Genome-Wide Association Study Identifies PNPLA3 I148M Variant Associated with Elevated Transaminase Levels after Induction Therapy in Pediatric ALL Patients

Current regimens for remission induction therapy of pediatric acute lymphoblastic leukemia (ALL) include multiple potentially hepatotoxic drugs, including asparaginase. The objective of our genome-wide association study (GWAS) was to identify genetic loci associated with elevated alanine transaminase (ALT) levels immediately after remission induction in children with ALL. The patients included were enrolled on St. Jude Children's Research Hospital (SJCRH) protocols Total XV (n = 373) or Total XVI (n = 342); germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome Beadchip arrays. In multivariate analysis, risk factors associated with higher ALT included older age, higher body mass index, European (versus African) ancestry, treatment with PEGylated E. coli asparaginase (versus native E. coli asparaginase), and receiving additional doses of asparaginase during induction due to high level of minimal residual disease at day 15-19 of induction. GWAS identified an association between I148M PNPLA3 rs738409 (C>G) variant and post-induction ALT (Figure 1A; P = 7.9x10^-9; median ALT of 34, 45, and 58 IU/L in CC, GC and GG genotypes, respectively), and the effect of the PNPLA3 variant was consistent for both protocols, both ALL risk groups, and among patients of European, African, and Hispanic ancestry. The PNPLA3 variant has previously been linked to elevated ALT and to the development of steatosis in adults;[PMID: 22001757; 18820647] in mice, this same variant led to a loss of catalytic function and to an increase of PNPLA3 accumulation in hepatic lipid droplets and to the development of steatosis.[PMID: 24917523] Within patients of African ancestry, we identified a variant near PIGV rs12748152 (C>T) associated with lower ALT levels at P = 1.7x10^-8; median ALT of 28 and 6 IU/L in CC and TC genotypes, respectively (Figure 1B), consistent with lower ALT values observed in patients of African ancestry. The PIGV variant explained 7% of the variation in ALT for patients of African ancestry. The results of our study suggest that post-remission induction ALT levels may be related to treatment-related variables, such as increased asparaginase exposure, and to host genetic factors, at least some of which contribute to hepatic dysfunction in settings outside of ALL therapy.  

Figure 1. Alanine transaminase (ALT) levels by PNPLA3 or PIGV genotype