PNPLA3: A Validation Study in a Spanish Cohort rs738409 and Hepatotoxicity in Children With B‐cell Acute Lymphoblastic Leukemia: A Validation Study in a Spanish Cohort

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To the Editor: We have read with interest the recent study by Liu et al.1 published in Clinical Pharmacology & Therapeutics. The authors identified the single‐nucleotide polymorphism rs738409 in PNPLA3 strongly associated with hepatotoxicity, measured as the elevation of alanine aminotransferase higher than 5.0‐fold of upper limit of normal (ULN), after induction therapy in pediatric patients with acute lymphoblastic leukemia (ALL).
Because this association should be confirmed in the context of different childhood ALL treatment protocols, phases, or populations, we analyzed the association of rs738409 in a cohort of 138 Spanish children, mainly of European descent (98.6%), with B‐cell precursor ALL homogeneously treated with LAL/SHOP94/99/2005 protocols, which were previously described.2 Genomic DNA was extracted from patients' remission peripheral blood or bone marrow using the phenol‐chloroform method, as previously described.3 We carried out an allele‐specific polymerase chain reaction (Table1) with 100% of genotyping success. In our study, hepatic toxicity was measured as elevation of aspartate aminotransferase/alanine aminotransferase and graded according to the Spanish Society of Pediatric Hematology and Oncology standards, adapted from the World Health Organization criteria. Hepatotoxicity was considered from grade 2 to 4 (>2.6*ULN) and high hepatotoxicity from grades 3 to 4 (>5.1*ULN). The highest grade of toxicity observed for each patient during induction therapy was recorded. Written consent was obtained from all patients or their parents before sample collection; ethics committee board (CEISH/102R/2011) approval was obtained and the study was carried out according to the Declaration of Helsinki.
In our cohort of children, 43 patients (31.2%) developed hepatic toxicity (grades 2–4). Of them, 25 (18.1%) developed high hepatotoxicity (grades 3–4). In the association analysis, we found that rs738409 CG/GG genotypes were associated with a 2.6‐fold increased risk of high hepatotoxicity (95% confidence interval:1.09–6.64; P = 0.029) in our population of Spanish children (Table1). This result was in agreement with the results found by Liu et al.1
In conclusion, our findings confirm the association of rs738409 in PNPLA3 with hepatotoxicity during the induction phase of pediatric ALL therapy. As Liu et al.1 mentioned, this result highlights the interest of pharmacogenetic variants overlapping with risk variants. Although our study has the limitation of a smaller sample size, together with other replication studies, it could help to confirm that rs738409 is a novel marker for hepatotoxicity during the induction phase of ALL therapy.
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