Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding SNP, rs4149056T>C, in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for SLCO1B1 and simvastatin-induced myopathy.

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 nonsynonymous (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.

Cholesterol reduction from statin therapy has been one of the greatest public health successes in modern medicine. Simvastatin is among the most commonly used prescription medications. A non-synonymous coding single-nucleotide polymorphism (SNP), rs4149056, in SLCO1B1 markedly increases systemic exposure to simvastatin and the risk of muscle toxicity. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A) and clinical outcome for all statins. The strength of the evidence is high for myopathy with simvastatin. We limit our recommendations accordingly.

Coordinated recombination of homologous antigen receptor loci is thought to be important for allelic exclusion. Here, we show that homologous Ig alleles pair in a stage-specific manner that mirrors the recombination patterns of these loci. The frequency of homologous Ig pairing was substantially reduced in the absence of the RAG1-RAG2 recombinase and was rescued in Rag1-/- developing B cells with a transgene expressing a RAG1 active site mutant that supports DNA binding but not cleavage. The introduction of DNA breaks on one Ig allele induced ATM-dependent repositioning of the other allele to pericentromeric heterochromatin. ATM activated by the cleaved allele acts in trans on the uncleaved allele to prevent bi-allelic recombination and chromosome breaks or translocations.

Key Points• A genome-wide study of the association of over 5 million SNPs with methotrexate clearance in 1279 patients treated with HDMTX in multicenter COG trials 9904 and 9905.• We replicated the finding that inherited variations in SLCO1B1 are the most important genetic variations influencing methotrexate clearance.Methotrexate clearance can influence the cure of and toxicity in children with acute lymphoblastic leukemia (ALL). We estimated methotrexate plasma clearance for 1279 patients with ALL treated with methotrexate (24-hour infusion of a 1 g/m 2 dose or 4-hour infusion of a 2 g/m 2 dose) on the Children's Oncology Group P9904 and P9905 protocols. Methotrexate clearance was lower in older children (P ‫؍‬ 7 ؋ 10 ؊7 ), girls (P ‫؍‬ 2.7 ؋ 10 ؊4 ), and those who received a delayed-intensification phase (P ‫؍‬ .0022). A genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in the organic anion transporter gene SLCO1B1 (P ‫؍‬ 2.1 ؋ 10 ؊11 ). This replicates findings using different schedules of high-dose methotrexate in St Jude ALL treatment protocols; a combined meta-analysis yields a P value of 5.7 ؋ 10 ؊19 for the association of methotrexate clearance with SLCO1B1 SNP rs4149056. IntroductionHigh-dose methotrexate (HDMTX) is an important element of chemotherapy in the treatment of acute lymphoblastic leukemia (ALL) and other malignancies. [1][2][3][4] Mikkelsen et al 5 showed that a 1 g/m 2 dose given over 24 hours resulted in significantly greater active methotrexate polyglutamates in leukemic cells than the same dose given over 4 hours. In a randomized clinical trial, investigators from the Children's Oncology Group (COG) tested the efficacy and toxicity of a 2 g/m 2 dose over 4 hours versus a 1 g/m 2 dose over 24 hours. 6,7 The systemic exposure to methotrexate (ie, plasma concentration over time) is related to cure and toxicity in children with ALL. 8,9 In a group of children with ALL who were treated and monitored at a single institution (St Jude Children's Research Hospital), with extensive prospective therapeutic drug monitoring, even including pharmacokinetically guided dosage adjustments, we identified variants in the SLCO1B1 gene that were associated with methotrexate clearance in a genome-wide association study (GWAS). 10,11 Herein, we sought to test whether we could replicate these GWAS findings in a large cohort of patients treated with alternative HDMTX schedules on the COG multi-institutional trials P9904 and P9905. MethodsThis study was approved by the institutional review boards of all participating institutions, and informed consent was obtained in accordance with the Declaration of Helsinki. Patients in P9904 included National Cancer Institute (NCI) standard-risk (age 1.00-9.99 years and initial white blood cell count [WBC]Ͻ 50 000/L) patients with an ETV6-RUNX1 translocation or simultaneous trisomies of chromosomes 4 and 10, whereas patients in P9905 included a mixture of NCI standard-risk patients without favorable genetic lesions, NCI high-risk (age...

Background Asparaginase and steroids can cause hypertriglyceridemia in children with acute lymphoblastic leukemia (ALL). There are no guidelines for screening or management of patients with severe hypertriglyceridemia (>1000 mg/dL) during ALL therapy. Patients and Methods Fasting lipid profiles were obtained prospectively at 4 time-points for 257 children consecutively enrolled on a frontline ALL study. Risk factors were evaluated by the exact chi-square test. Details of adverse events and management of hypertriglyceridemia were extracted retrospectively. Results Eighteen of 257 (7%) patients developed severe hypertriglyceridemia. Older age and treatment with higher doses of asparaginase and steroids on the standard/high-risk arm were significant risk factors. Severe hypertriglyceridemia was not associated with pancreatitis after adjustment for age and treatment arm or with osteonecrosis after adjustment for age. However, patients with severe hypertriglyceridemia had a 2.5 to 3 times higher risk of thrombosis compared to patients without, albeit the difference was not statistical significant. Of the 30 episodes of severe hypertriglyceridemia in 18 patients, 7 were managed conservatively while the others with pharmacotherapy. Seventeen of 18 patients continued to receive asparaginase and steroids. Triglyceride levels normalized after completion of ALL therapy in all 12 patients with available measurements. Conclusion Asparaginase- and steroid-induced transient hypertriglyceridemia can be adequately managed with dietary modifications and close monitoring without altering chemotherapy. Patients with severe hypertriglyceridemia were not at increased risk of adverse events, with a possible exception of thrombosis. The benefit of pharmacotherapy in decreasing symptoms and potential complications requires further investigation.

Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and leukemia cell resistant to glucocorticoids confers a poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the sensitivity to prednisolone of primary leukemia cells from 444 newly diagnosed ALL patients, revealing significantly higher expression of caspase 1 (CASP1) and its activator NLRP3 in glucocorticoid resistant leukemia cells, due to significantly lower somatic methylation of CASP1 and NLRP3 promoters. Over-expression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1 overexpressing ALL. Our findings establish a new mechanism by which the NLRP3/CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on glucocorticoid transcriptional response suggests this mechanism could also modify glucocorticoid effects in other diseases.

STAT5 is abnormally activated in patients with acute lymphoblastic leukemia, and increased STAT5 activation synergizes with PAX5 and EBF1 to induce disease.