title: Inactive matrix Gla protein is causally related to adverse health outcomes: a Mendelian randomization study in a Flemish population.
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 (P≥0.13), 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.
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Liu
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Gu
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Thijs
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Marjo H J
authors.initials: MH
authors.lastname: Knapen
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Citterio
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Thibault
authors.initials: T
authors.lastname: Petit
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Simona Delli
authors.initials: SD
authors.lastname: Carpini
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Lotte
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jin
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barlassina
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kuznetsova
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Peter
authors.initials: P
authors.lastname: Verhamme
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Harry A
authors.initials: HA
authors.lastname: Struijker-Boudier
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy.
authors.forename: Cees
authors.initials: C
authors.lastname: Vermeer
authors.affiliation: From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology (Y.-P.L., Y.-M.G., L.T., T.P., Z.-Y.Z., L.J., Y.J., T.K., J.A.S.) and the Centre for Molecular and Vascular Biology (P.V.), KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; VitaK (M.H.J.K., C.V.) and Department of Pharmacology (H.A.S.), Maastricht University, Maastricht, The Netherlands; Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy (E.S., C.B., D.C.); and Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute (L.C., S.D.C.) and School of Nephrology, University Vita-Salute San Raffaele (P.M.), Milan, Italy. jan.staessen@med.kuleuven.be ja.staessen@maastrichtuniversity.nl.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Staessen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001530:Belgium / Q000453:epidemiology; D002135:Calcium-Binding Proteins / Q000097:blood* / Q000235:genetics / Q000502:physiology; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D004781:Environmental Exposure; D016326:Extracellular Matrix Proteins / Q000097:blood* / Q000235:genetics / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D014813:Vitamin K Deficiency / Q000097:blood / Q000453:epidemiology; D000097568:Matrix Gla Protein
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D000097568:Matrix Gla Protein
keywords: Mendelian randomization; matrix Gla protein; mortality