Pharmacogenomics & Personalized Medicine

Pharmacogenomics and Personalized Medicine

1. Definitions, scope & terminology

• Pharmacogenetics is the study of the genetic basis for variation in drug response, and usually implies large effects of a small number of DNA variants — historically focused on a single genetic marker as a predictor of drug response (G&G 14e Ch.7, p.131; Shargel 8e Ch.21, p.1).
• Pharmacogenomics studies larger numbers of variants — across an individual or a population — to explain the genetic influences on drug response; it implies recognition that more than one genetic variant contributes (G&G 14e Ch.7, p.131; Katzung 16e Ch.5, p.77).
• The two terms are often used interchangeably; the FDA defines pharmacogenomics as "the study of variations of DNA and RNA characteristics as related to drug response" and pharmacogenetics as "the study of variations in DNA sequence as related to drug response" (Shargel 8e Ch.21, p.1).
• The core tasks of the modern field are: discovering which variants (or combinations) have functional consequences for drug effects, validating those discoveries, and applying them both to patient care and to drug discovery (G&G 14e Ch.7, p.131).
• Precision medicine (also called stratified or personalized medicine) uses genetic information to guide drug and dose selection for subgroups of patients or individual patients — the right drug at the right dose at the right time (Katzung 16e Ch.5, p.77; Vogel 4e Personalized Medicine, p.4235).
• Personalized/precision medicine (PM) capitalises on an individual's molecular, genomic, cellular, clinical, behavioural, physiological, and environmental parameters to inform prevention, diagnosis, and treatment; pharmacogenomics (PGx) forms the basis of PM by using genetic information to tailor therapy, optimise efficacy, promote adherence, minimise side effects, and reduce costs (Vogel 4e Personalized Medicine, p.4235).

Glossary of core terms (harmonised across Katzung 16e Ch.5 pp.78–79 and Shargel 8e Ch.21 pp.12–13)

• Allele — one of two or more alternative forms of a gene at the same genetic locus (arising by mutation); e.g. CYP2D6\3* is a variant allele of the drug-metabolising enzyme CYP2D6 (Katzung 16e Ch.5, p.78).
• Genotype — the alleles at a specific locus that an individual carries; phenotype — the observable expression of that gene/those genes (Shargel 8e Ch.21, p.13).
• Genetic polymorphism — a variation in gene sequence occurring in ≥1% of the general population, yielding multiple alleles/variants; distinct from a mutation, which occurs in <1% of the population (Shargel 8e Ch.21, p.2).
• Single-nucleotide polymorphism (SNP / SNV) — a base-pair substitution; the smallest and commonest form of genetic variation (Katzung 16e Ch.5, p.78; G&G 14e Ch.7, p.132 calls the substitution of a single base pair a single-nucleotide variant, SNV).
• Synonymous SNP — a coding-region substitution that does not change the amino acid; non-synonymous SNP (nsSNP) — a coding-region substitution that does change the amino acid (Shargel 8e Ch.21, p.2).
• Copy-number variant (CNV) — a large deletion or duplication of a DNA segment (entire genes/chromosomes can be deleted, duplicated, inverted) (G&G 14e Ch.7, p.132).
• Haplotype — a series of alleles found together at a linked locus on a chromosome; the constellation of variants inherited as a unit. Each gene has two haplotypes (one maternal, one paternal) (G&G 14e Ch.7, p.133; Katzung 16e Ch.5, p.78).
• Diplotype — the pair of alleles (one maternal + one paternal) carried by an individual, written in star nomenclature (e.g. \1/\17) (Katzung 16e Ch.5, p.78).
• Linkage disequilibrium — the non-random association of alleles at two or more loci that descend from a single ancestral chromosome; an association study may flag a variant in linkage disequilibrium with the true functional variant rather than the functional variant itself, and these patterns are population-specific (G&G 14e Ch.7, p.133).
• Hardy–Weinberg equilibrium — the principle that allele frequencies remain constant across generations in the absence of evolutionary influence; used to predict homozygote/heterozygote frequencies from allele frequencies (Katzung 16e Ch.5, p.78, p.81).