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Identifying the genotype behind the phenotype: a role model found in VKORC1 and its association with warfarin dosing.

ABSTRACT: 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.

SUBMITTER: Crawford DC

PROVIDER: S-EPMC3112050 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Identifying the genotype behind the phenotype: a role model found in VKORC1 and its association with warfarin dosing.

Crawford Dana C DC Ritchie Marylyn D MD Rieder Mark J MJ

Pharmacogenomics 20070501 5

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 ...[more]

PMID: 17465713

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Project description:The polymorphisms of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) are important genetic factors for warfarin dose determinations. The present study aimed to investigate the contribution of the CYP2C9 and VKORC1 genotypes to warfarin dose requirement in atrial fibrillation (AF) patients, and to evaluate the clinical application of a warfarin-dosing algorithm. A total of 122 AF patients with a target international normalized ratio of 2.0 to 3.0 were included to determine the genotypes of CYP2C9 (rs1057910) and VKORC1 (rs9923231). A warfarin-dosing algorithm was developed based on age, height, and the CYP2C9 and VKORC1 genotypes of AF patients. The results indicated that the mean warfarin daily dose requirement was lower in the CYP2C9*1/*3 genotype compared with those in the homozygous wild-type CYP2C9*1/*1 patients (P<0.05), and was higher in patients with the VKORC1 AG and GG genotypes compared with those with the AA genotype (P<0.05). The multivariate regression model showed that age, height, and the CYP2C9 and VKORC1 genotypes were the best variables for estimating warfarin dose (R2=56.4%). A new warfarin-dosing algorithm was developed and its validity was confirmed in a second cohort of AF patients. During the 50-day follow-up, 63.3% (19/30) of control group patients and 86.7% (26/30) of patients in the experimental group acquired the warfarin maintenance dose. Among all the patients who acquired the warfarin maintenance dose, the mean time elapse from initiation until warfarin maintenance dose was significantly less in the experimental group (25.8±1.7 day) compared to the control group (33.1±1.9 day) (P<0.05). There was significant linear correlation between predicted warfarin maintenance dose and actual dose (r=0.822, P<0.01). In conclusion, a new warfarin-dosing algorithm was developed based on the CYP2C9 and VKORC1 genotypes, and it can shorten the time elapse from initiation until warfarin maintenance dose in AF patients with warfarin therapy.

Dataset Information

Identifying the genotype behind the phenotype: a role model found in VKORC1 and its association with warfarin dosing.

Publications

Identifying the genotype behind the phenotype: a role model found in VKORC1 and its association with warfarin dosing.

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