Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects.
OBJECTIVE
Methotrexate plasma concentration is related to its clinical effects. Our aim was to identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL).


METHODS
We performed a genome-wide analysis of 500,568 germline single-nucleotide polymorphisms (SNPs) to identify how inheritance affects methotrexate plasma disposition among 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m(2). SNPs were validated in an independent cohort of 206 patients.


RESULTS
Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, SLCO1B1. Two SNPs in SLCO1B1, rs11045879 (P = 1.7 x 10(-10)) and rs4149081 (P = 1.7 x 10(-9)), were in linkage disequilibrium (LD) with each other (r(2) = 1) and with a functional polymorphism in SLCO1B1, T521C (rs4149056; r(2) > 0.84). rs11045879 and rs4149081 were validated in an independent cohort of 206 patients (P = .018 and P = .017), as were other SLCO1B1 SNPs residing in different LD blocks. SNPs in SLCO1B1 were also associated with GI toxicity (odds ratio, 15.3 to 16.4; P = .03 to .004).


CONCLUSIONS
A genome-wide interrogation identified inherited variations in a plausible, yet heretofore low-priority candidate gene, SLCO1B1, as important determinants of methotrexate's pharmacokinetics and clinical effects.
Treviño
Lisa R
LR
St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Shimasaki
Noriko
N
Yang
Wenjian
W
Panetta
John C
JC
Cheng
Cheng
C
Pei
Deqing
D
Chan
Diana
D
Sparreboom
Alex
A
Giacomini
Kathleen M
KM
Pui
Ching-Hon
CH
Evans
William E
WE
Relling
Mary V
MV
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D016014:Linear Models; D015810:Linkage Disequilibrium; D027381:Liver-Specific Organic Anion Transporter 1; D016015:Logistic Models; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D008727:Methotrexate