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

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

Sabine R Zwakenberg  1 , Stephen Burgess  2 , Ivonne Sluijs  1 , Elisabete Weiderpass  3 ; EPIC-CVD consortium; Joline W J Beulens  4 , Yvonne T van der Schouw  5
Affiliations
Multicenter Study

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

Sabine R Zwakenberg et al. Clin Nutr. 2020 Apr.

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.

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Conflict of interest statement

Conflict of interest: SRZ and JWJB are supported by the Senior Dr. Dekker grant (2013T120) from The Dutch Heart Foundation. IS is supported by a personal Dr. Dekker Junior Postdoctoral grant (2015T19) from The Dutch Heart Foundation. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1
Figure 1
The results of the Mendelian Randomization analyses for circulating phylloquinone in EPIC-CVD (n=9,296 cases), CARDIOGRAMplusC4D (n=60,801 cases) and UK Biobank (n=33,000 cases), and the pooled association (n=103,097 cases). The results are derived from the IVW analyses and presented as RR per ln-nmol/L increase in circulating phylloquinone.
Figure 2
Figure 2
The results of the Mendelian Randomization analyses for circulating dp-ucMGP (rs4236) in EPIC-CVD, CARDIOGRAMplusC4D and UK Biobank, and the pooled association (EPIC-CVD, CARDIOGRAMplusC4D and UK Biobank). The results are derived from the IVW analyses and presented as RR per every 10 μg/L decrease in dp-ucMGP.
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