Inactive matrix gla protein is causally related to adverse health outcomes: A mendelian randomization study in a flemish population

Yan Ping Liu, Yu Mei Gu, Lutgarde Thijs, Marjo H J Knapen, Erika Salvi, Lorena Citterio, Thibault Petit, Simona Delli Carpini, Zhenyu Zhang, Lotte Jacobs, Yu Jin, Cristina Barlassina, Paolo Manunta, Tatiana Kuznetsova, Peter Verhamme, Harry A. Struijker-Boudier, Daniele Cusi, Cees Vermeer, Jan A. Staessen

Research output: Contribution to journalArticle

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 (P0.13), 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.

Original languageEnglish
Pages (from-to)463-470
Number of pages8
JournalHypertension
Volume65
Issue number2
DOIs
Publication statusPublished - Feb 21 2015

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Random Allocation
Mendelian Randomization Analysis
Mortality
Health
Population
Vitamin K Deficiency
Vitamin K
Causality
matrix Gla protein
Cardiovascular Diseases
Genotype
Confidence Intervals
Neoplasms
Proteins

Keywords

  • matrix Gla protein
  • Mendelian randomization
  • mortality

ASJC Scopus subject areas

  • Internal Medicine
  • Medicine(all)

Cite this

Inactive matrix gla protein is causally related to adverse health outcomes : A mendelian randomization study in a flemish population. / 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.

In: Hypertension, Vol. 65, No. 2, 21.02.2015, p. 463-470.

Research output: Contribution to journalArticle

Liu, YP, Gu, YM, Thijs, L, Knapen, MHJ, Salvi, E, Citterio, L, Petit, T, Carpini, SD, Zhang, Z, Jacobs, L, Jin, Y, Barlassina, C, Manunta, P, Kuznetsova, T, Verhamme, P, Struijker-Boudier, HA, Cusi, D, Vermeer, C & Staessen, JA 2015, 'Inactive matrix gla protein is causally related to adverse health outcomes: A mendelian randomization study in a flemish population', Hypertension, vol. 65, no. 2, pp. 463-470. https://doi.org/10.1161/HYPERTENSIONAHA.114.04494
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. / Inactive matrix gla protein is causally related to adverse health outcomes : A mendelian randomization study in a flemish population. In: Hypertension. 2015 ; Vol. 65, No. 2. pp. 463-470.
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