ArticlePharmacogenetics and genomics2018
Ontogeny-related pharmacogene changes in the pediatric liver transcriptome.
Article in Pharmacogenetics and genomics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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6 citing papers in PubMed, 11 citations in OpenAlex.
- Carnosine Dipeptidase(Cndp): An emerging therapeutic target for metabolic diseases and cancers.Genes & diseases · 2026Review
- Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug Metabolism Mediated by Cytochrome P450 Enzymes.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Statistics and Machine Learning in Mass Spectrometry-Based Metabolomics Analysis.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Transcriptome-Wide Analysis of Human Liver Reveals Age-Related Differences in the Expression of Select Functional Gene Clusters and Evidence for a PPP1R10-Governed 'Aging Cascade'.Pharmaceutics · 2021Article
- Review
- Ontogeny Related Changes in the Pediatric Liver Metabolome.Frontiers in pediatrics · 2020Article
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Authors and funding
7 authors at 4 institutions in 1 country.
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Abstract
objectivesThe 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
methodsA 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.
resultsWe 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<1×10(-9) with false discovery rate<5×0(-5)): ADCY1, PTPRD, CNDP1, DCAF12L1 and HIP1. Gene set analysis determined ontogeny-related transcriptomic changes in the renin-angiotensin pathway (P<0.002), with lower expression of the pathway, in general, observed in liver samples from younger participants.
conclusionConsidering that the renin-angiotensin pathway plays a central role in blood pressure and plasma sodium concentration, and our observation that ACE and PTPRD expression increased over the spectrum of childhood development, this finding could potentially impact the dosing of an entire class of drugs known as ACE-inhibitors in pediatric patients.
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