Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition

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 A...

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Published in:Genome research Vol. 22; no. 1; p. 1
Main Authors: Ramsey, Laura B, Bruun, Gitte H, Yang, Wenjian, Treviño, Lisa R, Vattathil, Selina, Scheet, Paul, Cheng, Cheng, Rosner, Gary L, Giacomini, Kathleen M, Fan, Yiping, Sparreboom, Alex, Mikkelsen, Torben S, Corydon, Thomas J, Pui, Ching-Hon, Evans, William E, Relling, Mary V
Format: Journal Article
Language:English
Published: United States 01.01.2012
Subjects:
Adolescent
Antimetabolites, Antineoplastic - administration & dosage
Antimetabolites, Antineoplastic - pharmacokinetics
Child
Child, Preschool
Clinical Trials as Topic
Cohort Studies
Exons
Female
Haplotypes
Humans
Infant
Male
Methotrexate - administration & dosage
Methotrexate - pharmacokinetics
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Organic Anion Transporters - genetics
Organic Anion Transporters - metabolism
Pharmacogenetics - methods
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism
Solute Carrier Organic Anion Transporter Family Member 1b1
ISSN:1549-5469, 1549-5469
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Summary: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.
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ISSN:1549-5469
1549-5469
DOI:10.1101/gr.129668.111