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. Mullighan; J. Zhang; W. E. Evans; S. Jeha; C. H. Pui; M. V. Relling

doi:10.1002/cpt.629

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

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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 language	English (US)
Pages (from-to)	131-140
Number of pages	10
Journal	Clinical pharmacology and therapeutics
Volume	102
Issue number	1
DOIs	https://doi.org/10.1002/cpt.629
State	Published - Jul 1 2017

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

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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., ... Relling, M. V. (2017). Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy. Clinical pharmacology and therapeutics, 102(1), 131-140. https://doi.org/10.1002/cpt.629

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

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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.",

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AU - Yang, W.

AU - Cheng, C.

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AU - Kornegay, N.

AU - Liu, C.

AU - Ramsey, L. B.

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AU - Hunger, S. P.

AU - Devidas, M.

AU - Yang, J. J.

AU - Mullighan, C. G.

AU - Zhang, J.

AU - Evans, W. E.

AU - Jeha, S.

AU - Pui, C. H.

AU - Relling, M. V.

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N2 - 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.

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

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