Category:Pharmacogenomic phenotypes

A pharmacogenomic phenotype is a category that describes how fast, or how completely, a person carries out a particular step of medicine metabolism, inferred from the genes they carry. This category collects the wiki's reference pages for the metabolizer phenotypes: the named groupings, poor, intermediate, normal, rapid, and ultrarapid, into which patients are sorted so that the medicines handled by a given drug-metabolizing enzyme can be dosed to the person rather than to a population average.

The vocabulary has a precise birthplace. In the mid-1970s, at St Mary's Hospital Medical School in London, Robert Smith and his colleagues were studying debrisoquine, an antihypertensive medicine. As part of the work Smith took a dose of it himself, and suffered a hypotensive collapse far out of proportion to the amount. The investigation that followed showed that he, and a minority of the people tested, excreted almost none of the hydroxylated breakdown product of debrisoquine: their capacity to metabolize it was very low. Smith and colleagues called this minority poor metabolizers and the majority extensive metabolizers, and their 1977 report of the debrisoquine polymorphism is one of the founding documents of pharmacogenetics.^[1] The enzyme responsible was later identified as CYP2D6. Within a few years the same kind of split had been found for other enzymes, including the bimodal distribution of thiopurine S-methyltransferase activity reported by Richard Weinshilboum in 1980.^[2] The terms have been with the field ever since, and they are the terms this category is built on.

A metabolizer phenotype is reached from genotype by a defined translation. A drug-metabolizing enzyme is encoded by a gene; the gene exists in variant forms, the alleles, which differ in how much working enzyme they produce; and a person carries two alleles, one from each parent, together called the diplotype. The diplotype is translated into a phenotype, in some cases through an intermediate activity score that assigns each allele a numerical value and sums the two. The rules for that translation have been standardised: a consensus harmonisation between the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group fixed both the phenotype terms and the genotype-to-phenotype mapping, so that a given diplotype yields the same phenotype label whichever laboratory or guideline reports it.^[3]

Five phenotype labels are in use, though not every gene carries all five. The poor metabolizer has little or no enzyme activity; the intermediate metabolizer has reduced activity; the normal metabolizer has the typical, reference activity to which standard doses are calibrated; the rapid metabolizer has somewhat increased activity; and the ultrarapid metabolizer has substantially increased activity. A gene with no established gain-of-function allele, such as CYP2C9, CYP3A4, UGT1A1, TPMT, or NUDT15, has only the poor, intermediate, and normal phenotypes. A gene with gain-of-function alleles, such as CYP2C19 or CYP2B6, carries the full five. The normal metabolizer was, until the 2020 harmonisation, called the extensive metabolizer, the very term Smith's group coined; it was renamed because clinicians were reading "extensive" as "greater than normal" when it meant "typical".

The two consortia do not entirely agree on which genes warrant a phenotype scheme at all. CYP3A4 is the clearest case: the Dutch Pharmacogenetics Working Group tiers it into poor, intermediate, and normal metabolizers on the basis of the decreased-function CYP3A4\*22 allele,^[4] while CPIC does not assign CYP3A4 a metabolizer phenotype, holding that environmental induction and inhibition dominate its variability. The wiki indexes the DPWG CYP3A4 phenotypes here, and the CYP3A4 phenotype pages state plainly that the construct is less settled than the others.

What a phenotype means clinically depends on what the enzyme does to the medicine in question, and the direction can run either way. If the enzyme activates a medicine from an inactive prodrug, then low activity means too little active medicine and high activity means too much; if the enzyme clears a medicine, then low activity means accumulation and high activity means underexposure. A single phenotype is therefore not "good" or "bad" on its own; it is good or bad only against a particular medicine. A phenotype can also be imitated by a drug interaction: a strong enzyme inhibitor can convert a genetically normal metabolizer into a functional intermediate or poor metabolizer for as long as the inhibitor is present, an effect called phenocopying.

The wiki maintains a separate page for each metabolizer phenotype of each clinically important enzyme because the phenotype, not the gene, is the unit a prescriber acts on, and because each phenotype is the entity that the wiki's pharmacogenomic interaction layer references when it records that a medicine should be avoided, substituted, or dose-adjusted for a given metabolizer group.

CYP2D6 (codeine and tramadol activation; tricyclic antidepressants; many antipsychotics):

• CYP2D6 poor metabolizer
• CYP2D6 intermediate metabolizer
• CYP2D6 normal metabolizer
• CYP2D6 ultrarapid metabolizer

CYP2C19 (clopidogrel activation; proton pump inhibitors; SSRIs; voriconazole):

• CYP2C19 poor metabolizer
• CYP2C19 intermediate metabolizer
• CYP2C19 normal metabolizer
• CYP2C19 rapid metabolizer
• CYP2C19 ultrarapid metabolizer

CYP2C9 (warfarin; phenytoin; NSAIDs):

• CYP2C9 poor metabolizer
• CYP2C9 intermediate metabolizer
• CYP2C9 normal metabolizer

CYP2B6 (efavirenz; methadone):

• CYP2B6 poor metabolizer
• CYP2B6 intermediate metabolizer
• CYP2B6 normal metabolizer
• CYP2B6 rapid metabolizer
• CYP2B6 ultrarapid metabolizer

CYP3A4 (quetiapine, tacrolimus, statins, and a very wide substrate range; phenotype framework defined by the DPWG, not by CPIC):

• CYP3A4 poor metabolizer
• CYP3A4 intermediate metabolizer
• CYP3A4 normal metabolizer

UGT1A1 (irinotecan; atazanavir; the Gilbert syndrome phenotype):

• UGT1A1 poor metabolizer
• UGT1A1 intermediate metabolizer
• UGT1A1 normal metabolizer

TPMT (the thiopurines: azathioprine, mercaptopurine, thioguanine):

• TPMT poor metabolizer
• TPMT intermediate metabolizer
• TPMT normal metabolizer

NUDT15 (the thiopurines; the parallel gene to TPMT):

• NUDT15 poor metabolizer
• NUDT15 intermediate metabolizer
• NUDT15 normal metabolizer

This category collects the metabolizer phenotypes of the drug-metabolizing enzymes. It does not collect the enzymes themselves: those are reference pages in their own right, gathered in Category:Drug-metabolizing enzymes, and each phenotype page is a satellite of one of them. It also does not extend to every gene-based grouping relevant to pharmacogenomics. The phenotypes of drug transporters, and the variant-based risk categories of non-enzyme loci such as the HLA alleles that govern severe hypersensitivity reactions, are different in kind and are collected separately. The boundary here is the metabolizer phenotype: poor, intermediate, normal, rapid, or ultrarapid, of an enzyme that metabolizes medicines.

Each phenotype page is a definitional satellite of its enzyme page. It leads with a definition of the phenotype, then covers the genotype basis (which diplotypes produce it), the population frequency, the clinical consequences medicine by medicine, and, where it applies, phenocopying. The discovery history and the full substrate range of the enzyme are not repeated on every phenotype page; they live once, on the enzyme page. Each phenotype page is also the human-readable companion to a phenotype:<gene>_<level> entity in the wiki's pharmacogenomic interaction layer.

These pages live in the dedicated Phenotype: namespace.