Marc Blondon1, Mary Cushman1, Nancy Jenny1, Erin D Michos1, Nicholas L Smith1, Bryan Kestenbaum1, Ian H de Boer1. 1. Division of Angiology and Hemostasis (M.B.), Geneva University Hospitals and Faculty of Medicine, 1205 Geneva, Switzerland; Department of Medicine and Pathology & Laboratory Medicine (M.C.), University of Vermont College of Medicine, Burlington, Vermont 05401; Department of Pathology & Laboratory Medicine (N.J.), University of Vermont College of Medicine, Burlington, Vermont 05446; Department of Medicine (Cardiology) (E.D.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Epidemiology (N.L.S.), University of Washington, Seattle, Washington 98195; Group Health Research Institute (N.L.S.), Group Health Cooperative, Seattle, Washington 98112; Seattle Epidemiologic Research and Information Center (N.L.S.), Veterans Affairs Office of Research and Development, Seattle, Washington 98108; and Department of Epidemiology and Nephrology (B.K., I.H.d.B.), University of Washington, Seattle, Washington 98195.
Abstract
CONTEXT: Mechanisms explaining documented associations of 25-hydroxyvitamin D [25(OH)D] deficiency with increased risks of cardiovascular disease (CVD) and venous thromboembolism may relate to adverse hemostatic and inflammatory responses. OBJECTIVE: To evaluate whether 25(OH)D deficiency is associated with a prothrombotic and proinflammatory biological profile. DESIGN: Cross-sectional analyses. SETTING: The Multi-Ethnic Study of Atherosclerosis, a multicenter prospective cohort of American adults. PARTICIPANTS: Up to 6554 adults free of CVD. MAIN OUTCOME MEASURES: Ten hemostatic biomarkers (D-dimer, fibrinogen, factor VIII, plasmin-antiplasmin, and homocysteine [n = 6443]; von Willebrand factor, soluble tissue factor, plasminogen activator inhibitor-1 (PAI-1), total tissue factor pathway inhibitor (TFPI), and soluble thrombomodulin [n = 814]), and three inflammatory biomarkers (IL-6, C-reactive protein [n = 6443], and TNF-α soluble receptor [n = 3802]). RESULTS: Among 6443 subjects (46.6% men; mean age, 62.1 years; mean body mass index, 28.3 kg/m(2)) of White (37.8%), Black (27.2%), Chinese (12.2%), and Hispanic (21.8%) race/ethnicity, mean 25(OH)D was 25.3 ng/mL. After multiple adjustment, 25(OH)D concentrations were associated with concentrations of IL-6 and homocysteine and also with concentrations of PAI-1 and TFPI: per 10 ng/mL decrement in 25(OH)D, 5.1% higher IL-6 (95% confidence interval [CI], 3.4-6.9; P < .001); 3.7% higher homocysteine (95% CI, 3.0-4.3; P < .001); 7.0% higher PAI-1 (95% CI, 0.9-13.6; P = .025); and 2.1% higher TFPI (95% CI, 0.0-4.2; P = .047), without racial/ethnic heterogeneity. No significant associations were observed for other hemostatic and inflammatory biomarkers. CONCLUSIONS: Increased inflammation as reflected by higher circulating IL-6 and increased homocysteine concentrations may represent mechanisms linking 25(OH)D deficiency to greater risks of CVD and perhaps venous thromboembolism. Low concentrations of 25(OH)D were also associated with PAI-1 and TFPI concentrations, but not with other hemostatic biomarkers.
CONTEXT: Mechanisms explaining documented associations of 25-hydroxyvitamin D [25(OH)D] deficiency with increased risks of cardiovascular disease (CVD) and venous thromboembolism may relate to adverse hemostatic and inflammatory responses. OBJECTIVE: To evaluate whether 25(OH)D deficiency is associated with a prothrombotic and proinflammatory biological profile. DESIGN: Cross-sectional analyses. SETTING: The Multi-Ethnic Study of Atherosclerosis, a multicenter prospective cohort of American adults. PARTICIPANTS: Up to 6554 adults free of CVD. MAIN OUTCOME MEASURES: Ten hemostatic biomarkers (D-dimer, fibrinogen, factor VIII, plasmin-antiplasmin, and homocysteine [n = 6443]; von Willebrand factor, soluble tissue factor, plasminogen activator inhibitor-1 (PAI-1), total tissue factor pathway inhibitor (TFPI), and soluble thrombomodulin [n = 814]), and three inflammatory biomarkers (IL-6, C-reactive protein [n = 6443], and TNF-α soluble receptor [n = 3802]). RESULTS: Among 6443 subjects (46.6% men; mean age, 62.1 years; mean body mass index, 28.3 kg/m(2)) of White (37.8%), Black (27.2%), Chinese (12.2%), and Hispanic (21.8%) race/ethnicity, mean 25(OH)D was 25.3 ng/mL. After multiple adjustment, 25(OH)D concentrations were associated with concentrations of IL-6 and homocysteine and also with concentrations of PAI-1 and TFPI: per 10 ng/mL decrement in 25(OH)D, 5.1% higher IL-6 (95% confidence interval [CI], 3.4-6.9; P < .001); 3.7% higher homocysteine (95% CI, 3.0-4.3; P < .001); 7.0% higher PAI-1 (95% CI, 0.9-13.6; P = .025); and 2.1% higher TFPI (95% CI, 0.0-4.2; P = .047), without racial/ethnic heterogeneity. No significant associations were observed for other hemostatic and inflammatory biomarkers. CONCLUSIONS: Increased inflammation as reflected by higher circulating IL-6 and increased homocysteine concentrations may represent mechanisms linking 25(OH)D deficiency to greater risks of CVD and perhaps venous thromboembolism. Low concentrations of 25(OH)D were also associated with PAI-1 and TFPI concentrations, but not with other hemostatic biomarkers.
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