Genes affecting warfarin response-interactive or additive?
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ABSTRACT:
SUBMITTER: Cavallari LH
PROVIDER: S-EPMC5639939 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:The response to the anticoagulant drug warfarin is greatly affected by genetic polymorphisms in the VKORC1 and CYP2C9 genes. Genotyping these polymorphisms has been shown to be important in reducing the time of the trial and error process for finding the maintenance dose of warfarin thus reducing the risk of adverse effects of the drug. METHOD:We developed a real-time isothermal DNA amplification system for genotyping three single nucleotide polymorphisms (SNPs) that influence warfarin response. For each SNP, real-time isothermal Helicase Dependent Amplification (HDA) reactions were performed to amplify a DNA fragment containing the SNP. Amplicons were detected by fluorescently labeled allele specific probes during real-time HDA amplification. RESULTS:Fifty clinical samples were analyzed by the HDA-based method, generating a total of 150 results. Of these, 148 were consistent between the HDA-based assays and a reference method. The two samples with unresolved HDA-based test results were repeated and found to be consistent with the reference method. CONCLUSION:The HDA-based assays demonstrated a clinically acceptable performance for genotyping the VKORC1 -1639G>A SNP and two SNPs (430C>T and 1075A>C) for the CYP2C9 enzyme (CYP2C9*2 and CYP2C9*3), all of which are relevant in warfarin pharmacogenentics.
| S-EPMC2991486 | biostudies-literature
Project description:Patients starting warfarin often experience lengthy dose-titration periods, when they are at high risk for bleeding and thromboembolism. However, relatively little is known about why some patients take longer than others to reach maintenance dose. Thus, we sought to identify social, clinical, and genetic factors associated with prolonged time to maintenance dose (TTM).We conducted a time-to-event analysis, using a prospective cohort of patients initiating warfarin (N?=?390). Additionally, we examined whether changes in post-initiation factors were associated with TTM. Finally, we performed a secondary analysis in a subcohort (N?=?156) assessing the effect of adherence on TTM.No genetic or post-initiation factors were significantly associated with TTM. However, previous use of warfarin [hazard ratio (HR)?=?0.64; 95% confidence interval (CI) 0.46, 0.88], current smoking status (HR?=?0.61; 95%CI 0.39, 0.96), fewer than four doctor's visits in the previous year (HR?=?0.63 vs 4-12 visits; 95%CI 0.46, 0.88), and worse general health status (HR?=?0.63; 95%CI 0.47, 0.84) were significantly associated with longer TTM. Use of illegal injectable drugs (HR?=?2.51; 95%CI 1.17, 5.39) was associated with shorter TTM. On secondary analysis, the HR for better adherence and TTM was 1.70 (95%CI 0.88, 3.27).Time to maintenance dose was associated with pre-existing behavioral factors, health care utilization, and health quality but not clinical comorbidities or genetic factors in patients initiating warfarin. Future studies are needed to determine whether warfarin patients with prolonged TTM would have better outcomes on alternative agents.
| S-EPMC4570031 | biostudies-literature
Project description:BACKGROUND:The application of pharmacogenetic results requires demonstrable correlations between a test result and an indicated specific course of action. We developed a computational decision-support tool that combines patient-specific genotype and phenotype information to provide strategic dosage guidance. This tool, through estimating quantitative and temporal parameters associated with the metabolism- and concentration-dependent response to warfarin, provides the necessary patient-specific context for interpreting international normalized ratio (INR) measurements. METHODS:We analyzed clinical information, plasma S-warfarin concentration, and CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genotypes for 137 patients with stable INRs. Plasma S-warfarin concentrations were evaluated by VKORC1 genotype (-1639G>A). The steady-state plasma S-warfarin concentration was calculated with CYP2C9 genotype-based clearance rates and compared with actual measurements. RESULTS:The plasma S-warfarin concentration required to yield the target INR response is significantly (P < 0.05) associated with VKORC1 -1639G>A genotype (GG, 0.68 mg/L; AG, 0.48 mg/L; AA, 0.27 mg/L). Modeling of the plasma S-warfarin concentration according to CYP2C9 genotype predicted 58% of the variation in measured S-warfarin concentration: Measured [S-warfarin] = 0.67(Estimated [S-warfarin]) + 0.16 mg/L. CONCLUSIONS:The target interval of plasma S-warfarin concentration required to yield a therapeutic INR can be predicted from the VKORC1 genotype (pharmacodynamics), and the progressive changes in S-warfarin concentration after repeated daily dosing can be predicted from the CYP2C9 genotype (pharmacokinetics). Combining the application of multivariate equations for estimating the maintenance dose with genotype-guided pharmacokinetics/pharmacodynamics modeling provides a powerful tool for maximizing the value of CYP2C9 and VKORC1 test results for ongoing application to patient care.
| S-EPMC3131846 | biostudies-literature
Project description:Spatial attention and expectation are two critical top-down mechanisms controlling perceptual inference. Based on previous research it remains unclear whether their influence on perceptual decisions is additive or interactive. We developed a novel multisensory approach that orthogonally manipulated spatial attention (i.e. task-relevance) and expectation (i.e. signal probability) selectively in audition and evaluated their effects on observers' responses in vision. Critically, while experiment 1 manipulated expectation directly via the probability of task-relevant auditory targets across hemifields, experiment 2 manipulated it indirectly via task-irrelevant auditory non-targets. Surprisingly, our results demonstrate that spatial attention and signal probability influence perceptual decisions either additively or interactively. These seemingly contradictory results can be explained parsimoniously by a model that combines spatial attention, general and spatially selective response probabilities as predictors with no direct influence of signal probability. Our model provides a novel perspective on how spatial attention and expectation facilitate effective interactions with the environment.
| S-EPMC5928039 | biostudies-literature
Project description:In synergy studies, one focuses on compound combinations that promise a synergistic or antagonistic effect. With the help of high-throughput techniques, a huge amount of compound combinations can be screened and filtered for suitable candidates for a more detailed analysis. Those promising candidates are chosen based on the deviance between a measured response and an expected non-interactive response. A non-interactive response is based on a principle of no interaction, such as Loewe Additivity or Bliss Independence. In a previous study, we introduced, an explicit formulation of the hitherto implicitly defined Loewe Additivity, the so-called Explicit Mean Equation. In the current study we show that this Explicit Mean Equation outperforms the original implicit formulation of Loewe Additivity and Bliss Independence when measuring synergy in terms of the deviance between measured and expected response, called the lack-of-fit. Further, we show that computing synergy as lack-of-fit outperforms a parametric approach. We show this on two datasets of compound combinations that are categorized into synergistic, non-interactive, and antagonistic.
| S-EPMC6901947 | biostudies-literature
Project description:As previous work has highlighted the significance of the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes with respect to cannabis dependence (CD), this study sought to characterize the neural mechanisms that underlie these genetic effects. To this end, we collected DNA samples and fMRI data using a cue-elicited craving paradigm in thirty-seven 3-day-abstinent regular marijuana users. The participants were grouped according to their genotype on two single-nucleotide polymorphisms (SNPs) earlier associated with CD phenotypes: rs2023239 in CNR1 and rs324420 in FAAH. Between-group comparisons showed that carriers of the CNR1 rs2023239 G allele had significantly greater activity in reward-related areas of the brain, such as the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG), and anterior cingulate gyrus (ACG), during exposure to marijuana cues, as compared with those with the A/A genotype for this SNP. The FAAH group contrasts showed that FAAH rs324420 C homozygotes also had greater activation in widespread areas within the reward circuit, specifically in the OFC, ACG, and nucleus accumbens (NAc), as compared with the FAAH A-allele carriers. Moreover, there was a positive correlation between neural response in OFC and NAc and the total number of risk alleles (cluster-corrected p<0.05). These findings are in accord with earlier reported associations between CNR1 and FAAH and CD intermediate phenotypes, and suggest that the underlying mechanism of these genetic effects may be enhanced neural response in reward areas of the brain in carriers of the CNR1 G allele and FAAH C/C genotype in response to marijuana cues.
| S-EPMC2820137 | biostudies-literature
Project description:Genetic polymorphisms in the gene encoding cytochrome P450 (CYP) 4F2, a vitamin K oxidase, affect stable warfarin dose requirements and time to therapeutic INR. CYP4F2 is part of the CYP4F gene cluster, which is highly polymorphic and exhibits a high degree of linkage disequilibrium, making it difficult to define causal variants. Our objective was to examine the effect of genetic variability in the CYP4F gene cluster on expression of the individual CYP4F genes and warfarin response. mRNA levels of the CYP4F gene cluster were quantified in human liver samples (n = 149) obtained from a well-characterized liver bank and fine mapping of the CYP4F gene cluster encompassing CYP4F2, CYP4F11, and CYP4F12 was performed. Genome-wide association study (GWAS) data from a prospective cohort of warfarin-treated patients (n = 711) was also analyzed for genetic variations across the CYP4F gene cluster. In addition, SNP-gene expression in human liver tissues and interactions between CYP4F genes were explored in silico using publicly available data repositories. We found that SNPs in CYP4F2, CYP4F11, and CYP4F12 were associated with mRNA expression in the CYP4F gene cluster. In particular, CYP4F2 rs2108622 was associated with increased CYP4F2 expression while CYP4F11 rs1060467 was associated with decreased CYP4F2 expression. Interestingly, these CYP4F2 and CYP4F11 SNPs showed similar effects with warfarin stable dose where CYP4F11 rs1060467 was associated with a reduction in daily warfarin dose requirement (?1 mg/day, Pc = 0.017), an effect opposite to that previously reported with CYP4F2 (rs2108622). However, inclusion of either or both of these SNPs in a pharmacogenetic algorithm consisting of age, body mass index (BMI), gender, baseline clotting factor II level, CYP2C9?2 rs1799853, CYP2C9?3 rs1057910, and VKORC1 rs9923231 improved warfarin dose variability only by 0.5-0.7% with an improvement in dose prediction accuracy of ?1-2%. Although there is complex regulation across the CYP4F gene cluster, the opposing effects between the two SNPs in the CYP4F gene cluster appear to compensate for each other and their effect on warfarin dose requirement is unlikely to be clinically significant.
| S-EPMC5449482 | biostudies-literature
Project description:ObjectivesAs the most frequently prescribed anticoagulant, warfarin has large inter-individual variability in dosage. Genetic polymorphisms could largely explain the differences in dosage requirement. rs9923231 (VKORC1), rs7294 (VKORC1), rs1057910 (CYP2C9), rs2108622 (CYP4F2), and rs699664 (GGCX) involved in the warfarin action mechanism and the circulatory vitamin K were selected to investigate their polymorphism characteristics and their effects on the pharmacodynamics and pharmacokinetics of warfarin in Chinese population.Methods220 patients with cardiac valve replacement were recruited. International normalized ratio and plasma warfarin concentrations were determined. The five genetic polymorphisms were genotyping by pyro-sequencing. The relationships of maintenance dose, plasma warfarin concentration and INR were assessed among groups categorized by genotypes.Resultsrs9923231 and rs7294 in VKORC1 had the analogous genotype frequencies (D': 0.969). 158 of 220 recruited individuals had the target INR (1.5-2.5). Patients with AA of rs9923231 and CC of rs7294 required a significantly lower maintenance dose and plasma concentration than those with AG and TC, respectively. The mean weekly maintenance dose was also significantly lower in CYP2C9 rs1057910 mutated heterozygote than in patients with the wild homozygote. Eliminating the influence from environment factors (age, body weight and gender), rs9923231 and rs1057910 could explain about 32.0% of the variability in warfarin maintenance dose; rs7294 could explain 26.7% of the variability in plasma concentration. For patients with allele G of rs9923231 and allele T of rs7294, higher plasma concentration was needed to achieve the similar goal INR.ConclusionsA better understanding of the genetic variants in individuals can be the foundation of warfarin dosing algorithm and facilitate the reasonable and effective use of warfarin in Chinese.
| S-EPMC4296935 | biostudies-literature
Project description:Stressors created by multiple resource industries can result in cumulative effects over time and space. Many studies have evaluated single stressors and assumed that cumulative effects can be understood by adding stressors together. However, there is growing evidence that interactive effects are important in structuring biological communities. We evaluated whether the effects of multiple stressors in the boreal forest (linear features, energy, forestry) combine additively or interactively by testing a candidate model set of 12 cumulative effects models of abundance for 27 landbird species. We fitted paired additive and interactive Generalized Additive Models and examined model predictions in the Athabasca Oil Sands Area of Alberta, Canada, and a theoretical no-disturbance version of the study area. Of the 27 species examined, an additive disturbance model was the best for nine species, while an interactive disturbance model was the best for 11 species. In the current study area, disturbance models predicted strong increases in abundance for species associated with deciduous forest and open habitats (winning species) and moderate decreases for species associated with conifer forest (losing species). We found a 15% change in landbird community composition between the current study area, with 8.4% disturbance, and the theoretical no-disturbance study area. Complex synergistic and antagonistic interactions among stressors were observed for 39% of landbird species, with the majority of interactions observed being synergistic. Stressors with relatively small disturbance areas, such as narrow linear disturbances, frequently interacted with other stressors to affect species' responses, and energy sector stressors often had additive or interactive effects with forestry stressors. Interactive cumulative effects from multiple sectors will make it increasingly difficult for industry and land managers to manage impacts unless interactions among stressors are incorporated into cumulative effects assessments and regional land use planning processes.
| S-EPMC6852527 | biostudies-literature
Project description:Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to various warfarin doses, but the role of these variants during initial anticoagulation is not clear.In 297 patients starting warfarin therapy, we assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events. The study outcomes were the time to the first INR within the therapeutic range, the time to the first INR of more than 4, the time above the therapeutic INR range, the INR response over time, and the warfarin dose requirement.As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first INR within the therapeutic range (P=0.02) and to the first INR of more than 4 (P=0.003). In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range (P=0.57) but was a significant predictor of the time to the first INR of more than 4 (P=0.03). Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy.Initial variability in the INR response to warfarin was more strongly associated with genetic variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9.
| S-EPMC3894627 | biostudies-literature