Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study

Clin Nutr. 2020 Apr;39(4):1131-1136. doi: 10.1016/j.clnu.2019.04.024. Epub 2019 May 7.

Abstract

Background and aims: Multiple observational studies and small-scale intervention studies suggest that high vitamin K intake is associated with improved markers for cardiovascular health. Circulating phylloquinone solely represents phylloquinone (vitamin K1) intake, while dephosphorylated uncarboxylated Matrix Gla Protein (dp-ucMGP) represents both phylloquinone and menaquinone (vitamin K2) intake. This study aims to investigate the causal relationship between genetically predicted vitamin K concentrations and the risk of CHD via a two-sample Mendelian Randomization approach.

Design: We used data from three studies: the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD case-cohort study, CARDIOGRAMplusC4D and the UK Biobank, resulting in 103,097 CHD cases. Genetically predicted vitamin K concentrations were measured using SNPs related to circulating phylloquinone and dp-ucMGP. We calculated a genetic risk score (GRS) including four SNPs (rs2108622, rs2192574, rs4645543 and rs6862071) related to circulating phylloquinone levels from a genome wide association study. Rs4236 was used as an instrumental variable for dp-ucMGP. Inverse-variance weighted (IVW) analysis was used to obtain Risk Ratios (RRs) for the causal relationship between phylloquinone and dp-ucMGP concentrations and CHD risk.

Results: Using the genetic score for circulating phylloquinone, we found that circulating phylloquinone was not causally related to CHD risk (RR 1.00 (95%-CI: 0.98; 1.04)). Lower genetically predicted dp-ucMGP concentration was associated with a lower CHD risk with a RR of 0.96 (95%-CI: 0.93; 0.99) for every 10 μg/L decrease in dp-ucMGP.

Conclusions: This study did not confirm a causal relationship between circulating phylloquinone and lower CHD risk. However, lower dp-ucMGP levels may be causally related with a decreased CHD risk. This inconsistent result may reflect the influence of menaquinones in the association with CHD.

Keywords: Coronary heart disease; Epidemiology; Matrix Gla protein; Mendelian randomization; Phylloquinone; Vitamin K.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers / blood
  • Calcium-Binding Proteins / genetics*
  • Coronary Disease / blood*
  • Coronary Disease / genetics*
  • Extracellular Matrix Proteins / genetics*
  • Female
  • Humans
  • Male
  • Matrix Gla Protein
  • Mendelian Randomization Analysis
  • Middle Aged
  • Risk Assessment
  • Vitamin K 1 / blood*

Substances

  • Biomarkers
  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • Vitamin K 1