Background: Matrix Gla-protein is a vitamin K-dependent protein that strongly inhibits arterial calcification. Vitamin K deficiency leads to production of inactive nonphosphorylated and uncarboxylated MGP (dp−μcMGP). The risk associated with dp–μcMGP in the population is unknown.

Methods: In a Flemish population study, we measured circulating dp–μcMGP at baseline (1996−2011), genotyped MGP and recorded adverse health outcomes until December 31,2012. We assessed the multivariable-adjusted association of adverse health outcomes with dp–μcMGP and we applied a Mendelian randomization analysis based on MGP genotypes.

Results: Among 2318 participants, baseline dp–μcMGP averaged 3.61 μg/liter. Over 14.1 years (median), 197 deaths occurred, 58 from cancer and 70 form cardiovascular disease, and 85 participants experienced coronary events. The risk of death and non-cancer mortality curvilinearly increased (P≤0.008) by 15.0% (95% confidence interval, 6.9−25.3) and by 21.5% (11.1−32.9) for a doubling of the nadir: 1.43 and 0.97 μg/liter, respectively. With higher dp–μcMGP, cardiovascular mortality log-linearly increased (hazard ratio for dp–μcMGP doubling, 1.14[1.01−1.28]; P=0.027), but coronary events log-linearly decreased (0.93 [0.88−0.99]; P=0.021). dp−μcMGP levels were associated (P≤0.001) with MGP variants rs2098435, rs4236 and rs2430692. For non-cancer mortality and coronary events (P≤0.022), but not for total and cardiovascular mortality (P≥0.13), the Mendelian randomization analysis suggested causality. In a nested case-control study, 64 patients with coronary events had lower dp–μcMGP than 107 matched controls (3.51 vs. 4.54 μg/liter; P=0.012).

Conclusions: Higher dp–μcMGP predicts total, non-cancer and cardiovascular mortality, but lower coronary risk. For non-cancer mortality and coronary events, these associations are likely causal.