Genetic Evidence Supporting Causal Roles of mTOR-Dependent Proteins in Rheumatic Fever: A Two-Sample Randomized...

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Cardiovascular Research

Background:

• Dysregulated signaling molecules downstream of mTOR are observed in rheumatic fever (RF).
• The causal role of mTOR in RF pathogenesis remains unclear.
• This research investigates the direct causal links between mTOR-dependent proteins and RF.

Purpose of the Study:

• To elucidate the causal relationship between mTOR signaling pathway proteins and rheumatic fever (RF).
• To identify specific mTOR-dependent proteins that influence RF risk.
• To explore potential therapeutic targets within the mTOR pathway for RF intervention.

Main Methods:

• A two-sample Mendelian randomization (MR) study design was employed.
• Utilized GWAS data from the INTERVAL study for mTOR targets and the Integrated Epidemiology Unit for RF cases and controls.
• Applied inverse-variance weighted (IVW), MR-Egger, and weighted median methods with sensitivity analyses.

Main Results:

• A significant inverse causal association was found between RP-S6K and RF risk (OR=0.97, P=0.027).
• ATG7 showed a significant positive causal association with RF risk (OR=1.05, P=0.047).
• No significant causal associations were detected for EIF4A, EIF4G, or EIF4E-BP2 with RF risk.

Conclusions:

• Mendelian randomization provides robust evidence for a causal link between the mTOR pathway and RF.
• RP-S6K and ATG7 emerge as potential therapeutic targets for RF risk reduction.
• Repurposing existing drugs targeting RP-S6K and ATG7 may offer novel strategies for RF management.