Ontogeny-related pharmacogene changes in the pediatric liver transcriptome

Objectives The majority of drug dosing studies are based on adult populations, with modification of the dosing for children based on size and weight. This rudimentary approach for drug dosing children is limited, as biologically a child can differ from an adult in far more aspects than just size and weight. Specifically, understanding the ontogeny of childhood liver development is critical in dosing drugs that are metabolized through the liver, as the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Therefore, we set out to determine pharmacogenes that change over childhood development, followed by a secondary agnostic analysis, assessing changes transcriptome wide. Materials and methods A total of 47 human liver tissue samples, with between 10 and 13 samples in four age groups spanning childhood development, underwent pair-end sequencing. Kruskal–Wallis and Spearman's rank correlation tests were used to determine the association of gene expression levels with age. Gene set analysis based on the pathways in KEGG utilized the gamma method. Correction for multiple testing was completed using q-values. Results We found evidence for increased expression of 'very important pharmacogenes', for example, coagulation factor V (F5) (P=6.7×10−7), angiotensin I converting enzyme (ACE) (P=6.4×10−3), and solute carrier family 22 member 1 (SLC22A1) (P=7.0×10−5) over childhood development. In contrast, we observed a significant decrease in expression of two alternative CYP3A7 transcripts (P=1.5×10−5 and 3.0×10−5) over development. The analysis of genome-wide changes detected transcripts in the following genes with significant changes in mRNA expression (P

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