PURPOSE: 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). PATIENTS AND 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). CONCLUSION: 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.
PURPOSE: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). PATIENTS AND 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). CONCLUSION: 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.
Authors: Julius Gudmundsson; Patrick Sulem; Valgerdur Steinthorsdottir; Jon T Bergthorsson; Gudmar Thorleifsson; Andrei Manolescu; Thorunn Rafnar; Daniel Gudbjartsson; Bjarni A Agnarsson; Adam Baker; Asgeir Sigurdsson; Kristrun R Benediktsdottir; Margret Jakobsdottir; Thorarinn Blondal; Simon N Stacey; Agnar Helgason; Steinunn Gunnarsdottir; Adalheidur Olafsdottir; Kari T Kristinsson; Birgitta Birgisdottir; Shyamali Ghosh; Steinunn Thorlacius; Dana Magnusdottir; Gerdur Stefansdottir; Kristleifur Kristjansson; Yu Bagger; Robert L Wilensky; Muredach P Reilly; Andrew D Morris; Charlotte H Kimber; Adebowale Adeyemo; Yuanxiu Chen; Jie Zhou; Wing-Yee So; Peter C Y Tong; Maggie C Y Ng; Torben Hansen; Gitte Andersen; Knut Borch-Johnsen; Torben Jorgensen; Alejandro Tres; Fernando Fuertes; Manuel Ruiz-Echarri; Laura Asin; Berta Saez; Erica van Boven; Siem Klaver; Dorine W Swinkels; Katja K Aben; Theresa Graif; John Cashy; Brian K Suarez; Onco van Vierssen Trip; Michael L Frigge; Carole Ober; Marten H Hofker; Cisca Wijmenga; Claus Christiansen; Daniel J Rader; Colin N A Palmer; Charles Rotimi; Juliana C N Chan; Oluf Pedersen; Gunnar Sigurdsson; Rafn Benediktsson; Eirikur Jonsson; Gudmundur V Einarsson; Jose I Mayordomo; William J Catalona; Lambertus A Kiemeney; Rosa B Barkardottir; Jeffrey R Gulcher; Unnur Thorsteinsdottir; Augustine Kong; Kari Stefansson Journal: Nat Genet Date: 2007-07-01 Impact factor: 38.330
Authors: T Abe; M Unno; T Onogawa; T Tokui; T N Kondo; R Nakagomi; H Adachi; K Fujiwara; M Okabe; T Suzuki; K Nunoki; E Sato; M Kakyo; T Nishio; J Sugita; N Asano; M Tanemoto; M Seki; F Date; K Ono; Y Kondo; K Shiiba; M Suzuki; H Ohtani; T Shimosegawa; K Iinuma; H Nagura; S Ito; S Matsuno Journal: Gastroenterology Date: 2001-06 Impact factor: 22.682
Authors: Ching-Hon Pui; Dario Campana; Deqing Pei; W Paul Bowman; John T Sandlund; Sue C Kaste; Raul C Ribeiro; Jeffrey E Rubnitz; Susana C Raimondi; Mihaela Onciu; Elaine Coustan-Smith; Larry E Kun; Sima Jeha; Cheng Cheng; Scott C Howard; Vickey Simmons; Amy Bayles; Monika L Metzger; James M Boyett; Wing Leung; Rupert Handgretinger; James R Downing; William E Evans; Mary V Relling Journal: N Engl J Med Date: 2009-06-25 Impact factor: 91.245
Authors: Nilesh J Samani; Jeanette Erdmann; Alistair S Hall; Christian Hengstenberg; Massimo Mangino; Bjoern Mayer; Richard J Dixon; Thomas Meitinger; Peter Braund; H-Erich Wichmann; Jennifer H Barrett; Inke R König; Suzanne E Stevens; Silke Szymczak; David-Alexandre Tregouet; Mark M Iles; Friedrich Pahlke; Helen Pollard; Wolfgang Lieb; Francois Cambien; Marcus Fischer; Willem Ouwehand; Stefan Blankenberg; Anthony J Balmforth; Andrea Baessler; Stephen G Ball; Tim M Strom; Ingrid Braenne; Christian Gieger; Panos Deloukas; Martin D Tobin; Andreas Ziegler; John R Thompson; Heribert Schunkert Journal: N Engl J Med Date: 2007-07-18 Impact factor: 91.245
Authors: Laura B Ramsey; Gitte H Bruun; Wenjian Yang; Lisa R Treviño; Selina Vattathil; Paul Scheet; Cheng Cheng; Gary L Rosner; Kathleen M Giacomini; Yiping Fan; Alex Sparreboom; Torben S Mikkelsen; Thomas J Corydon; Ching-Hon Pui; William E Evans; Mary V Relling Journal: Genome Res Date: 2011-12-06 Impact factor: 9.043
Authors: Evita van de Steeg; Els Wagenaar; Cornelia M M van der Kruijssen; Johanna E C Burggraaff; Dirk R de Waart; Ronald P J Oude Elferink; Kathryn E Kenworthy; Alfred H Schinkel Journal: J Clin Invest Date: 2010-07-19 Impact factor: 14.808
Authors: Deepa Bhojwani; Noah D Sabin; Deqing Pei; Jun J Yang; Raja B Khan; John C Panetta; Kevin R Krull; Hiroto Inaba; Jeffrey E Rubnitz; Monika L Metzger; Scott C Howard; Raul C Ribeiro; Cheng Cheng; Wilburn E Reddick; Sima Jeha; John T Sandlund; William E Evans; Ching-Hon Pui; Mary V Relling Journal: J Clin Oncol Date: 2014-02-18 Impact factor: 44.544
Authors: Amy Webb; Audrey C Papp; Jonathan C Sanford; Kun Huang; Jeffrey D Parvin; Wolfgang Sadee Journal: Pharmacogenet Genomics Date: 2013-05 Impact factor: 2.089
Authors: Gabriele Stocco; Wenjian Yang; Kristine R Crews; William E Thierfelder; Giuliana Decorti; Margherita Londero; Raffaella Franca; Marco Rabusin; Maria Grazia Valsecchi; Deqing Pei; Cheng Cheng; Steven W Paugh; Laura B Ramsey; Barthelemy Diouf; Joseph Robert McCorkle; Terreia S Jones; Ching-Hon Pui; Mary V Relling; William E Evans Journal: Hum Mol Genet Date: 2012-07-30 Impact factor: 6.150