Follistatin levels and endocrine disorders: A two-sample Mendelian randomization study

Area of Science:

• Endocrinology and Genetics
• Metabolic and Bone Diseases

Background:

• Follistatin (FST) is a glycoprotein hormone with known roles in regulating endocrine functions.
• The causal relationship between FST levels and major endocrine diseases remains incompletely understood.
• Investigating FST's role is crucial for understanding disease pathogenesis and identifying potential therapeutic targets.

Purpose of the Study:

• To elucidate the causal links between follistatin (FST) levels and endocrine diseases including PCOS, T2DM, obesity, and OP.
• To utilize a robust two-sample Mendelian randomization (MR) approach for assessing genetic causality.
• To explore potential FST roles as biomarkers or therapeutic targets in endocrine and bone metabolism.

Main Methods:

• Two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data.
• Instrumental variables for FST levels were sourced from the IEU database.
• Outcome data for PCOS, T2DM, obesity, and OP were obtained from the FinnGen database; Inverse-variance weighted (IVW), MR-Egger, and Weighted Median methods were employed, alongside sensitivity analyses.

Main Results:

• Genetically predicted higher FST levels showed a significant causal association with increased risk of PCOS (OR=1.129) and T2DM (OR=1.103).
• No significant causal link was found between FST levels and obesity or osteoporosis in the primary analysis.
• Reverse MR analysis indicated a causal association between T2DM and elevated FST, and between OP and reduced FST levels.

Conclusions:

• Elevated FST levels are causally associated with an increased risk of developing PCOS and T2DM.
• Reduced FST levels are causally linked to osteoporosis, suggesting a role in bone metabolism.
• FST may represent a potential biomarker or therapeutic target for PCOS, T2DM, and osteoporosis.