Methotrexate Clearance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA76037 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:<p>Methotrexate plasma concentration is related to its clinical effects. To identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL), we performed a genome-wide analysis (GWAS) of 500,568 germline single-nucleotide polymorphisms (SNPs) in 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m2. SNPs were validated in an independent cohort of 206 patients. Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, <i>SLCO1B1</i> (rs11045879 (P = 1.7 x 10<sup>-10</sup>) and rs4149081 (P = 1.7 x 10<sup>-9</sup>) (Trevino et al, PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/19901119" target="_blank">19901119</a>). To test whether rare variants in <i>SLCO1B1</i> could alter its function, we genotyped <i>SLCO1B1</i> exons in a slightly larger group of 699 children with ALL who received methotrexate and identified 93 single nucleotide polymorphisms (SNPs). We found several common and rare non-synonymous (NS) SNPs associated with methotrexate clearance.</p> <p>NS SNPs predicted to be functionally damaging (common or rare) were more likely to be found among patients with the lowest adjusted methotrexate clearance (lowest 10%) than patients with high clearance (highest 10%). Four <i>SLCO1B1</i> haplotypes were associated with reduced methotrexate clearance and we verified that these haplotypes have lower function with in vitro transport assays. We were able to quantitatively account for a third of the population variability in clearance of methotrexate with clinical and genetic covariates. This data set includes the dependent variable of methotrexate clearance and all of the SNP data available from arrays, sequencing, and genotyping.</p>
| phs000426.v1.p1 | EGA
Project description:<p>We estimated the plasma clearance of methotrexate from 1279 acute lymphoblastic leukemia (ALL) patients treated on the Children Oncology Group 9904 and 9905 trials (<a href="http://clinicaltrials.gov/show/NCT00005585">http://clinicaltrials.gov/show/NCT00005585</a> and <a href="http://clinicaltrials.gov/show/NCT00005596)">http://clinicaltrials.gov/show/NCT00005596</a>). Patients received either a 24-hour infusion of a 1 g/m2 dose or 4-hour infusion of a 2 g/m2 dose). Methotrexate clearance was lower in older children (p=7 x 10-7), females (p=2.7 x 10-4), and patients who received a delayed intensification phase (p=0.0022). In a genome-wide analysis, methotrexate clearance was associated with polymorphisms in the SLCO1B1 gene (p=2.1 x 10-11), which encodes for an organic anion transporter. This replicates findings using different schedules of high-dose methotrexate in ALL patients treated on St. Jude protocols. A combined meta-analysis yields a p-value of 5.7 x 10-19 for the association of methotrexate clearance with SLCO1B1 SNP rs4149056 (Trevino et al, PMID 19901119 and Ramsey et al, PMID 23233662). This data set includes the dependent variable of methotrexate clearance and all of the SNP data available from arrays.</p>
| phs000637.v1.p1 | EGA
Project description:<p>We estimated the plasma clearance of methotrexate from 1279 acute lymphoblastic leukemia (ALL) patients treated on the Children Oncology Group 9904 and 9905 trials (<a href="http://clinicaltrials.gov/show/NCT00005585">http://clinicaltrials.gov/show/NCT00005585</a> and <a href="http://clinicaltrials.gov/show/NCT00005596)">http://clinicaltrials.gov/show/NCT00005596</a>). Patients received either a 24-hour infusion of a 1 g/m2 dose or 4-hour infusion of a 2 g/m2 dose). Methotrexate clearance was lower in older children (p=7 x 10-7), females (p=2.7 x 10-4), and patients who received a delayed intensification phase (p=0.0022). In a genome-wide analysis, methotrexate clearance was associated with polymorphisms in the SLCO1B1 gene (p=2.1 x 10-11), which encodes for an organic anion transporter. This replicates findings using different schedules of high-dose methotrexate in ALL patients treated on St. Jude protocols. A combined meta-analysis yields a p-value of 5.7 x 10-19 for the association of methotrexate clearance with SLCO1B1 SNP rs4149056 (Trevino et al, PMID 19901119 and Ramsey et al, PMID 23233662). This data set includes the dependent variable of methotrexate clearance and all of the SNP data available from arrays.</p>
| phs000637 | dbGaP
Project description:<p>Methotrexate plasma concentration is related to its clinical effects. To identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL), we performed a genome-wide analysis (GWAS) of 500,568 germline single-nucleotide polymorphisms (SNPs) in 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m2. SNPs were validated in an independent cohort of 206 patients. Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, <i>SLCO1B1</i> (rs11045879 (P = 1.7 x 10<sup>-10</sup>) and rs4149081 (P = 1.7 x 10<sup>-9</sup>) (Trevino et al, PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/19901119" target="_blank">19901119</a>). To test whether rare variants in <i>SLCO1B1</i> could alter its function, we genotyped <i>SLCO1B1</i> exons in a slightly larger group of 699 children with ALL who received methotrexate and identified 93 single nucleotide polymorphisms (SNPs). We found several common and rare non-synonymous (NS) SNPs associated with methotrexate clearance.</p> <p>NS SNPs predicted to be functionally damaging (common or rare) were more likely to be found among patients with the lowest adjusted methotrexate clearance (lowest 10%) than patients with high clearance (highest 10%). Four <i>SLCO1B1</i> haplotypes were associated with reduced methotrexate clearance and we verified that these haplotypes have lower function with in vitro transport assays. We were able to quantitatively account for a third of the population variability in clearance of methotrexate with clinical and genetic covariates. This data set includes the dependent variable of methotrexate clearance and all of the SNP data available from arrays, sequencing, and genotyping.</p>
| phs000426 | dbGaP
Project description:bulk sequencing outputs of Caco2 cells after exposure to permeability modifying and permeability rescuing agents. To identify the molecular drivers for methotrexate-induced barrier dysfunction, we conducted RNA sequencing on Caco2 spheroids treated with methotrexate and lactoferrin. Given our observation that barrier function was compromised as early as 4-6 hours after exposure to methotrexate, we isolated RNA from spheroids 4-hour post-treatment to capture the transcriptional events responsible for initiating the processes.
2020-01-10 | GSE140066 | GEO
Project description:Caco2 response to methotrexate, lactoferrin, and methotrexate-lactoferrin co-exposure
| PRJNA588171 | ENA
Project description:This SuperSeries is composed of the following subset Series: GSE9947: Transcriptional analysis of Leishmania infantum methotrexate resistant strains using full-genome DNA microarrays GSE9948: Transcriptional analysis of Leishmania major methotrexate resistant strains using full-genome DNA microarrays Keywords: SuperSeries Refer to individual Series
2010-05-25 | E-GEOD-9949 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series:; GSE11440: Role of Caveolin 1, E-Cadherin, Enolase 2 and PKCa on resistance to methotrexate in human HT29 colon cancer cells; GSE16066: Networking of differentially expressed genes in CaCo2 human colon cancer cells resistant to methotrexate; GSE16070: Networking of differentially expressed genes in human MCF7 breast cancer cells resistant to methotrexate; GSE16080: Networking of differentially expressed genes in human MDA-MB-468 breast cancer cells resistant to methotrexate; GSE16082: Networking of differentially expressed genes in human MIA PaCa2 pancreatic cancer cells resistant to methotrexate; GSE16085: Networking of differentially expressed genes in human K562 erythtoblastic leukemia cells resistant to methotrexate; GSE16089: Networking of differentially expressed genes in human Saos-2 osteosarcoma cells resistant to methotrexate Experiment Overall Design: Refer to individual Series
2009-09-11 | E-GEOD-16648 | biostudies-arrayexpress
Project description:cea06-02_folate - methotrexate treatment - global analysis of the folate metabolism in Arabidopsis - Treatment of cells of Arabidopsis by methotrexate which is an inhibitor of the synthesis of the folate. Consequently, the pool of folates presents a strong reduction. The goal of this project is to look at the variations of expression in the Arabidopsis genome and specifically in some genes implied in the metabolism of the folate. Keywords: time course,treated vs untreated comparison
2008-12-19 | GSE10675 | GEO