title: Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy.
abstract: Remission induction therapy for acute lymphoblastic leukemia (ALL) includes medications that may cause hepatotoxicity, including asparaginase. We used a genome-wide association study to identify loci associated with elevated alanine transaminase (ALT) levels after induction therapy in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols. Germline DNA was genotyped using arrays and exome sequencing. Adjusting for age, body mass index, ancestry, asparaginase preparation, and dosage, the PNPLA3 rs738409 (C>G) I148M variant, previously associated with fatty liver disease risk, had the strongest genetic association with ALT (P = 2.5 × 10-8). The PNPLA3 rs738409 variant explained 3.8% of the variability in ALT, and partly explained race-related differences in ALT. The PNPLA3 rs738409 association was replicated in an independent cohort of 2,285 patients treated on Children's Oncology Group protocol AALL0232 (P = 0.024). This is an example of a pharmacogenetic variant overlapping with a disease risk variant.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Fernandez
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Panetta
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: N
authors.initials: N
authors.lastname: Kornegay
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Ramsey
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Karol
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Janke
authors.affiliation: Maine Children's Cancer Program, Scarborough, Maine, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Larsen
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: N
authors.initials: N
authors.lastname: Winick
authors.affiliation: Department of Pediatrics, New York University Langone Medical Center, New York, New York, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Carroll
authors.affiliation: Department of Pediatrics, University of California School of Medicine, San Francisco, California, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Raetz
authors.affiliation: Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Department of Biostatistics, Colleges of Medicine, Public Health & Health Professions, University of Florida, Gainesville, Florida, USA.
authors.forename: M
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jeha
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: C-H
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000410:Alanine Transaminase / Q000097:blood*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001215:Asparaginase / Q000008:administration & dosage / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000235:genetics; D002648:Child; D000078331:Correlation of Data; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D000071184:Pharmacogenomic Variants / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics; D012074:Remission Induction / Q000379:methods; D018570:Risk Assessment / Q000379:methods; D014481:United States / Q000453:epidemiology; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D000410:Alanine Transaminase; D000970:Antineoplastic Agents; D001215:Asparaginase; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent