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Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy
Y Liu1, C A Fernandez1, C Smith1
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Clinical Pharmacology and Therapeutics
|January 17, 2017
Summary
A genome-wide study identified the PNPLA3 rs738409 variant associated with elevated alanine transaminase (ALT) levels during acute lymphoblastic leukemia (ALL) induction therapy in children. This finding may help predict liver toxicity in ALL patients.
Area of Science:
- Genetics
- Pharmacology
- Pediatric Oncology
Background:
- Acute lymphoblastic leukemia (ALL) remission induction therapy involves medications like asparaginase, which can cause liver toxicity (hepatotoxicity).
- Elevated alanine transaminase (ALT) levels are a key indicator of drug-induced liver injury during ALL treatment.
- Genetic factors may influence individual susceptibility to medication-induced hepatotoxicity in pediatric ALL patients.
Purpose of the Study:
- To identify genetic loci associated with elevated ALT levels in children undergoing ALL induction therapy.
- To investigate the role of germline genetic variants in predicting asparaginase-induced hepatotoxicity.
- To explore the overlap between pharmacogenetic variants and known disease risk variants.
Main Methods:
- Genome-wide association study (GWAS) using germline DNA from children with ALL treated on St. Jude Children's Research Hospital (SJCRH) protocols.
- Genotyping performed via arrays and exome sequencing.
- Statistical analysis adjusted for covariates including age, BMI, ancestry, asparaginase preparation, and dosage, with replication in an independent cohort.
Main Results:
- The PNPLA3 rs738409 (I148M) variant showed the strongest association with elevated ALT levels (P = 2.5 × 10-8).
- This variant explained 3.8% of the variability in ALT levels and partially accounted for race-related differences.
- The association was successfully replicated in a separate cohort of 2,285 patients from the Children's Oncology Group (COG) AALL0232 study (P = 0.024).
Conclusions:
- The PNPLA3 rs738409 variant is a significant genetic predictor of elevated ALT levels during ALL induction therapy.
- This pharmacogenetic finding highlights a potential overlap with genetic risk factors for fatty liver disease.
- These results may inform personalized medicine approaches to mitigate liver toxicity in pediatric ALL patients.
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