OBJECTIVE

We assessed four pharmacogenetic tests: 1) cytochrome P450, subfamily IIC, polypeptide 9 (), 2) vitamin K epoxide reductase subunit protein 1 (), 3) apolipoprotein E (), and 4) methylenetetrahydrofolate reductase () for their associations with patient’s response to therapy with warfarin ( and ), statins (), or antifolate chemotherapy ().

DATA SOURCES

Published studies were identified through an electronic search up to October 2007, and relevant bibliographies were reviewed. Focused searches for specific topics were conducted through April 2008 to identify published randomized controlled trials, systematic reviews, and ongoing clinical trials.

METHODS

We included studies of any design that evaluated adults and abstracted data on all relevant clinical and laboratory outcomes. When sufficient data were available from studies making the same comparisons, the data were summarized in a meta-analysis. Additional subgroup, sensitivity, and meta-regression analyses were conducted as appropriate.

RESULTS

The 99 included articles reported 103 studies: 29 tested the association of and the response to warfarin; 19 tested the association of and the response to warfarin; 44 tested the association of and the response to statins; and 11 tested the association of with the response to antifolate chemotherapy. CYP2C9 AND VKORC1 GENE POLYMORPHISMS AND RESPONSE TO WARFARIN THERAPY: Of the 29 studies of gene polymorphisms, 26 evaluated their association with responses to maintenance does of warfarin. The remaining three studies were randomized controlled trials that evaluated response to therapy based on dosage-based algorithms among patients with pharmacogenetic test results. Carriers of the gene variant alleles or had lower mean maintenance warfarin dose requirements than did non-carriers. Few studies investigated the relationship between genetic variations in or and warfarin dose requirements in the induction phase. variants were associated with an increased rate of bleeding complications during the induction phase of warfarin therapy, but the studies did not report whether affected patients had normal or supratherapeutic INR ranges. As with the variants, carriers of the three common variants (alleles T, G, and C) required lower mean maintenance doses of warfarin than did non-carriers. Studies of and had significant between-study heterogeneity. Few studies evaluated the relationship between pharmacogenetic test results and patient- and disease-related factors or response to therapy. No study addressed how therapeutic choices affected the benefits, harms, or adverse effects of patients from subsequent therapeutic management after pharmacogenetic testing for and . APO E GENOTYPE AND STATIN TREATMENT: In studies of the genotype (e2 carriers, e3 homozygotes, and e4 carriers) and statin treatment, the pooled reduction in total and LDL cholesterol from baseline values was lower for all three genotypes but did not differ significantly among them. These studies also had significant between-study heterogeneity. Although few studies included certain subgroups, factors that may affect the associations between all three genotypes and response to statin therapy were ethnicity, sex, familial hyperlipidemia, the type of statin used, and possibly the presence of diabetes. No studies addressed the effects of therapeutic choice: there were no data on the benefits, harms, or adverse effects on patients from subsequent therapeutic management after pharmacogenetic testing for the three genotypes. MTHFR GENE POLYMORPHISMS AND RESPONSE TO CHEMOTHERAPY: Limited data preclude making meaningful inferences about the relationship between common variants in and chemotherapy of the folate metabolic pathway.

CONCLUSIONS

Certain and variants are associated with lower warfarin maintenance doses, and variants are associated with increased bleeding rates among patients who use warfarin. Total and LDL cholesterol levels among patients on statin therapy were lower than baseline values among patients with the three genotypes. Response to chemotherapy based on the folate metabolic pathway in solid organ cancers was not associated with genetic variations in . Overall, studies evaluating associations between the pharmacogenetic test results and the patient’s response to therapy for non-cancer and cancer conditions showed considerable variation in study designs, study populations, medication dosages, and the type of medications. This variation warrants caution when interpreting our results. Data on the relationships among pharmacogenetic test results and patient- and disease-related factors and on the patient’s response to therapy are limited. We found no data on the benefits, harms, or adverse effects from subsequent therapeutic management after pharmacogenetic testing. Detailed patient-level analyses are needed to adjust estimates for the effects of modifiers, such as age or tumor stage.