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Inactive Matrix Gla Protein Is a Novel Circulating Biomarker Predicting

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Inactive Matrix Gla Protein Is a Novel Circulating Biomarker Predicting www.nature.com/scientificreports OPEN Inactive matrix Gla protein is a novel circulating biomarker predicting retinal arteriolar Received: 5 June 2018 Accepted: 17 September 2018 narrowing in humans Published: xx xx xxxx Fang-Fei Wei1, Qi-Fang Huang1, Zhen-Yu Zhang1, Karel Van Keer2, Lutgarde Thijs1, Sander Trenson3, Wen-Yi Yang1, Nicholas Cauwenberghs 1, Blerim Mujaj1, Tatiana Kuznetsova1, Karel Allegaert4,5, Harry A. J. Struijker-Boudier6, Peter Verhamme7, Cees Vermeer8 & Jan A. Staessen 1,9 Active matrix Gla protein (MGP), a potent inhibitor of calcifcation in large arteries, protects against macrovascular complications. Recent studies suggested that active MGP helps maintaining the integrity of the renal and myocardial microcirculation, but its role in preserving the retinal microcirculation remains unknown. In 935 randomly recruited Flemish participants (mean age, 40.9 years; 50.3% women), we measured plasma desphospho-uncarboxylated MGP (dp–ucMGP), a marker of poor vitamin K status using an ELISA-based assay at baseline (1996–2010) and retinal microvascular diameters using IVAN software (Vasculomatic ala Nicola, version 1.1) including the central retinal arteriolar (CRAE) and venular (CRVE) equivalent and the arteriole-to-venule ratio (AVR) at follow-up (2008–2015). CRAE (P = 0.005) and AVR (P = 0.080) at follow-up decreased across tertiles of the dp–ucMGP distribution. In unadjusted models, for a doubling of dp–ucMGP at baseline, CRAE and AVR at follow-up respectively decreased by 1.40 µm (95% confdence interval [CI], 0.32 to 2.48; P = 0.011) and 0.006 (CI, 0.001 to 0.011; P = 0.016). In multivariable-adjusted models accounting for sex, baseline characteristics and follow-up duration, these estimates were −1.03 µm (CI, −1.96 to −0.11; P = 0.028) and −0.007 (CI, −0.011 to −0.002; P = 0.007). Additional adjustment for changes from baseline to follow-up in major baseline characteristics yielded as estimates −0.91 µm (CI, −1.82 to −0.01; P = 0.048) and −0.006 (95% CI, −0.011 to −0.001; P = 0.014), respectively. Circulating inactive dp–ucMGP is a long-term predictor of smaller retinal arteriolar diameter in the general population. Our observations highlight the possibility that vitamin K supplementation might promote retinal health. Non-mydriatic retinal photography allows non-invasive visualisation of the retinal microvasculature in popula- tion surveys1–4. Numerous studies demonstrated that the diameters of the retinal microvessels carry important prognostic information5–7, smaller arteriolar diameter6,7, wider venular calibre7, and lower arteriolar-to-venular diameter ratio5 predicting cardiovascular mortality6, coronary heart disease5 and lacunar stroke7. Matrix Gla protein (MGP) is a 11-kD protein synthesised by vascular smooth muscle and endothelial cells8. Activation of MGP requires two posttranslational modifcations: vitamin-K dependent γ-glutamate carboxyla- tion and serine phosphorylation8. Inactive desphospho-uncarboxylated MGP (dp-ucMGP) is a marker of poor 1Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium. 2Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium. 3Division of Cardiology, University Hospitals Leuven, Leuven, Belgium. 4Research Unit Organ Systems, Department of Development and Regeneration, University of Leuven, Leuven, Belgium. 5Department of Pediatric Surgery and Intensive Care and Neonatology, Erasmus Medical Centre, Sophia Children’s Hospital, Rotterdam, The Netherlands. 6Department of Pharmacology, Maastricht University, Maastricht, The Netherlands. 7Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium. 8R&D Group VitaK, Maastricht University, Maastricht, The Netherlands. 9Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. Correspondence and requests for materials should be addressed to J.A.S. (email: [email protected]) SCIENTIFIC REPORTS | (2018) 8:15088 | DOI:10.1038/s41598-018-33257-6 1 www.nature.com/scientificreports/ Characteristics Category of dp-ucMGP P Value Limits (μg/L) <2.88 2.88–4.58 ≥4.58 Number of participants (%) 311 (33.3) 311 (33.3) 313 (33.4) All patients in category Women 166 (53.4) 148 (47.6) 156 (49.8) 0.35 Smokers 88 (28.3) 86 (27.6) 36 (11.5)‡ <0.001 Drinking alcohol 133 (42.8) 125 (40.2) 138 (44.1) 0.60 Hypertension 61 (19.6) 61 (19.6) 99 (31.6)‡ <0.001 Antihypertensive treatment 27 (8.7) 28 (9.0) 53 (16.9)† 0.001 Diabetes mellitus 12 (3.9) 6 (1.9) 9 (2.9) 0.36 Mean (SD) of characteristic Age (years) 39.2 (12.3) 39.4 (14.7) 44.1 (16.0)‡ <0.001 Body mass index (kg/m2) 24.3 (3.8) 24.7 (4.0) 26.3 (4.8)‡ <0.001 Systolic pressure (mm Hg) 120.3 (13.0) 121.6 (14.8) 125.8 (16.1)‡ <0.001 Diastolic pressure (mm Hg) 75.7 (10.0) 75.3 (11.3) 78.0 (11.6)† 0.006 Serum total cholesterol (mmol/L) 5.11 (0.97) 5.04 (0.93) 5.29 (1.06)‡ 0.004 Serum HDL cholesterol (mmol/L) 1.45 (0.40) 1.46 (0.41) 1.38 (0.34)* 0.037 Plasma glucose (mmol/L) 5.03 (1.08) 5.03 (1.09) 5.18 (1.14) 0.14 Geometric mean (IQR) of characteristic dp-ucMGP (μg/L) 1.84 (1.56–2.50) 3.64 (3.30–4.04)‡ 6.10 (5.15–6.79)‡ <0.001 Table 1. Baseline characteristics of participants by tertiles of the dp-ucMGP distribution. Abbreviations: dp- ucMGP, desphospho-uncarboxylated matrix Gla protein. Baseline refers to the date of blood collection for dp-ucMGP measurement. To convert dp-ucMGP from μg/L into pmol/L, multiply by 94.299. Hypertension was a blood pressure of ≥140 mm Hg systolic or ≥90 mm Hg diastolic or use of antihypertensive drugs. Diabetes mellitus was a fasting plasma glucose of ≥126 mg/dL (7.0 mmol/L) or use of antidiabetic agents. P-values denote the signifcance of the diference in prevalence (chi-squared test) or means (ANOVA) across tertiles of the distribution of dp-ucMGP. Signifcance of the diference with the adjacent lower third: *P ≤ 0.05; †P ≤ 0.01; ‡P ≤ 0.001. vitamin K status9,10. Once activated, MGP is a potent locally acting inhibitor of calcifcation in large arteries8 and protects against macrovascular complications11 and arterial stifening10,12. MGP is expressed in renal13,14 and myo- cardial microvessels15, where the activated protein contributes to maintaining organ function. Similarly, MGP is abundantly expressed in the eye16–19, where it takes part in preserving the structural integrity of the trabecular meshwork (TM)16,17, the sclera18 and the retinal ganglion cells19. A naturally fuorescent MGP transgenic mouse model also demonstrated MGP expression in the retinal vasculature20. In view of these observations13–20, we hypothesised that retinal microvascular traits, as exemplifed by retinal arteriolar and venular diameters, might be associated with inactive dp-ucMGP. We assessed in the Flemish Study on Environment, Genes, and Health Outcomes (FLEMENGHO)11,14 whether circulating inactive dp-ucMGP predicted retinal microvascular diame- ters 11 years afer the measurement of the biomarker. Results Characteristics of participants. All 935 participats were White Europeans, of whom 470 (50.3%) were female. Te study population consisted of 138 singletons and 797 related subjects, belonging to 164 one-gener- ation families and to 101 multi-generation pedigrees. In all participants, mean baseline values (SD) were 40.9 (14.6) years for age, 122.6 (14.9) mm Hg and 76.4 (11.0) mm Hg for systolic and diastolic blood pressure, and 25.1 (4.3) kg/m2 for body mass index. At baseline, 108 participants were on antihypertensive drug treatment, of whom 41 (4.4%) were taking diuretics, 87 (9.3%) inhibitors of the renin-angiotensin system, and 15 (1.6%) vas- odilators. At baseline, the geometric mean of dp-ucMGP was 3.45 μg/L and the interquartile range encompassed 2.50 μg/L and 5.16 μg/L. Te median interval between baseline and follow-up was 11.0 years (interquartile range, 9.0–13.3 years). In all participants, central retinal arteriolar (CRAE) and venular (CRVE) equivalent and arteri- ole-to-venule ratio (AVR) at follow-up averaged 150.6 (14.0) µm, 218.3 (19.0) µm and 0.69 (0.06), respectively. Furthermore, the prevalence of glaucoma was about 1% in participants over 40 years old. Tere were no statisti- cally signifcant diferences in plasma levels of dp-ucMGP and retinal vascular diameters between the fve patients with glaucoma and the 518 participants aged 40 years or above without glaucoma (P ≥ 0.41). Unadjusted analyses. Across tertiles of the baseline dp-ucMGP (Table 1), age, body mass index, blood pressure, total cholesterol and the frequency of hypertension increased (P ≤ 0.006), but high-density lipoprotein (HDL) cholesterol and the prevalence of smoking decreased (P ≤ 0.037). Table 2 lists the retinal microvascu- lar traits of participants by tertiles of the distribution of dp-ucMGP. CRAE (P = 0.005) and AVR (P = 0.080) decreased with higher category of dp-ucMGP. Figure 1 demonstrates that in unadjusted analyses dp-ucMGP increased (P < 0.001) across ffhs of the distributions of baseline age, whereas CRAE, CRVE and AVR decreased (P ≤ 0.022). SCIENTIFIC REPORTS | (2018) 8:15088 | DOI:10.1038/s41598-018-33257-6 2 www.nature.com/scientificreports/ Characteristics Category of dp-ucMGP P Value Limits (μg/L) <2.88 2.88–4.58 ≥4.58 Central retinal arteriolar calibre (µm) 152.1 (14.3) 151.0 (13.9) 148.8 (13.5) 0.005 Central retinal venular calibre (µm) 218.7 (18.4) 219.2 (18.9) 217.0 (19.9) 0.33 Arteriole-to-venule ratio 0.70 (0.06) 0.69 (0.06) 0.69 (0.06) 0.080 Table 2.
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