title: Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunction and Intima-Media Thickness: The Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) Study.
abstract: Previous studies suggested that the lectin-complement pathway plays a complex role in cardiovascular disease (CVD). To date, no prospective human studies have investigated the relationship between the initiating factor of the lectin pathway, that is, mannose-binding lectin (MBL), and low-grade inflammation, endothelial dysfunction, or carotid intima-media thickness (cIMT). Moreover, MBL-associated proteases (MASPs) and MBL-associated proteins (MAps), which mediate downstream complement activation, have not been studied in the development of CVD.
  
  
  
  In a prospective cohort (n=574; age 60±7 years; 7-year follow-up), we investigated longitudinal associations of plasma MBL, MASP-1, MASP-2, MASP-3, and MAp44 with biomarker scores that reflect low-grade inflammation and endothelial dysfunction, respectively, and with cIMT. We also investigated their associations with incident CVD (n=73). In adjusted analyses, low-grade inflammation was lowest in the middle tertile (TMiddle) of MBL, that is, TMiddle was 0.19 SD (0.03 to 0.34) lower than TLow, and 0.15 SD (-0.02 to 0.31) lower than THigh. cIMT was 28 μm (-50 to -5) lower in the highest MBL tertile (THigh) than in TMiddle and did not differ between TLow and TMiddle. MBL was not associated with endothelial dysfunction or CVD. MASP-1 and MASP-2 were not associated with any cardiovascular outcomes. MASP-3 and MAp44 were, independently of MBL levels, associated with endothelial dysfunction (per 1 SD higher MASP-3: β=0.10 SD [0.02 to 0.18]; per 1 SD higher MAp44 β=0.12 SD [0.04 to 0.20]) but not with low-grade inflammation, cIMT, or CVD.
  
  
  
  High MBL may contribute to low cIMT, whereas the association of MBL with low-grade inflammation was nonlinear. MASP-1 and MASP-2 were not associated with adverse cardiovascular outcomes. MASP-3 and MAp44 may play a role in endothelial dysfunction, potentially independent of lectin-pathway activation.
authors.affiliation: From the Department of Internal Medicine (E.H., C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G.), CARIM School for Cardiovascular Diseases (EH, C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G., I.C.W.A.), Department of Epidemiology, School for Public Health and Primary Care (CAPHRI) (I.C.W.A.), Maastricht University Medical Centre, Maastricht, The Netherlands; Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands (E.J.M.F.); and Department of Biomedicine, Aarhus University, Aarhus, Denmark (I.T.H.-P., S.T.). e.hertle@maastrichtuniversity.nl.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hertle
authors.affiliation: From the Department of Internal Medicine (E.H., C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G.), CARIM School for Cardiovascular Diseases (EH, C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G., I.C.W.A.), Department of Epidemiology, School for Public Health and Primary Care (CAPHRI) (I.C.W.A.), Maastricht University Medical Centre, Maastricht, The Netherlands; Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands (E.J.M.F.); and Department of Biomedicine, Aarhus University, Aarhus, Denmark (I.T.H.-P., S.T.).
authors.forename: Ilja C W
authors.initials: IC
authors.lastname: Arts
authors.affiliation: From the Department of Internal Medicine (E.H., C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G.), CARIM School for Cardiovascular Diseases (EH, C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G., I.C.W.A.), Department of Epidemiology, School for Public Health and Primary Care (CAPHRI) (I.C.W.A.), Maastricht University Medical Centre, Maastricht, The Netherlands; Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands (E.J.M.F.); and Department of Biomedicine, Aarhus University, Aarhus, Denmark (I.T.H.-P., S.T.).
authors.forename: Carla J H
authors.initials: CJ
authors.lastname: van der Kallen
authors.affiliation: From the Department of Internal Medicine (E.H., C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G.), CARIM School for Cardiovascular Diseases (EH, C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G., I.C.W.A.), Department of Epidemiology, School for Public Health and Primary Care (CAPHRI) (I.C.W.A.), Maastricht University Medical Centre, Maastricht, The Netherlands; Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands (E.J.M.F.); and Department of Biomedicine, Aarhus University, Aarhus, Denmark (I.T.H.-P., S.T.).
authors.forename: Edith J M
authors.initials: EJ
authors.lastname: Feskens
authors.affiliation: From the Department of Internal Medicine (E.H., C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G.), CARIM School for Cardiovascular Diseases (EH, C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G., I.C.W.A.), Department of Epidemiology, School for Public Health and Primary Care (CAPHRI) (I.C.W.A.), Maastricht University Medical Centre, Maastricht, The Netherlands; Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands (E.J.M.F.); and Department of Biomedicine, Aarhus University, Aarhus, Denmark (I.T.H.-P., S.T.).
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.affiliation: From the Department of Internal Medicine (E.H., C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G.), CARIM School for Cardiovascular Diseases (EH, C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G., I.C.W.A.), Department of Epidemiology, School for Public Health and Primary Care (CAPHRI) (I.C.W.A.), Maastricht University Medical Centre, Maastricht, The Netherlands; Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands (E.J.M.F.); and Department of Biomedicine, Aarhus University, Aarhus, Denmark (I.T.H.-P., S.T.).
authors.forename: Ingeborg T
authors.initials: IT
authors.lastname: Hoffmann-Petersen
authors.affiliation: From the Department of Internal Medicine (E.H., C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G.), CARIM School for Cardiovascular Diseases (EH, C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G., I.C.W.A.), Department of Epidemiology, School for Public Health and Primary Care (CAPHRI) (I.C.W.A.), Maastricht University Medical Centre, Maastricht, The Netherlands; Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands (E.J.M.F.); and Department of Biomedicine, Aarhus University, Aarhus, Denmark (I.T.H.-P., S.T.).
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.affiliation: From the Department of Internal Medicine (E.H., C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G.), CARIM School for Cardiovascular Diseases (EH, C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G., I.C.W.A.), Department of Epidemiology, School for Public Health and Primary Care (CAPHRI) (I.C.W.A.), Maastricht University Medical Centre, Maastricht, The Netherlands; Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands (E.J.M.F.); and Department of Biomedicine, Aarhus University, Aarhus, Denmark (I.T.H.-P., S.T.).
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
authors.affiliation: From the Department of Internal Medicine (E.H., C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G.), CARIM School for Cardiovascular Diseases (EH, C.J.H.v.d.K., C.G.S., C.D.A.S., M.M.J.v.G., I.C.W.A.), Department of Epidemiology, School for Public Health and Primary Care (CAPHRI) (I.C.W.A.), Maastricht University Medical Centre, Maastricht, The Netherlands; Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands (E.J.M.F.); and Department of Biomedicine, Aarhus University, Aarhus, Denmark (I.T.H.-P., S.T.).
authors.forename: Marleen M J
authors.initials: MM
authors.lastname: van Greevenbroek
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002339:Carotid Arteries / Q000000981:diagnostic imaging* / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000097:blood* / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000503:physiopathology; D059168:Carotid Intima-Media Thickness; D003920:Diabetes Mellitus / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005838:Genotype; D006801:Humans; D015994:Incidence; D007249:Inflammation / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D037601:Mannose-Binding Lectin / Q000097:blood* / Q000235:genetics; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000032:analysis*; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D017711:Nonlinear Dynamics; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
chemical_list: D015415:Biomarkers; D037601:Mannose-Binding Lectin; C084067:MASP1 protein, human; C105296:MASP2 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases
keywords: carotid intima; complement system proteins; inflammation; lectin-complement pathway; media thickness