Systematic investigation of gengetically determined plasma and urinary biomarkers to identify potential detection and intervention targets for vascular calcification

Background: Vascular calcification (VC) is prevalent among patients with atherosclerosis, hypertension, diabetes, elderly individuals, and those with chronic kidney disease. However, effective diagnostic and therapeutic strategies are lacking. Plasma and urinary biomarkers are commonly used in clinical settings to assess disease progression. Objective: This study investigates causal relationships between plasma/urinary biomarkers and VC using Mendelian randomization (MR), aiming to identify potential targets for VC intervention, and to assess whether biomarkers mediate the effects of modifiable risk factors on VC. Methods: We performed two-sample bidirectional MR using large-scale genome-wide association study data (n=363,228 for biomarkers, n=28,654 for VC) to investigate the causal effects of plasma/urinary biomarkers on VC. Then, a literature review was performed to identify common VC risk factors, followed by univariate MR to select risk factors associated with both VC and biomarkers. Finally, mediation analysis was conducted to explored whether biomarkers mediate the effects of modifiable risk factors on VC. Results: MR analysis identified 7 plasma biomarkers linked to VC, 5 of which were positively correlated. A literature review revealed 856 VC risk factors, with 28 identified through univariate MR analysis, 11 of which correlated with identified biomarkers. Mediation analysis showed that 5 biomarkers (TRIG, GGT, CA, BILD, SHBG) partially mediated the effects of 4 modifiable risk factors on VC. Conclusion: This study identifies several clinically common used biomarkers for diagnosing and treating VC, suggesting that modulating these biomarkers through lifestyle changes, such as controlling smoking, intake of milk, blood pressure and diabetes, may slow VC progression in patients.