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

Y. Liu, C. A. Fernandez, C. Smith, W. Yang, C. Cheng, J. C. Panetta, N. Kornegay, C. Liu, L. B. Ramsey, S. E. Karol, L. J. Janke, E. C. Larsen, N. Winick, W. L. Carroll, M. L. Loh, E. A. Raetz, S. P. Hunger, M. Devidas, J. J. Yang, C. G. MullighanJ. Zhang, W. E. Evans, S. Jeha, C. H. Pui, M. V. Relling

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)131-140
Number of pages10
JournalClinical Pharmacology and Therapeutics
Volume102
Issue number1
DOIs
StatePublished - Jul 1 2017

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Transaminases
Alanine Transaminase
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Genome
Asparaginase
Liver
Exome
Remission Induction
Genome-Wide Association Study
Fatty Liver
Therapeutics
Liver Diseases
Body Mass Index
DNA
Research

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy. / Liu, Y.; Fernandez, C. A.; Smith, C.; Yang, W.; Cheng, C.; Panetta, J. C.; Kornegay, N.; Liu, C.; Ramsey, L. B.; Karol, S. E.; Janke, L. J.; Larsen, E. C.; Winick, N.; Carroll, W. L.; Loh, M. L.; Raetz, E. A.; Hunger, S. P.; Devidas, M.; Yang, J. J.; Mullighan, C. G.; Zhang, J.; Evans, W. E.; Jeha, S.; Pui, C. H.; Relling, M. V.

In: Clinical Pharmacology and Therapeutics, Vol. 102, No. 1, 01.07.2017, p. 131-140.

Research output: Contribution to journalArticle

Liu, Y, Fernandez, CA, Smith, C, Yang, W, Cheng, C, Panetta, JC, Kornegay, N, Liu, C, Ramsey, LB, Karol, SE, Janke, LJ, Larsen, EC, Winick, N, Carroll, WL, Loh, ML, Raetz, EA, Hunger, SP, Devidas, M, Yang, JJ, Mullighan, CG, Zhang, J, Evans, WE, Jeha, S, Pui, CH & Relling, MV 2017, 'Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy', Clinical Pharmacology and Therapeutics, vol. 102, no. 1, pp. 131-140. https://doi.org/10.1002/cpt.629
Liu, Y. ; Fernandez, C. A. ; Smith, C. ; Yang, W. ; Cheng, C. ; Panetta, J. C. ; Kornegay, N. ; Liu, C. ; Ramsey, L. B. ; Karol, S. E. ; Janke, L. J. ; Larsen, E. C. ; Winick, N. ; Carroll, W. L. ; Loh, M. L. ; Raetz, E. A. ; Hunger, S. P. ; Devidas, M. ; Yang, J. J. ; Mullighan, C. G. ; Zhang, J. ; Evans, W. E. ; Jeha, S. ; Pui, C. H. ; Relling, M. V. / Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy. In: Clinical Pharmacology and Therapeutics. 2017 ; Vol. 102, No. 1. pp. 131-140.
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