Integrative multi-omics Mendelian randomization and functional validation identifies RNASET2 as a novel therapeutic...

Area of Science:

• Genomics and Autoimmune Diseases
• Molecular Biology and Therapeutics
• Translational Medicine

Background:

• Autoimmune thyroiditis (AIT) is a common autoimmune disorder leading to hypothyroidism, with a need for disease-modifying therapies.
• Current treatments for AIT do not fully address the underlying pathogenesis.
• Identifying novel therapeutic targets is crucial for advancing AIT treatment.

Purpose of the Study:

• To identify and validate novel therapeutic targets for autoimmune thyroiditis (AIT).
• To explore the role of Ribonuclease T2 (RNASET2) as a potential therapeutic target for AIT.
• To bridge genetic discoveries with potential clinical applications for AIT.

Main Methods:

• Integrative genomics approach combining GWAS, eQTL, pQTL, and mQTL analyses across two AIT cohorts.
• Bidirectional Mendelian randomization (MR) and SMR/HEIDI tests for causal inference.
• Functional validation using a 3D thyrocyte spheroid model, RNASET2 quantification, and gene manipulation (knockdown/rescue).

Main Results:

• Multi-omics integration nominated RNASET2 as a causal protective factor against AIT.
• RNASET2 genetic signals (pQTL, eQTL) correlated with decreased AIT risk; mQTLs with increased risk.
• Recombinant RNASET2 mitigated inflammation and apoptosis in a 3D thyrocyte model, while RNASET2 knockdown exacerbated it.

Conclusions:

• RNASET2 is established as a promising therapeutic target for autoimmune thyroiditis (AIT).
• RNASET2 augmentation offers a potential disease-modifying strategy for AIT.
• This research provides a translational pathway from genetic findings to clinical AIT therapies.