I0.1. Pharmacogenetics

What is pharmacogenetics?

The study of how a person's genetic variations and gene makeup influences their response to drugs

What is the purpose of pharmacogenetic testing?

To guide medication selection, dosage, and reduce adverse effects by understanding a patient's genetic profile

What are the benefits of pharmacogenetic testing?

Drug efficacy, drug choice, metabolism rates, avoiding overdose, risk prediction, avoiding allergies, tailored approach, and reducing trial-and-error

What gene variants are tested for warfarin dosing?

CYP2C9 and VKOR1 gene variants

What gene variant is tested for clopidogrel response?

CYP2C19 variants

What is the HLA-B*5701 allele relevant to?

It is tested before prescribing abacavir (HIV medication) — carriers have a significantly increased risk of severe hypersensitivity reaction

What gene variant affects opioid metabolism?

CYP2D6 variants — affect how individuals metabolise opioids like codeine and tramadol

Which genes affect metabolism of psychiatric medications?

CYP2D6 and CYP2C19 — affecting metabolism and response to SSRIs and antipsychotics

What is the relevance of CYP2D6 variants in breast cancer treatment?

Certain CYP2D6 variants reduce activation of tamoxifen, potentially affecting treatment outcomes

What gene affects statin metabolism?

SLCO1B1 — variants can affect metabolism of statins like atorvastatin or simvastatin and risk of side effects

What are the three types of genetic variants that influence drug response?

SNPs (base pair substitution altering protein conformation), insertions/deletions (frameshift altering translated protein), and copy number variations (altering number and order of genes)

What is the cytochrome P450 (CYP) superfamily?

A group of enzymes that play important roles in drug detoxification and cellular metabolism

What percentage of oxidative drug metabolism is attributed to CYPs?

80% of oxidative metabolism and 50% of overall elimination of clinical drugs

What is debrisoquine and why is it relevant to pharmacogenetics?

An antihypertensive drug metabolised by CYP2D6 — used as a model to study genetic variation in drug metabolism

What mutation affects CYP2D6 activity in debrisoquine metabolism?

A 188C>T SNP resulting in a P34S amino acid substitution (proline to serine at position 34), making CYP2D6 unstable with decreased catalytic activity

What did comparison of Swedish and Chinese populations show about CYP2D6?

Chinese cohorts had lower enzyme activity — indicated by a rightward shift in metabolic ratio for mutant variants

What is an ultrarapid metaboliser in the context of CYP2D6?

A person with extra copies (CNV) of the CYP2D6 gene — a Swedish family was found to have 12 extra copies, metabolising debrisoquine ultrarapidly

How does CYP2D6 gene duplication frequency vary geographically?

It increases going south in Europe — high incidence in Spain and Italy may be linked to the Arabian conquest in the Mediterranean

What is gene therapy?

Altering the genes inside body cells to treat or stop disease by artificially transferring nucleic acids to somatic cells

What are the three goals of gene therapy?

Replace a defective gene, add a functional copy of a defective gene, or add a therapeutically useful gene in target cells

What is gene augmentation therapy?

Adding DNA containing a functional gene to a cell to produce a functional protein — used for diseases like cystic fibrosis where a gene fails to produce a protein

What is gene inhibition therapy?

Introducing a gene that inhibits expression of another gene or interferes with a protein's activity — used in cancer to reduce oncogene activity

What is gene therapy for cell killing?

Inserting DNA into diseased cells to cause their death — either via a suicide gene producing a toxic protein or by marking the cell for immune attack

Why is targeted delivery important in gene therapy for cell killing?

To avoid causing death of normally functioning cells

What is in vivo gene therapy?

Direct delivery of genetic material intravenously or locally to a specific organ via a vector that inserts the gene into target cells

What is ex vivo gene therapy?

Removing specific cells from a patient, genetically altering them in a laboratory, then transplanting them back

What cells are most commonly used in ex vivo gene therapy?

Haematopoietic stem cells (HSCs) — used to treat blood and immunological diseases

What is genotype-guided therapy?\n\n

A therapeutic approach that utilizes an individual's genetic information to inform drug selection and dosing, optimizing treatment efficacy and minimizing side effects.\n\n

What is the significance of the TPMT gene in pharmacogenetics?\n\n

TPMT (Thiopurine S-methyltransferase) gene variants influence the metabolism of thiopurine medications used in conditions like leukemia, affecting toxicity and treatment effectiveness.\n\n

How does the UGT1A1 gene relate to irinotecan treatment?\n\n

Variants in the UGT1A1 gene can affect the metabolism of irinotecan, an anticancer drug, leading to increased risk of toxicity in patients with certain genetic profiles.\n\n

What role do pharmacogenetic biomarkers play?\n\n

Biomarkers indicate how individuals may respond to specific medications, aiding in personalized medicine approaches to minimize adverse drug reactions and maximize efficacy.\n\n

Why is pharmacogenetic testing important in antidepressant therapy?\n\n

It helps determine the most effective medication and dosage based on genetic variations affecting the metabolism of antidepressants, leading to improved treatment outcomes.\n\n

What are somatic mutations in pharmacogenetics?\n\n

Genetic alterations acquired during a person’s lifetime affecting tumor characteristics and responses to targeted chemotherapy drugs, relevant in cancer pharmacogenetics.\n\n