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Genome‐Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy
Author(s) -
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
Publication year - 2017
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.629
Subject(s) - medicine , alanine transaminase , aspartate transaminase , pharmacogenetics , genome wide association study , exome sequencing , oncology , exome , liver disease , gastroenterology , single nucleotide polymorphism , bioinformatics , biology , genetics , gene , genotype , mutation , alkaline phosphatase , biochemistry , enzyme
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.