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3.2 Inactive Matrix Gla Protein is Causally Related to Health Outcomes: A Mendelian Randomization Study in a Flemish Population

Abstract

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) fora 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.

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Liu, YP., Gu, YM., Thijs, L. et al. 3.2 Inactive Matrix Gla Protein is Causally Related to Health Outcomes: A Mendelian Randomization Study in a Flemish Population. Artery Res 8, 125 (2014). https://doi.org/10.1016/j.artres.2014.09.064

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  • DOI: https://doi.org/10.1016/j.artres.2014.09.064