Building Individualized Medicine: Prevention of Adverse Reactions to Warfarin Therapy

Abstract

Warfarin is the most widely used oral anticoagulant in the world for patients with venous thrombosis, pulmonary embolism, chronic atrial fibrillation, and prosthetic heart valves. Approximately 30 genes contribute to therapeutic effects of warfarin, and genetic polymorphisms in these genes may modulate its anticoagulant activity. In contrast to monogenic pharmacogenetic traits, warfarin drug response is a polygenic trait, and development of diagnostic tools predictive of adverse reactions to warfarin requires a novel approach. A combination of two strategies, biochemical isolation of allelic variants and linkage disequilibrium association studies, was used to find an association between genetic polymorphisms in the candidate genes and warfarin response. A strong association was found between genetic polymorphisms in six genes, including VKORC1, CYP2C9, PROC, EPHX1, GGCX, and ORM1, and interindividual variability in the anticoagulant effect of warfarin; the strongest predictors were VKORC1 and CYP2C9. Generation of single nucleotide polymorphism (SNP)-based dense genetic maps made it possible to identify haplotypes associated with drugresponse phenotypes. Discrimination between haplotypes associated with warfarin dose phenotypes can be achieved by a limited set of informative polymorphisms (tag SNPs). The use of tag SNPs in pharmacogenomic analysis provides a promising tool for dissecting polygenic traits of drug response.The human genome is variable both within generations (more than 7 million SNPs with a minor allele frequency at least 5%) and between generations (175 mutations per diploid genome per generation) (Kruglyak and Nickerson, 2001). Genetic variations make us unique in many senses, including our response to drug therapy. Pharmacogenomics uses the tools of human genetics to tailor medicinal treatment to an individual's genetic makeup. To this end, phenotypic manifestations (a therapeutic outcome or an adverse drug event, ADE) are considered in relation to the underlying genetic background of a patient.In a pregenome era, these studies were based on biochemical isolation and characterization of drug-metabolizing enzymes and their genes, followed by sequence and functional analysis of possible mutant variants. Characterization of mutations led to development of a genotyping assay that was used to perform genetic analysis of patient DNA. Initial achievements of pharmacogenomics were related to detection of simple monogenic traits, e.g., abrogation of drug metabolism due to inactivation of a single enzyme. Characterization of inactivating mutations in arylamine-N-acetyltransferase 2, cytochrome P450 2D6, and thiopurine S-methyltransferase provided molecular mechanisms of adverse drug events caused by izoniazid, debrisoquine, and mercaptopurine (Gonzalez et al., 1988;Vatsis et al., 1991;Krynetski et al., 1995). Biochemical analysis does not rely on statistical evaluation of genetic markers and therefore works equally well for common and rare genotypes. Such functional studies require extensive know...

An evaluation of nine genetic variants related to metabolism and mechanism of action of warfarin as applied to stable dose prediction

“…For the present study, we attempted to validate reported associations between warfarin dose and candidate genetic variants. For this study, candidate genes were selected based on published reports [10,14] and also on biological plausibility relating to warfarin and vitamin K function and metabolism. For example, vitamin K 1 is absorbed from the small intestine through an apolipoprotein E (apoE) receptor specific uptake [15].…”

“…Another possible approach is to attempt to improve dose prediction by adding additional genetic loci to the dosing algorithm. Approximately 30 genes may impact the therapeutic effects of warfarin, and many of these have been studied to determine if sequence variations modulate the anticoagulant activity of warfarin [10]. For the present study, we tested the widely recognized CYP2C9 and VKORC1 SNPs and selected variants in five of the most promising additional candidate genes: EPHX1, APOE, PROC, CALU [11] and an additional cytochrome gene CYP4F [12].…”

Introducing Pharmacy Students to Pharmacogenomic Analysis

“…Evaluating a patient's genetic background prior to beginning pharmacotherapy is increasingly becoming a reality in pharmacy practice. 10 Clinically important and well-characterized genetic polymorphisms have been identified as important predictors of adverse events; existing technology has made the detection and interpretation of these polymorphisms fast and easy enough to be routinely used in diagnostic centers. In the past several years, the US Food and Drug Administration has recommended genetic tests for several polymorphic enzymes including cytochrome P450 isoforms 2D6 and 2C9; thiopurine S-methyltransferase (TPMT); and vitamin K epoxide reductase complex, subunit 1.…”

Anticoagulation therapy: patients attitude, knowledge, and concerns regarding their effects on the international normalized ratio (INR) in Saudi Arabia

“…Inter-individual response to the drug varies due to presence of genetic sequence variant that may require several dose changes throughout the course of therapy to obtain steady INR levels [5]. Patient counselling and education will improve response to INR; therefore, achieving desired outcomes.…”