SLCO1B1 Variants and Methotrexate Clearance

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, SLCO1B1 (rs11045879 (P = 1.7 x 10-10) and rs4149081 (P = 1.7 x 10-9) (Trevino et al, PMID: 19901119). To test whether rare variants in SLCO1B1 could alter its function, we genotyped SLCO1B1 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. 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 SLCO1B1 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.]]>
Participant has a confirmed diagnosis of non-B-cell acute lymphoblastic leukemia (ALL) Participant is less than or equal to 18 years of age Written, informed consent following NCI, IRB, FDA, and OPRR Guidelines Patient received high-dose methotrexate as part of protocol-directed therapy for ALL ]]>
Patients treated on two clinical trials are included here. Total XIIIB included consolidation therapy of two weekly doses of methotrexate (2 g/m2 over 2 hours, followed by leucovorin) and 6-mercaptopurine (75 mg/m2 per night for 2 weeks)(Pui et al. 2004 Blood 104(9): 2690-2696. PMID: 15251979; Kishi et al. 2007 Blood 109(10): 4151-4157. PMID: 17264302). Subsequent therapy included identical methotrexate and 6-mercaptopurine doses administered every 8 weeks up to 1 year. Total XV included four doses of methotrexate during consolidation, each given over 24 hours with dosage adjusted to achieve a steady-state plasma concentration of 33 µM (low-risk arm) or 65 µM (standard/high-risk arm) (Pui et al. 2009 N Engl J Med 360(26): 2730-2741. PMID: 19553647). Total XIIIB first patient enrolled: August 1994 Total XIIIB last patient enrolled: July 1998 Total XV first patient enrolled: July 2000 Total XV last patient enrolled: October 2007 ]]>