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

Sabine R. Zwakenberg, Stephen Burgess, Ivonne Sluijs, Elisabete Weiderpass, Joline W. J. Beulens, Yvonne T. van der Schouw

Research output: Contribution to journalArticleAcademicpeer-review

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.
LanguageEnglish
JournalClinical Nutrition
DOIs
Publication statusPublished - 2019

Cite this

Zwakenberg, Sabine R. ; Burgess, Stephen ; Sluijs, Ivonne ; Weiderpass, Elisabete ; Beulens, Joline W. J. ; van der Schouw, Yvonne T. / Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study. In: Clinical Nutrition. 2019.
@article{e793f0a2809e476598969a9cad146035,
title = "Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study",
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.",
author = "Zwakenberg, {Sabine R.} and Stephen Burgess and Ivonne Sluijs and Elisabete Weiderpass and Beulens, {Joline W. J.} and {van der Schouw}, {Yvonne T.}",
year = "2019",
doi = "10.1016/j.clnu.2019.04.024",
language = "English",
journal = "Clinical Nutrition",
issn = "0261-5614",
publisher = "Churchill Livingstone",

}

Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study. / Zwakenberg, Sabine R.; Burgess, Stephen; Sluijs, Ivonne; Weiderpass, Elisabete; Beulens, Joline W. J.; van der Schouw, Yvonne T.

In: Clinical Nutrition, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study

AU - Zwakenberg, Sabine R.

AU - Burgess, Stephen

AU - Sluijs, Ivonne

AU - Weiderpass, Elisabete

AU - Beulens, Joline W. J.

AU - van der Schouw, Yvonne T.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85065619629&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31103344

U2 - 10.1016/j.clnu.2019.04.024

DO - 10.1016/j.clnu.2019.04.024

M3 - Article

JO - Clinical Nutrition

T2 - Clinical Nutrition

JF - Clinical Nutrition

SN - 0261-5614

ER -