A systematic review and a meta‐analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism ...on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC‐homozygotes, T‐allele carriers required an 8.3% (95% confidence interval (CI): 5.6–11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.
Clinical Pharmacology & Therapeutics (2012); 92 6, 746–756. doi:10.1038/clpt.2012.184
There is substantial variation in the dose of warfarin required to achieve therapeutic anticoagulation. In this study, mathematical models for warfarin dosage were constructed that used either ...clinical factors alone or clinical and genetic factors. The model incorporating genetic factors, when tested retrospectively with data from an international cohort, provided better estimates than a model that included only clinical factors.
Mathematical models for warfarin dosage were constructed that used either clinical factors alone or clinical and genetic factors. The model incorporating genetic factors provided better estimates than a model that included only clinical factors.
Warfarin is the most widely used oral anticoagulant agent worldwide; more than 30 million prescriptions were written for this drug in the United States in 2004.
1
The appropriate dose of warfarin is difficult to establish because it can vary by a factor of 10 among patients, and the consequences of taking an incorrect dose can be catastrophic. Because incorrect doses contribute to a high rate of adverse effects, there is interest in developing improved strategies for determining the appropriate dose.
2
Clinical factors, demographic variables, and variations in two genes — cytochrome P450, family 2, subfamily C, polypeptide 9 (
CYP2C9
. . .
Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data Original Article, N Engl J Med 2009:360;753-764.. In Table 2 (page 758), the mean absolute errors in both cohorts should have ...been expressed as means with 95% confidence intervals rather than as means ±SE. The change affects the data in Table 2, the column heads, and the first footnote. In the first paragraph of the Doses Predicted by the Three Models subsection of Results (page 758), the parenthetical data should have read, “(8.5 mg per week 95% confidence interval {CI}, 8.0 to 9.0) vs. 9.9 mg per week 95% CI, 9.3 to 10.4 and 13.0 mg per week 95% CI, 12.4 to 13.6, respectively; P<0.001 for both comparisons).” In addition, in the International Warfarin Pharmacogenetics Consortium pharmacogenetic dosing algorithm in Supplementary Appendix 2, the example given for CYP2C9 should have been represented as *C/*C instead of *C*C. The data have been validated and further examples for use added. The article has been corrected and Supplementary Appendix 2 replaced at NEJM.org.
Summary Background VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian ...descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. Methods We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 −1639G→A, followed by the composite genotype of C YP2C9*2 and CYP2C9*3 . We prespecified a genome-wide significance threshold of p<5×10−8 in the discovery cohort and p<0·0038 in the replication cohort. Findings The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10−8 ). This association was confirmed in the replication cohort (p=5·04×10−5 ); analysis of the two cohorts together produced a p value of 4·5×10−12 . Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). Interpretation A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3 . Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. Funding National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.
Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 −1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better ...capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 −1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 −1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the −1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.
Abstract While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not ...been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy (“PRINCE”, NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.
The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta‐analysis at the individual patients level to capture the possible ...effect of ethnicity, gene—gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta‐analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients’ data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7–10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.
The cytochrome P450 (
CYP
)
4F2
gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta‐analysis at the individual patients level to capture the possible ...effect of ethnicity, gene—gene interaction, or other drugs on the association and to verify if inclusion of
CYP
4F2*3
variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta‐analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients’ data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The
CYP
4F2*3
polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (
CI
) 7–10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the
CYP
4F2*3
in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.
Many genome-wide association studies focus on associating single loci with target phenotypes. However, in the setting of rare variation, accumulating sufficient samples to assess these associations ...can be difficult. Moreover, multiple variations in a gene or a set of genes within a pathway may all contribute to the phenotype, suggesting that the aggregation of variations found over the gene or pathway may be useful for improving the power to detect associations.
Here, we present a method for aggregating single nucleotide polymorphisms (SNPs) along biologically relevant pathways in order to seek genetic associations with phenotypes. Our method uses all available genetic variants and does not remove those in linkage disequilibrium (LD). Instead, it uses a novel SNP weighting scheme to down-weight the contributions of correlated SNPs. We apply our method to three cohorts of patients taking warfarin: two European descent cohorts and an African American cohort. Although the clinical covariates and key pharmacogenetic loci for warfarin have been characterized, our association metric identifies a significant association with mutations distributed throughout the pathway of warfarin metabolism. We improve dose prediction after using all known clinical covariates and pharmacogenetic variants in VKORC1 and CYP2C9. In particular, we find that at least 1% of the missing heritability in warfarin dose may be due to the aggregated effects of variations in the warfarin metabolic pathway, even though the SNPs do not individually show a significant association.
Our method allows researchers to study aggregative SNP effects in an unbiased manner by not preselecting SNPs. It retains all the available information by accounting for LD-structure through weighting, which eliminates the need for LD pruning.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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