TY - JOUR
T1 - Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk
T2 - 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
N1 - Funding Information:
We thank all EPIC participants and staff for their contribution to the study. We thank staff from the EPIC-CVD and EPIC-InterAct Coordinating Centres for carrying out sample preparation and data-handling work, particularly Sarah Spackman (EPIC-CVD Data Manager) and Nicola Kerrison (EPIC-InterAct Data Manager). EPIC-CVD has been supported by the European Union Framework 7 ( HEALTH-F2-2012-279233 ), the European Research Council ( 268834 ), the UK Medical Research Council ( G0800270 and MR/L003120/1 ), the British Heart Foundation ( SP/09/002 and RG/08/014 and RG13/13/30194 ), and the UK National Institute of Health Research . The establishment of the random subcohort was supported by the EU Sixth Framework Programme (grant LSHM_CT_2006_037197 to the InterAct project) and the Medical Research Council Epidemiology Unit (grants MC_UU_12015/1 and MC_UU_12015/5 ). The coordination of EPIC is financially supported by the European Commission and the International Agency for Research on Cancer . The funders played no role in the design of the study; the collection, analysis, and interpretation of the data; or the decision to approve publication of the finished manuscript.
Funding Information:
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.
Publisher Copyright:
© 2019 The Author(s)
PY - 2020/4/1
Y1 - 2020/4/1
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.
KW - Coronary heart disease
KW - Epidemiology
KW - Matrix Gla protein
KW - Mendelian randomization
KW - Phylloquinone
KW - Vitamin K
UR - https://www.scopus.com/pages/publications/85065619629
U2 - 10.1016/j.clnu.2019.04.024
DO - 10.1016/j.clnu.2019.04.024
M3 - Article
C2 - 31103344
SN - 0261-5614
VL - 39
SP - 1131
EP - 1136
JO - Clinical Nutrition
JF - Clinical Nutrition
IS - 4
ER -