ArticleGenome research2012
Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition.
Article in Genome research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00137111 (Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia), which is not on this map. Cited by 136 papers, 6 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Who cites it
136 citing papers in PubMed, 6 syntheses or guidelines pooled it, 259 citations in OpenAlex.
- Genomewide Association Study of Simvastatin Pharmacokinetics.Clinical pharmacology and therapeutics · 2022Pooled it
- The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms.Clinical pharmacology and therapeutics · 2022Guideline
- Genetic markers in methotrexate treatments.The pharmacogenomics journal · 2018Pooled it
- Abundance of Hepatic Transporters in Caucasians: A Meta-Analysis.Drug metabolism and disposition: the biological fate of chemicals · 2016Pooled it
- The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update.Clinical pharmacology and therapeutics · 2014Guideline
- The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy.Clinical pharmacology and therapeutics · 2012Guideline
- Organic Anion Transporter Gene Variants Associated With Plasma Exposure and Long-Term Response to Atrasentan in Patients With Diabetic Kidney Disease.Clinical pharmacology and therapeutics · 2022Trial
- Performance of Plasma Coproporphyrin I and III as OATP1B1 Biomarkers in Humans.Clinical pharmacology and therapeutics · 2021Trial
- Urinary coproporphyrin I/(I + III) ratio as a surrogate for MRP2 or other transporter activities involved in methotrexate clearance.British journal of clinical pharmacology · 2014Trial
- Trial
- Trial
- OATP1B1 polymorphism as a determinant of erythromycin disposition.Clinical pharmacology and therapeutics · 2012Trial
- Comment on: Development and validation of high-dose methotrexate population pharmacokinetic models to inform clinical decisions on dosing.European journal of clinical pharmacology · 2026Article
- Response to the correspondence by Saba Mushtaq et al. regarding "Development and validation of high-dose methotrexate population pharmacokinetic models to inform clinical decisions on dosing".European journal of clinical pharmacology · 2026Article
- Development and validation of high-dose methotrexate population pharmacokinetic models to inform clinical decisions on dosing.European journal of clinical pharmacology · 2026Article
- Pharmacogenetic hSLCO1B1*14-Guided Dosing of Methotrexate in Transgenic Arthritic Mice Normalizes Exposure and Response.Clinical and translational science · 2026Article
- Review
- Translating pharmacogenomic sequencing data into drug response predictions-How to interpret variants of unknown significance.British journal of clinical pharmacology · 2025Review
- Implementation of pre-emptive testing of a pharmacogenomic panel in clinical practice: Where do we stand?British journal of clinical pharmacology · 2025Review
- Article
76 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Commented on by
Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
Abstract
Methotrexate is used to treat autoimmune diseases and malignancies, including acute lymphoblastic leukemia (ALL). Inter-individual variation in clearance of methotrexate results in heterogeneous systemic exposure, clinical efficacy, and toxicity. In a genome-wide association study of children with ALL, we identified SLCO1B1 as harboring multiple common polymorphisms associated with methotrexate clearance. The extent of influence of rare versus common variants on pharmacogenomic phenotypes remains largely unexplored. We tested the hypothesis that rare variants in SLCO1B1 could affect methotrexate clearance and compared the influence of common versus rare variants in addition to clinical covariates on clearance. From deep resequencing of SLCO1B1 exons in 699 children, we identified 93 SNPs, 15 of which were non-synonymous (NS). Three of these NS SNPs were common, with a minor allele frequency (MAF) >5%, one had low frequency (MAF 1%-5%), and 11 were rare (MAF <1%). NS SNPs (common or rare) predicted to be functionally damaging were more likely to be found among patients with the lowest methotrexate clearance than patients with high clearance. We verified lower function in vitro of four SLCO1B1 haplotypes that were associated with reduced methotrexate clearance. In a multivariate stepwise regression analysis adjusting for other genetic and non-genetic covariates, SLCO1B1 variants accounted for 10.7% of the population variability in clearance. Of that variability, common NS variants accounted for the majority, but rare damaging NS variants constituted 17.8% of SLCO1B1's effects (1.9% of total variation) and had larger effect sizes than common NS variants. Our results show that rare variants are likely to have an important effect on pharmacogenetic phenotypes.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.