Identifying the genotype behind the phenotype: a role model found in VKORC1 and its association with warfarin dosing.
Genotype-phenotype studies in pharmacogenomics promise to identify the genetic factors that contribute substantially to variation in individual drug response. While most genetic association studies have failed to deliver this promise, several recent examples serve as a reminder that these associations do exist and can be identified when investigated using well-designed studies. Here, we describe the path taken to identify the association between common vitamin K epoxide reductase complex subunit 1 genetic variation and warfarin dosing in patients. We also describe the key elements that led the way, such as definition of the phenotype, confirmation of a genetic component, determination of biological plausibility and selection of genetic polymorphisms. We also describe several avenues that are yet to be explored for the specific vitamin K epoxide reductase complex subunit 1 warfarin example that can also be generalized as future directions for many genetic association studies in pharmacogenomics. These future avenues will be best explored using diverse approaches encompassing clinical, statistical and genomic methods currently being developed for genotype-phenotype studies in human populations.
Crawford
Dana C
DC
Vanderbilt University, Center for Human Genetics Research, 519 Light Hall, Nashville, TN 37232, USA. crawford@chgr.mc.vanderbilt.edu
Ritchie
Marylyn D
MD
Rieder
Mark J
MJ
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008957:Models, Genetic; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013045:Species Specificity; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases