Causal association between circulating α-Klotho levels and venous thromboembolism: a two-sample Mendelian...

Area of Science:

• Genetics and Epidemiology
• Vascular Biology
• Biomarker Discovery

Background:

• Circulating α-Klotho levels may play a role in venous thromboembolism (VTE) development.
• The precise relationship between α-Klotho and VTE remains unclear.
• Investigating this link can identify novel therapeutic targets.

Purpose of the Study:

• To investigate the causal association between circulating α-Klotho levels and various types of VTE.
• To explore potential therapeutic implications of α-Klotho in VTE prevention and treatment.

Main Methods:

• A two-sample Mendelian Randomization (MR) study design.
• Utilized genome-wide association study (GWAS) data for exposure and outcome.
• Employed multiple MR methods including IVW, MR-Egger, RAPS, and weighted-median, with FDR correction for robustness.

Main Results:

• Elevated α-Klotho levels showed a negative causal association with lower-extremity deep vein thrombosis (DVT) after FDR correction (FDR P = 0.0296).
• Initial estimates also suggested associations with reduced odds of pulmonary embolism (PE) and combined DVT/PE, though not all reached statistical significance post-correction.
• Sensitivity analyses confirmed the robustness of the findings, and no reverse causal associations were detected.

Conclusions:

• Higher circulating α-Klotho levels are associated with a lower risk of lower-extremity DVT and PE.
• α-Klotho shows potential as a biomarker for VTE risk assessment and a target for therapeutic intervention.
• Further research is needed to elucidate the specific mechanisms by which α-Klotho influences VTE pathogenesis.