Transcription Factor Binding and Individual Genetic Risk of Valproate Teratogenicity

Area of Science:

• Genetics
• Pharmacology
• Developmental Biology

Background:

• Valproate (VPA) use in pregnancy is linked to birth defects, but individual risk varies, suggesting a genetic component.
• Understanding maternal genetic influence on VPA teratogenicity is crucial for preconception counseling and developing risk prediction biomarkers.

Purpose of the Study:

• To investigate the role of maternal genomic variants affecting transcription factor (TF) binding affinity in VPA-associated teratogenicity.
• To identify potential pharmacogenomic biomarkers for predicting VPA-induced birth defect risks.

Main Methods:

• Analysis of maternal exome variants from epilepsy pregnancy registries and genomics consortia.
• Application of a network-based approach to link variants to birth defect-associated genes and identify variant-sensitive TFs.
• Utilized gene burden tests and multi-modal evidence to identify key TFs and their interactions, including EP300, in an hESC model.

Main Results:

• Higher variant burden in VPA-exposed pregnancies compared to other antiseizure medications (ASMs) across 32 birth defect types (OR 1.73).
• Identified 359 variant-sensitive TFs, forming a connected network where EP300 interacted with 41% of these TFs.
• VPA exposure was shown to alter EP300-TF interactions in an embryonic stem cell model.

Conclusions:

• VPA-induced disruption of EP300-related gene regulation is a potential teratogenic mechanism underlying diverse birth defects.
• This mechanism is sensitive to genetic variation, supporting the development of pharmacogenomic risk biomarkers.
• Findings have implications for safer drug development and personalized medicine for women of childbearing potential.