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

Hypertension. 2015 Feb;65(2):463-70. doi: 10.1161/HYPERTENSIONAHA.114.04494. Epub 2014 Nov 24.

Abstract

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.

Keywords: Mendelian randomization; matrix Gla protein; mortality.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • 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

Substances

  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • matrix Gla protein