cancer ClassificationCarcinoma

Originate in epithelial origin, Most common ,80-90 percent of all cancer

SarcomaOriginates in supportive and connective tissues

MyelomaOriginates in the plasma cells of bone marrow

LeukemiaCancers of the bone marrow (the site of blood cell production)

LymphomaOriginate in glands or nodes of the lymphatic system

Is it due to Genetic Factors?

Small proportion is predisposed by inherited germline mutations behaving as mendelian traits

For many cancers, environmental factors are etiologically more important than heredity

Cancer is a genetic disease of somatic cells

End result of an accumulation of both inherited and somatic mutations in cell growth related genes

Is it due to Genetic Factors?

Germline mutations in at least 70 genes, and somatic mutations in at least 350 genes

In the majority of cancers, there is no clear-cut mode of inheritance, nor any clearly defined environmental cause

Evidence to help differentiate environmental and genetic factors comes from epidemiological, family and twin studies, disease associations, biochemical factors

Epidemiological Studies

Breast cancer

Women who have borne children have a lower riskThe younger the age has her first pregnancy, the lower riskThe later the age at menarche, the lower breast cancer riskVaries greatly between different populations

Gastric cancer

People from lower socioeconomic groups have an increased riskSalts and preservatives, nitrates, are possible carcinogensShows variations in incidence in different populationsHelicobacter pylori infection, increases the risk by five to six fold

Family Studies

The frequency with which other family members develop the same cancer can provide evidence for a genetic contribution.

For a woman who has a first-degree relative with breast cancer, the risk is between 1.5 and 3 times the risk for the general population.

In gastric cancer, first degree relatives have a 2-3 fold increased risk compared with the general population

Twin Studies

Concordance rates for breast cancer in both monozygotic (MZ) and dizygotic (DZ) twins are low

Only slightly greater in MZ female twins, at 17%, than the 13% found in DZ female twins.

This suggests, overall, that environmental factors are more important than genetic factors.

Disease Associations

Association of a particular blood group with a disease suggests a possible genetic contribution to the etiology.

It is estimated that those with blood group A have a 20% increased risk of developing gastric cancer

Blood group A pernicious anemia gastric cancer

Biochemical factors

Biochemical factors can determine the susceptibility to environmental carcinogens

Association between slow-acetylator status and bladder cancer

glutathione S-transferase activity, influences the risk of developing lung cancer in smokers

Viral FactorsCertain viruses are tumor-forming or oncogenic in humans

A limited number of DNA viruses, whereas a variety of RNA viruses, or retroviruses

Epstein-Barr (EBV) Burkitt lymphoma

HepatitisB (HBV) Hepatocellular carcinom