title: CYP450 genotype and pharmacogenetic association studies: a critical appraisal.
abstract: Despite strong pharmacological support, association studies using genotype-predicted phenotype as a variable have yielded conflicting or inconclusive evidence to promote personalized pharmacotherapy. Unless the patient is a genotypic poor metabolizer, imputation of patient's metabolic capacity (or metabolic phenotype), a major factor in drug exposure-related clinical response, is a complex and highly challenging task because of limited number of alleles interrogated, population-specific differences in allele frequencies, allele-specific substrate-selectivity and importantly, phenoconversion mediated by co-medications and inflammatory co-morbidities that modulate the functional activity of drug metabolizing enzymes. Furthermore, metabolic phenotype and clinical outcomes are not binary functions; there is large intragenotypic and intraindividual variability. Therefore, the ability of association studies to identify relationships between genotype and clinical outcomes can be greatly enhanced by determining phenotype measures of study participants and/or by therapeutic drug monitoring to correlate drug concentrations with genotype and actual metabolic phenotype. To facilitate improved analysis and reporting of association studies, we propose acronyms with the prefixes 'g' (genotype-predicted phenotype) and 'm' (measured metabolic phenotype) to better describe this important variable of the study subjects. Inclusion of actually measured metabolic phenotype, and when appropriate therapeutic drug monitoring, promises to reveal relationships that may not be detected by using genotype alone as the variable.
authors.affiliation: 8 Birchdale, Gerrards Cross, Buckinghamshire, UK.
authors.forename: Rashmi R
authors.initials: RR
authors.lastname: Shah
authors.affiliation: Clinical Pharmacology, Toxicology &, Therapeutic Innovation, Children's Mercy-Kansas City, 2401 Gillham Rd, Kansas City, MO 64108, USA.|School of Medicine, University of Missouri-Kansas City, MO, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.affiliation: CICAB Clinical Research Centre, Extremadura University Hospital & Medical School, Badajoz, Spain.
authors.forename: Adrián
authors.initials: A
authors.lastname: LLerena
authors.affiliation: Dr. Margarete Fischer-Bosch - Institut für Klinische Pharmakologie, 70376 Stuttgart Auerbachstr., 112 Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.affiliation: Centre for Translational Medicine, University of Bonn Medical School, Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Stingl
authors.affiliation: Department of Surgery & Cancer, Faculty of Medicine, Imperial College, South Kensington Campus, London, UK.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Smith
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D016903:Drug Monitoring; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D010597:Pharmacogenetics; D010641:Phenotype; D012107:Research Design; D018570:Risk Assessment; D013379:Substrate Specificity
chemical_list: D003577:Cytochrome P-450 Enzyme System
keywords: drug metabolizing enzymes; ethnicity; genotype; pharmacogenetic association studies; pharmacogenetics; phenoconversion; phenotype; substrate-selectivity; therapeutic drug monitoring