Association between Klotho and autoimmune diseases: A Mendelian randomization study and cross-sectional study

Area of Science:

• Genetics
• Immunology
• Endocrinology

Background:

• Autoimmune diseases (AIDs) involve complex genetic and environmental factors.
• Klotho, a protein hormone, is implicated in aging and various diseases, including AIDs.
• Understanding the causal relationship between Klotho and specific AIDs is crucial for therapeutic development.

Purpose of the Study:

• To investigate the potential causal relationship between Klotho and 15 different autoimmune diseases.
• To determine if Klotho levels can serve as a predictive biomarker for rheumatoid arthritis (RA).
• To explore the bidirectional causal effects between Klotho and RA.

Main Methods:

• Two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data.
• Identification of single-nucleotide polymorphisms (SNPs) associated with Klotho and 15 AIDs.
• Statistical analyses including inverse variance weighting, MR-Egger regression, heterogeneity tests, and cross-sectional validation.

Main Results:

• A significant inverse causal association was found between genetically predicted lower Klotho levels and an increased risk of rheumatoid arthritis (RA).
• No significant causal associations were observed between Klotho and the other 14 AIDs studied.
• Bidirectional MR analysis and cross-sectional data confirmed a negative correlation between Klotho and RA, without evidence of RA causing changes in Klotho.

Conclusions:

• Lower Klotho levels are genetically associated with a higher risk of developing rheumatoid arthritis.
• Klotho does not appear to have a causal role in the other 14 autoimmune diseases examined.
• Klotho may represent a potential predictive biomarker and therapeutic target for rheumatoid arthritis.