precision medicine

What is pharmacogenetics typically associated with?

Monogenic traits.

What does pharmacogenomics involve?

Genome-wide studies like GWAS.

How are the terms pharmacogenetics and pharmacogenomics sometimes distinguished?

Pharmacogenetics for inherited changes, pharmacogenomics for somatic changes (e.g., cancer), though they are often used interchangeably.

What is considered the first known example of pharmacogenetics?

G6PD deficiency causing haemolytic anaemia in response to fava beans.

What condition is caused by G6PD deficiency?

Haemolytic anaemia due to inability to manage oxidative stress.

What inheritance pattern does G6PD deficiency follow?

X-linked.

What are the activity classes of G6PD deficiency?

Class I (severe), Class II (1–10%), Class III (10–60%).

What environmental factor is G6PD deficiency distribution correlated with?

Malaria.

Why did drug metabolism mechanisms likely evolve?

To deal with plant toxins.

What are cytochrome P450 enzymes?

Monooxygenases that use haem iron to oxidize molecules, involved in metabolizing ~60% of prescribed drugs.

Where are cytochrome P450 enzymes mainly found?

In the endoplasmic reticulum of liver cells (hepatocytes).

Which P450 enzymes metabolize the majority of drugs?

CYP2D6 and CYP3A4.

What does the metabolic ratio (MR) indicate in CYP2D6 pharmacogenetics?

The ratio of drug to its metabolites; high MR indicates overdose risk.

What test did the FDA approve in 2004 related to CYP enzymes?

AmpliChip Cytochrome P450 genotyping test.

What is the second step of metabolism involving NAT enzymes?

N-acetylation by NAT1 and NAT2.

What population groups show a high rate of slow acetylation by NAT2?

50% of white Americans, 17% of Japanese.

Why can slow acetylators be at risk when taking isoniazid?

They may develop peripheral neuropathy.

What does UGT1A1 do in drug metabolism?

Catalyzes glucuronidation; defects affect bilirubin and sensitivity to irinotecan.

What do GSTM1 and GSTT1 genes affect?

Glutathione-S-transferase activity; defects impair detoxification.

What does warfarin do?

Acts as an anticoagulant by inhibiting vitamin K epoxide reductase.

What enzymes and genes influence warfarin response?

CYP2C9 and VKORC1.

What percentage of warfarin response variation is explained by CYP2C9 and VKORC1 variants?

50–60%.

What does the USDA recommend before prescribing warfarin?

Genotype testing, though it's not required.

What are thiopurine drugs used to treat?

ALL, IBD, autoimmune diseases, and organ transplant rejection.

What is TPMT and why is it important?

Thiopurine methyltransferase detoxifies purine drugs; variants can cause bone marrow toxicity.

What percent of Europeans are homozygous for low-activity TPMT variants?

0.3%.

What is HER2 and its relevance to breast cancer?

Overexpressed HER2 receptor is found in 20–30% of breast cancers.

How many HER2 receptors do normal vs. cancer cells have?

~20,000 in normal cells, up to 2 million in cancer cells.

What is Herceptin (trastuzumab)?

A monoclonal antibody that targets HER2 in breast cancer.

What other drugs target EGFR variants in cancer?

Lapatanib, Iressa (gefitinib), and Tarceva (erlotinib).

What are statins used for?

To lower cholesterol by inhibiting its biosynthesis.

What issue affects a small number of patients taking statins?

Myopathy.

What did the 2008 GWAS of statin myopathy discover?

SNP in SLCO1B1 gene associated with increased risk.

What is the odds ratio for statin-induced myopathy with homozygous CC genotype in SLCO1B1?

16.9.

What is the estimated frequency of pharmacogenetic risk variants in individuals?

~99% carry at least one actionable variant.

What does DTC stand for in personal genomics?

Direct-to-consumer.

What is 23andMe known for?

SNP analysis and consumer-accessible genetic testing for traits, ancestry, and health risk