Laura Pletsch-Borba1, Mirja Grafetstätter1, Anika Hüsing1, Theron Johnson1, Sandra González Maldonado1, Marie-Luise Groß1, Manja Kloss1, Michael Hoffmeister1, Peter Bugert1, Rudolf Kaaks1, Tilman Kühn2. 1. From the Divisions of Cancer Epidemiology (L.P.-B., M.G., A.H., M.-L.G., T.J., S.G.M., R.K., T.K.) and Clinical Epidemiology and Aging Research (M.H.), German Cancer Research Center (DKFZ), Heidelberg; Medical Faculty (L.P.-B., M.G.), Heidelberg University; Department of Preventive Oncology (M.-L.G.), National Center for Tumor Diseases, Heidelberg; Department of Neurology (M.K.), Heidelberg University; Institute of Transfusion Medicine and Immunology (P.B.), Medical Faculty Mannheim, Heidelberg University; and German Red Cross Blood Service Baden-Württemberg-Hessen (P.B.), Mannheim, Germany. 2. From the Divisions of Cancer Epidemiology (L.P.-B., M.G., A.H., M.-L.G., T.J., S.G.M., R.K., T.K.) and Clinical Epidemiology and Aging Research (M.H.), German Cancer Research Center (DKFZ), Heidelberg; Medical Faculty (L.P.-B., M.G.), Heidelberg University; Department of Preventive Oncology (M.-L.G.), National Center for Tumor Diseases, Heidelberg; Department of Neurology (M.K.), Heidelberg University; Institute of Transfusion Medicine and Immunology (P.B.), Medical Faculty Mannheim, Heidelberg University; and German Red Cross Blood Service Baden-Württemberg-Hessen (P.B.), Mannheim, Germany. t.kuehn@dkfz.de.
Abstract
OBJECTIVE: Because little is known about associations between biomarkers of vascular injury and stroke risk, we evaluated associations between plasma concentrations of 6 novel biomarkers of vascular injury and stroke risk in a population-based study. METHODS: A case-cohort subset of EPIC-Heidelberg (European Prospective Investigation for Cancer and Nutrition-Heidelberg) including incident stroke cases (n = 335) and a random subcohort (n = 2,418) was selected. Concentrations of intercellular adhesion molecule 3 (ICAM3), soluble E-selectin and P-selectin, soluble thrombomodulin (sTM), thrombopoietin, and glycoprotein IIb/IIIa were measured in baseline plasma samples. Weighted Cox regression analyses were used to assess associations between biomarker levels and stroke risk. RESULTS: Median follow-up in the subcohort and among cases was 9.8 (range, 0.1-12.5) years and 6.2 (range, 0.01-12.1) years, respectively. ICAM3 levels were associated with increased risk of incident stroke after multivariable adjustment (hazard ratio, highest vs lowest quartile: 1.64 [95% confidence interval, 1.15-2.32]; p linear trend < 0.001). This association was more apparent for ischemic (1.65 [1.12-2.45]; p linear trend < 0.01) than for hemorrhagic stroke (1.29 [0.60-2.78]; p linear trend = 0.3). We further observed a borderline significant trend for a positive association between sTM and overall stroke risk (1.47 [0.99-2.19]; p linear trend = 0.05). CONCLUSIONS: In this population-based study, circulating levels of ICAM3, an adhesion molecule shed by leukocytes, were associated with increased risk of incident stroke. Further mechanistic studies are needed to elucidate the pathophysiology underlying this association. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma levels of ICAM3 are associated with increased stroke risk.
OBJECTIVE: Because little is known about associations between biomarkers of vascular injury and stroke risk, we evaluated associations between plasma concentrations of 6 novel biomarkers of vascular injury and stroke risk in a population-based study. METHODS: A case-cohort subset of EPIC-Heidelberg (European Prospective Investigation for Cancer and Nutrition-Heidelberg) including incident stroke cases (n = 335) and a random subcohort (n = 2,418) was selected. Concentrations of intercellular adhesion molecule 3 (ICAM3), soluble E-selectin and P-selectin, soluble thrombomodulin (sTM), thrombopoietin, and glycoprotein IIb/IIIa were measured in baseline plasma samples. Weighted Cox regression analyses were used to assess associations between biomarker levels and stroke risk. RESULTS: Median follow-up in the subcohort and among cases was 9.8 (range, 0.1-12.5) years and 6.2 (range, 0.01-12.1) years, respectively. ICAM3 levels were associated with increased risk of incident stroke after multivariable adjustment (hazard ratio, highest vs lowest quartile: 1.64 [95% confidence interval, 1.15-2.32]; p linear trend < 0.001). This association was more apparent for ischemic (1.65 [1.12-2.45]; p linear trend < 0.01) than for hemorrhagic stroke (1.29 [0.60-2.78]; p linear trend = 0.3). We further observed a borderline significant trend for a positive association between sTM and overall stroke risk (1.47 [0.99-2.19]; p linear trend = 0.05). CONCLUSIONS: In this population-based study, circulating levels of ICAM3, an adhesion molecule shed by leukocytes, were associated with increased risk of incident stroke. Further mechanistic studies are needed to elucidate the pathophysiology underlying this association. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma levels of ICAM3 are associated with increased stroke risk.