Ontogeny-related pharmacogene changes in the pediatric liver transcriptome

Area of Science:

• Pharmacogenomics
• Pediatric Drug Development
• Liver Development

Background:

• Current pediatric drug dosing primarily relies on adult data adjusted for size and weight.
• Childhood liver development significantly alters drug metabolism, impacting efficacy and safety.
• Understanding ontogeny of liver function is critical for precise pediatric pharmacotherapy.

Purpose of the Study:

• To identify pharmacogenes exhibiting altered expression during childhood liver development.
• To conduct a transcriptome-wide analysis of age-related gene expression changes in the liver.
• To investigate the impact of developmental changes on drug metabolism pathways.

Main Methods:

• Analyzed 47 human liver tissue samples across four pediatric age groups using pair-end sequencing.
• Employed Kruskal-Wallis and Spearman's rank correlation tests to assess age-associated gene expression.
• Utilized KEGG pathway analysis and the gamma method for gene set enrichment, with q-value correction.

Main Results:

• Identified increased expression of key pharmacogenes like F5, ACE, and SLC22A1 with age.
• Observed decreased expression of CYP3A7 transcripts during childhood development.
• Detected significant genome-wide transcriptomic changes, including ADCY1, PTPRD, and others, with implications for the renin-angiotensin pathway.

Conclusions:

• Childhood liver development involves significant, age-dependent changes in pharmacogene expression.
• Increased expression of ACE and PTPRD, alongside renin-angiotensin pathway ontogeny, may influence ACE-inhibitor dosing in children.
• These findings highlight the need for age-specific pharmacogenomic data to optimize pediatric drug therapy.