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[Pharmacogenomics] What is precision medicine?

An approach that tailors disease prevention and treatment by considering differences in a person's genes, environment, and lifestyle.

[Pharmacogenomics] What is pharmacogenetics?

The study of how variants in one gene or a small number of genes affect a person's response to medications.

[Pharmacogenomics] What is pharmacogenomics (PGx)?

The study of how variants across many genes, complex pathways, or the whole genome affect medication response.

[Pharmacogenomics] What is the main difference between pharmacogenetics and pharmacogenomics?

Pharmacogenetics usually focuses on one or a few genes; pharmacogenomics examines many genes or the whole genome.

[Pharmacogenomics] What is the central flow of genetic information?

DNA is transcribed into RNA, and RNA is translated into protein.

[Pharmacogenomics] What is a codon?

A three-nucleotide sequence that specifies an amino acid or a stop signal during protein synthesis.

[Pharmacogenomics] What is a gene?

A sequence of DNA containing codons and regulatory information used to produce a functional product, usually a protein.

[Pharmacogenomics] What is an exon?

A coding portion of a gene that contributes to the final RNA and protein sequence.

[Pharmacogenomics] What is an intron?

A noncoding region of a gene that is removed from RNA before translation.

[Pharmacogenomics] What are regulatory regions of a gene?

DNA regions that control when and how strongly a gene is transcribed.

[Pharmacogenomics] What is a phenotype?

The observable or clinically expressed result of a genotype, such as eye color or a poor-metabolizer status.

[Pharmacogenomics] What is an allele?

One version of a gene or DNA sequence at a specific location on a chromosome.

[Pharmacogenomics] How many alleles do humans usually have at each autosomal gene location?

Two, one inherited from each parent.

[Pharmacogenomics] What is a wild-type allele?

The most common or reference allele, usually labeled *1 in pharmacogenomics.

[Pharmacogenomics] What is a variant allele?

An allele whose DNA sequence differs from the reference allele; in PGx it is commonly labeled with another star number such as *2 or *3.

[Pharmacogenomics] What is a genotype?

The combination of alleles a person carries at a gene.

[Pharmacogenomics] What does homozygous mean?

The person has two identical alleles at a gene.

[Pharmacogenomics] What does heterozygous mean?

The person has two different alleles at a gene.

[Pharmacogenomics] What is a star allele?

A PGx naming system in which a defined haplotype is labeled with an asterisk and number, such as CYP2D6*1.

[Pharmacogenomics] What is a haplotype?

A group of linked variants inherited together on one chromosome; one star allele represents one haplotype.

[Pharmacogenomics] What is a diplotype?

The pair of haplotypes inherited from both parents, such as 1/2; it is the person's genotype for that gene.

[Pharmacogenomics] What is a genetic variant?

A difference in DNA sequence compared with the reference sequence.

[Pharmacogenomics] What is a polymorphism?

A genetic variant present in more than 1% of a population.

[Pharmacogenomics] What is a mutation in the terminology used in these notes?

A rare genetic variant present in less than 1% of a population.

[Pharmacogenomics] What is a single-nucleotide polymorphism (SNP)?

A variant in which one nucleotide is replaced by another, such as A changing to G.

[Pharmacogenomics] What is a synonymous SNP?

A nucleotide change that does not change the amino acid or protein sequence; it is often called a silent variant.

[Pharmacogenomics] What is a nonsynonymous SNP?

A nucleotide change that changes the amino acid encoded and may alter the protein.

[Pharmacogenomics] How is p.Arg144Cys interpreted?

Cysteine replaces arginine at amino acid position 144 of the protein.

[Pharmacogenomics] What is an rs number?

A reference SNP identifier used to label a specific genetic variant, such as rs12777823.

[Pharmacogenomics] What is the clinical goal of pharmacogenomics?

To select a medication and dose that maximize benefit while reducing toxicity or treatment failure based on the patient's genetic profile.

[Pharmacogenomics] What clinical outcomes can PGx help prevent?

Adverse effects, toxicity, drug interactions, treatment failure, and unnecessary trial-and-error prescribing.

[Pharmacogenomics] In what disease areas is genotype-guided therapy commonly used?

Examples include cancer and cystic fibrosis, with expanding use in cardiology, psychiatry, neurology, pain, and infectious disease.

[Pharmacogenomics] Why can PGx testing be especially useful in older adults?

Older adults often have multimorbidity, polypharmacy, age-related changes, and a higher risk of adverse drug events.

[Pharmacogenomics] What is an important economic concern with PGx testing?

Testing can cost about $200 to $500 and may not be fully covered by insurance, although coverage and assistance programs are increasing.

[Pharmacogenomics] What are major social and ethical concerns with PGx testing?

Informed consent, shared decision-making, privacy, ownership of genetic data, and fear of employment or insurance discrimination.

[Pharmacogenomics] Why is informed consent important before PGx testing?

The patient should understand the purpose, benefits, limitations, risks, alternatives, and how the results may be used in the future.

[Pharmacogenomics] What specimens can be used for pharmacogenomic testing?

Blood or saliva.

[Pharmacogenomics] What logistical issue should be considered before ordering PGx testing?

Turnaround time and how results will be documented and communicated across the care team.

[Pharmacogenomics] What should patients be taught before PGx results are available?

The purpose of testing, how genes affect drug response, potential benefits and limitations, alternatives, and future usefulness.

[Pharmacogenomics] What should patients be taught after PGx results are available?

What the results mean and whether any medication or dose changes are recommended.

[Pharmacogenomics] What are Phase I drug-metabolism enzymes?

Enzymes, especially CYP450 enzymes, that commonly oxidize, reduce, or hydrolyze drugs.

[Pharmacogenomics] Which CYP450 enzymes were emphasized in the notes?

CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.

[Pharmacogenomics] What are examples of Phase II drug-metabolism enzymes?

NAT, UGT, glutathione S-transferase, and TPMT.

[Pharmacogenomics] Why is TPMT clinically important?

Reduced TPMT activity can decrease inactivation of thiopurines such as 6-mercaptopurine and increase the risk of severe hematologic toxicity.

[Pharmacogenomics] What is DPD?

Dihydropyrimidine dehydrogenase, a drug-metabolizing enzyme whose reduced activity can increase toxicity from certain fluoropyrimidines.

[Pharmacogenomics] Why is clopidogrel considered a prodrug?

It must be converted by CYP2C19 to an active metabolite that produces the antiplatelet effect.

[Pharmacogenomics] How can a CYP2C19 inducer affect clopidogrel?

It may increase formation of the active metabolite and increase bleeding risk.

[Pharmacogenomics] How can a CYP2C19 inhibitor such as omeprazole affect clopidogrel?

It may reduce activation of clopidogrel, decrease antiplatelet effect, and increase clotting risk.

[Pharmacogenomics] What is a normal metabolizer phenotype?

A phenotype with expected enzyme activity and usual drug activation or clearance.

[Pharmacogenomics] What is an ultrarapid metabolizer phenotype?

A phenotype with greater-than-normal enzyme activity, often from increased-function alleles or extra gene copies.

[Pharmacogenomics] Why can ultrarapid metabolism cause toxicity with a prodrug?

The prodrug may be converted to its active metabolite too quickly or in excessive amounts.

[Pharmacogenomics] Why can ultrarapid metabolism cause treatment failure with an active drug?

The active drug may be cleared too quickly to maintain an effective concentration.

[Pharmacogenomics] What is a poor metabolizer phenotype?

A phenotype with little or no functional enzyme activity, increasing exposure to some active drugs and reducing activation of some prodrugs.

[Pharmacogenomics] What is an activity score in PGx?

A numerical value assigned to alleles and added together to predict the metabolizer phenotype.

[Pharmacogenomics] What does “xN” mean in a star-allele result?

The person has multiple copies of that allele; copy-number increases are often associated with an ultrarapid phenotype.

[Pharmacogenomics] Why is CYP2D6 clinically important?

It is highly polymorphic and contributes to metabolism of up to about 25% of medications.

[Pharmacogenomics] What medication groups commonly contain CYP2D6 substrates?

Antidepressants, antipsychotics, opioids, and beta-blockers such as metoprolol and carvedilol.

[Pharmacogenomics] What happens when a CYP2D6 poor metabolizer takes tramadol?

Little active metabolite is produced, so the patient may have little or no analgesic effect.

[Pharmacogenomics] What is phenoconversion?

A drug interaction or other factor changes the observed metabolizer phenotype so it behaves differently from the genotype-predicted phenotype.

[Pharmacogenomics] How can paroxetine affect a CYP2D6 normal metabolizer?

As a strong CYP2D6 inhibitor, it can make the patient functionally resemble a poor metabolizer.

[Pharmacogenomics] How can duloxetine affect a CYP2D6 normal metabolizer?

It may reduce CYP2D6 activity enough for the patient to functionally resemble an intermediate metabolizer.

[Pharmacogenomics] What are drug-transporter polymorphisms?

Genetic variants in proteins that move drugs across the GI tract, into cells, across the blood-brain barrier, or into bile and urine.

[Pharmacogenomics] What is ABCB1?

The gene encoding P-glycoprotein, an ATP-binding cassette drug transporter.

[Pharmacogenomics] What is SLCO1B1?

The gene encoding OATP1B1, a transporter that helps move statins from blood into hepatocytes.

[Pharmacogenomics] How can decreased SLCO1B1 function affect simvastatin?

It raises simvastatin concentrations in plasma and increases the risk of myopathy.

[Pharmacogenomics] What is a drug-target polymorphism?

A genetic variant in the protein a medication acts on, which may alter medication sensitivity or response.

[Pharmacogenomics] What is VKORC1's relationship to warfarin?

VKORC1 is a pharmacologic target of warfarin; genetic variants can change warfarin dose requirements.

[Pharmacogenomics] What does CYP2C9 3/3 mean in the notes' case?

The patient inherited the same no-function *3 allele from both parents and is homozygous for reduced CYP2C9 activity.

[Pharmacogenomics] What phenotype is associated with a CYP2C9 activity score of 0?

Poor metabolizer.

[Pharmacogenomics] Why can a CYP2C9 poor metabolizer be at high risk with warfarin?

Warfarin clearance is reduced, increasing the risk of excessive anticoagulation, bleeding, and toxicity.

[Pharmacogenomics] What is the PGx “traffic light” approach?

A simple way to classify drugs as use as directed, use with caution, or use with increased caution and more frequent monitoring.

[Pharmacogenomics] How should sertraline be started in a CYP2C19 normal or intermediate metabolizer according to the notes?

Start with the usual recommended dose and monitor response and adverse effects.

[Pharmacogenomics] How should sertraline be approached in a CYP2C19 poor metabolizer according to the notes?

Consider reducing the starting dose by about 50% and titrate carefully, or choose an alternative not mainly metabolized by CYP2C19.

[Pharmacogenomics] How should sertraline be approached in a CYP2C19 ultrarapid metabolizer according to the notes?

Start at the usual dose, but if response is inadequate at usual maintenance dosing, consider an alternative not mainly metabolized by CYP2C19.

[Pharmacogenomics] What resources were emphasized for PGx decisions?

CPIC guidelines, PharmGKB, and FDA labeling or DailyMed package inserts.

[AKI and CKD] What is normal urine output over 24 hours in the notes?

About 2 liters in 24 hours.

[AKI and CKD] What is nonoliguria?

Urine output greater than 500 mL in 24 hours.

[AKI and CKD] What is oliguria?

Urine output of about 100 to 500 mL in 24 hours.

[AKI and CKD] What is anuria?

Urine output less than 100 mL in 24 hours.

[AKI and CKD] What is acute kidney injury (AKI)?

An abrupt rise in serum creatinine, with or without decreased urine output, occurring over a short period of time.

[AKI and CKD] What substances accumulate during AKI?

Creatinine, urea, fluid, electrolytes, and metabolic wastes may accumulate.

[AKI and CKD] Why is serum creatinine a lagging marker of AKI?

It rises after kidney injury has already occurred, so early injury may be present before creatinine increases.

[AKI and CKD] What KDIGO creatinine rise within 48 hours meets AKI criteria?

An increase in serum creatinine of at least 0.3 mg/dL within 48 hours.

[AKI and CKD] What KDIGO creatinine change within 7 days meets AKI criteria?

Serum creatinine at least 1.5 times baseline within the prior 7 days.

[AKI and CKD] What KDIGO urine-output criterion meets AKI criteria?

Urine output less than 0.5 mL/kg/hour for at least 6 hours.

[AKI and CKD] What defines KDIGO AKI stage 1 by serum creatinine?

Serum creatinine 1.5 to 1.9 times baseline or an increase of at least 0.3 mg/dL.

[AKI and CKD] What defines KDIGO AKI stage 1 by urine output?

Urine output less than 0.5 mL/kg/hour for 6 to 12 hours.

[AKI and CKD] What defines KDIGO AKI stage 2 by serum creatinine?

Serum creatinine 2.0 to 2.9 times baseline.

[AKI and CKD] What defines KDIGO AKI stage 2 by urine output?

Urine output less than 0.5 mL/kg/hour for more than 12 hours.

[AKI and CKD] What defines KDIGO AKI stage 3 by serum creatinine?

Serum creatinine at least 3 times baseline, at least 4.0 mg/dL, or initiation of renal replacement therapy.

[AKI and CKD] What defines KDIGO AKI stage 3 by urine output?

Urine output less than 0.3 mL/kg/hour for 24 hours or anuria for 12 hours.

[AKI and CKD] What are the three major categories of AKI?

Prerenal, intrinsic or intrarenal, and postrenal AKI.

[AKI and CKD] What is prerenal AKI?

Reduced kidney perfusion without initial structural nephron damage, commonly caused by volume depletion or low blood flow.

[AKI and CKD] What is intrinsic or intrarenal AKI?

Structural injury to the glomeruli, tubules, or interstitium of the kidney.

[AKI and CKD] What is postrenal AKI?

Kidney dysfunction caused by obstruction of urinary outflow.

[AKI and CKD] What is acute kidney disease (AKD)?

Persistent or evolving kidney dysfunction lasting 8 days to 3 months, bridging AKI and CKD.

[AKI and CKD] How long does AKI generally last in the timeline used in the notes?

Up to 7 days.

[AKI and CKD] How long does CKD persist?

More than 3 months.

[AKI and CKD] Why is AKD clinically important?

It identifies patients with residual kidney dysfunction who are at high risk of progressing to CKD and need follow-up.

[AKI and CKD] Can AKD occur without a clearly documented prior AKI episode?

Yes; slow-onset injury such as slowly developing ATN may present as AKD.