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

• Published in: Artery research Vol. 8; no. 4; p. 125
• Main Authors: Liu, Y.-P., Gu, Y.-M., Thijs, L., Knapen, M., Salvi, E., Citterio, L., Petit, T., Carpini, S., Zhang, Z.-Y., Jacobs, L., Jin, Y., Barlassina, C., Manunta, P., Kuznetsova, T., Verhamme, P., Struijker-Boudier, H., Cusi, D., Vermeer, C., Staessen, J.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.12.2014; Springer Nature B.V
• Subjects: Cancer; Mortality; Oral Presentation Abstracts; Proteins
• DOI: 10.1016/j.artres.2014.09.064
• ISSN: 1872-9312

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.