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Genome‐Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy

Year: 2017
Type: article
Study design: Observational Study
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.
DOI: 10.1002/cpt.629
Authors: Y Liu, CA Fernandez, C Smith, W Yang, C Cheng, JC Panetta, N Kornegay, C Liu, LB Ramsey, SE Karol, LJ Janke, EC Larsen, N Winick, WL Carroll, ML Loh, EA Raetz, SP Hunger, M Devidas, JJ Yang, CG Mullighan, J Zhang, WE Evans, S Jeha, C‐H Pui, MV Relling
Institutions: St. Jude Children's Research Hospital, The University of Texas Southwestern Medical Center, NYU Langone Health, University of California, San Francisco, University of California San Francisco Medical Center, University of Utah, Children's Hospital of Philadelphia, University of Pennsylvania, University of Florida Health, University of Florida
Language: English
Field: Medicine
Open Access status: green
Awards: G1860110607, G2135062745, G22842288, G2513706269, G2554726104, G2634635869, G2688579988, G2901481919, Glucocorticoids in Lymphoblastic Leukemia, G301932103, Pharmacogenomics of Childhood Leukemia ALL, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), G421865639, Children's Oncology Group Statistics and Data Center, G5150888020, G609259107, PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL), Cancer Center Support Grant (CCSG), G997771125
OpenAlex ID: W2579395326
FWCI: 6.12
Cites: 46
Cited by: 58
Related to: 10