Multi-Omics Evidence from Genetics Reveals an Association between the Hypoglycemic Drug Target DPP4 and Primary...

Area of Science:

• Endocrinology
• Genetics
• Metabolic Disorders

Background:

• Primary ovarian failure (POF) is associated with metabolic dysregulation, including inflammation, oxidative stress, and mitochondrial dysfunction.
• Understanding the genetic and metabolic underpinnings of POF is crucial for developing preventative strategies.

Purpose of the Study:

• To investigate the causal relationship between hypoglycemic drug targets and POF risk.
• To explore the genetic and metabolic mechanisms linking diabetes-related dysregulation to POF.
• To identify potential therapeutic targets for POF prevention.

Main Methods:

• Summary-data-based Mendelian Randomization (MR) and colocalization analysis were used to assess causal links.
• Multi-omics data integration, including gene expression, protein levels, and DNA methylation, was employed.
• Two-sample MR and sensitivity analyses validated the findings and assessed pleiotropy and heterogeneity.

Main Results:

• Elevated dipeptidyl peptidase-IV (DPP4) expression and protein levels were significantly associated with reduced POF risk.
• Increased methylation at specific CpG sites within the DPP4 gene was linked to an increased risk of POF.
• DPP4 demonstrated a protective effect against POF, with robust validation through multi-omics and MR analyses.

Conclusions:

• Increased DPP4 gene expression and protein levels confer a protective effect against primary ovarian failure.
• Elevated methylation at specific DPP4 CpG sites is associated with an increased risk of POF.
• DPP4 emerges as a potential therapeutic target for the prevention of POF.