Using two-sample bidirectional Mendelian randomization across 363,228 individuals for biomarker GWAS data and 28,654 for vascular calcification (VC), this analysis identifies seven plasma biomarkers causally linked to VC. Five—including triglycerides (TRIG), gamma-glutamyltransferase (GGT), calcium (CA), bilirubin (BILD), and sex hormone-binding globulin (SHBG)—partially mediate the effects of four modifiable risk factors: smoking, milk intake, blood pressure, and diabetes. Notably, VC itself appears to reverse-causally elevate alkaline phosphatase, a recognized calcification enzyme.
Vascular calcification remains one of cardiovascular medicine's most therapeutically neglected problems—stiff, calcified vessels dramatically raise all-cause mortality yet lack approved pharmacological reversal agents. This MR approach, which uses genetic variants as instrumental variables to approximate causal inference without randomized trials, adds meaningful resolution to a murky literature. The SHBG finding is particularly intriguing: declining sex hormones with aging may directly accelerate arterial stiffening, suggesting a hormonal-calcification axis deserving dedicated trials. GGT's mediation role points toward liver metabolic health as an underappreciated lever. Practical implications center on already-actionable behaviors—smoking cessation and blood pressure control—now shown to operate partly through measurable biomarker pathways. Limitations are significant: MR assumes no pleiotropy violations, the VC GWAS sample (28,654) is modest, and findings remain observational at the population level. Crucially, this is a preprint posted to medRxiv and has not yet undergone peer review—effect sizes and causal interpretations could shift substantially. Directionally confirmatory of lifestyle-VC links, but mechanistically incremental rather than paradigm-shifting.
