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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 65; no. 2; pp. 463 - 470
• Main Authors: Liu, Yan-Ping, Gu, Yu-Mei, Thijs, Lutgarde, Knapen, Marjo H.J, Salvi, Erika, Citterio, Lorena, Petit, Thibault, Carpini, Simona Delli, Zhang, Zhenyu, Jacobs, Lotte, Jin, Yu, Barlassina, Cristina, Manunta, Paolo, Kuznetsova, Tatiana, Verhamme, Peter, Struijker-Boudier, Harry A, Cusi, Daniele, Vermeer, Cees, Staessen, Jan A
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.02.2015
• Subjects: Adult; Aged; Aged, 80 and over; Belgium - epidemiology; Calcium-Binding Proteins - blood; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - physiology; Cardiovascular Diseases - genetics; Cardiovascular Diseases - mortality; Chromosomes, Human, Pair 12 - genetics; Environmental Exposure; Extracellular Matrix Proteins - blood; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - physiology; Female; Follow-Up Studies; Gene-Environment Interaction; Genetic Predisposition to Disease; Genotype; Humans; Incidence; Kaplan-Meier Estimate; Linkage Disequilibrium; Male; Matrix Gla Protein; Mendelian Randomization Analysis; Middle Aged; Neoplasms - genetics; Neoplasms - mortality; Polymorphism, Single Nucleotide; Proportional Hazards Models; Protein Processing, Post-Translational; Vitamin K Deficiency - blood; Vitamin K Deficiency - epidemiology; Belgium; mortality; matrix Gla protein; Mendelian randomization
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.114.04494

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 matrix Gla protein (dp–ucMGP). The risk associated with dp–ucMGP in the population is unknown. In a Flemish population study, we measured circulating dp–ucMGP at baseline (1996–2011), genotyped MGP, recorded adverse health outcomes until December 31, 2012, and assessed the multivariable-adjusted associations of adverse health outcomes with dp–ucMGP. We applied a Mendelian randomization analysis using MGP genotypes as instrumental variables. Among 2318 participants, baseline dp–ucMGP averaged 3.61 μg/L. Over 14.1 years (median), 197 deaths occurred, 58 from cancer and 70 from cardiovascular disease; 85 participants experienced a coronary event. 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/L, respectively). With higher dp–ucMGP, cardiovascular mortality log-linearly increased (hazard ratio for dp–ucMGP 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–ucMGP 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. Higher dp–ucMGP predicts total, non-cancer and cardiovascular mortality, but lower coronary risk. For non-cancer mortality and coronary events, these associations are likely causal.