Background and aim

The metabolic roles in arterial calcification remain largely unclear. We aimed to elucidate the associations between nuclear magnetic resonance (NMR) metabolic biomarkers with site- and sex-specific arterial calcification as well as their causal nature.

Methods

This study included participants from the Rotterdam Study (RS, N = 1062), Leiden Longevity Study (LLS, N = 272), and UK Biobank (UKBB, N = 271,793). In RS and LLS, we applied linear regression (both overall and sex-stratified) to assess the association between NMR metabolic biomarkers and arterial calcification at coronary artery (CAC), aortic arch (AAC), and aortic valve (AVC). Two-sample Mendelian randomization (MR) was employed using genome-wide association study of NMR biomarkers (N = 115,082) and CAC (N = 26,909) to infer their genetic causality. Biomarkers with consistent observational and causal associations were further examined for associations with coronary heart disease (CHD) in UKBB.

Results

From multiple-testing correction (P-value < 4.39 × 10-4), three fatty acids ratio biomarkers were associated with decreased CAC burden: Omega_6_pct (Beta: -0.10, SE: 0.03, P-value: 2.94 × 10-4), PUFA_by_MUFA (Beta: -0.10, SE: 0.03, P-value: 3.08 × 10-4), and PUFA_pct (Beta: -0.10, SE: 0.03, P-value: 3.33 × 10-4). Sex-stratification revealed glycoprotein acetyls (GlycA) associated with CAC in males only (Beta: 0.13, SE: 0.04, P-value: 3.10 × 10-4). MR identified 17 biomarkers causally associated with CAC, 14 of which were subsequently associated with CHD in UKBB.

Conclusions

We identified NMR-based metabolic biomarkers, particularly fatty acid ratios, that were significantly and causally associated with CAC burden. GlycA was associated with CAC in males only. Replication in UKBB further underscores their clinical relevance with CHD.

© 2026 The Authors. Published by Elsevier B.V.