Aino Salminen1, Efthymia Vlachopoulou2, Aki S Havulinna2, Taina Tervahartiala2, Wolfgang Sattler2, Marja-Liisa Lokki2, Markku S Nieminen2, Markus Perola2, Veikko Salomaa2, Juha Sinisalo2, Seppo Meri2, Timo Sorsa2, Pirkko J Pussinen2. 1. From the Department of Oral and Maxillofacial Diseases (A.S., T.T., T.S., P.J.P.), Transplantation Laboratory, Medicum (E.V., M.-L.L.), Institute for Molecular Medicine Finland (M.P.), Immunobiology Research Program, Research Programs Unit (S.M.), and Department of Bacteriology and Immunology, Haartman Institute (S.M.), University of Helsinki, Finland; Department of Oral and Maxillofacial Diseases, Helsinki University Hospital, Finland (A.S., T.T., T.S., P.J.P.); Division of Periodontology, Department of Dental Medicine, Karolinska Institute, Huddinge, Sweden (A.S., T.S.); Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., M.P., V.S.); Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria (W.S.); and Division of Cardiology, HUCH Heart and Lung Center, Helsinki University Hospital, Finland (M.S.N., J.S.). aino.m.salminen@helsinki.fi. 2. From the Department of Oral and Maxillofacial Diseases (A.S., T.T., T.S., P.J.P.), Transplantation Laboratory, Medicum (E.V., M.-L.L.), Institute for Molecular Medicine Finland (M.P.), Immunobiology Research Program, Research Programs Unit (S.M.), and Department of Bacteriology and Immunology, Haartman Institute (S.M.), University of Helsinki, Finland; Department of Oral and Maxillofacial Diseases, Helsinki University Hospital, Finland (A.S., T.T., T.S., P.J.P.); Division of Periodontology, Department of Dental Medicine, Karolinska Institute, Huddinge, Sweden (A.S., T.S.); Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., M.P., V.S.); Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria (W.S.); and Division of Cardiology, HUCH Heart and Lung Center, Helsinki University Hospital, Finland (M.S.N., J.S.).
Abstract
BACKGROUND: Matrix metalloproteinase 8 (MMP-8) is a proinflammatory enzyme expressed mainly by neutrophils. Elevated serum and plasma concentrations of MMP-8 are associated with the risk for and outcome of cardiovascular diseases (CVDs). The origin of circulating MMP-8 is not completely clear. METHODS AND RESULTS: We performed a genome-wide association study of serum MMP-8 levels in 2 populations comprising altogether 6049 individuals. Moreover, we studied whether MMP-8-associated variants are linked to increased risk of CVDs and overall mortality in >20 000 subjects. The strongest association with serum MMP-8 was found in locus 1q31.3, containing the gene for complement factor H (lead single nucleotide polymorphism: rs800292; P=2.4×10-35). In functional experiments, activation of the alternative pathway of complement in the carriers of rs800292 minor allele (Ile62 in factor H) led to decreased release of MMP-8 from neutrophils compared with the major allele (Val62 in factor H). Another association was detected in 1q21.3, containing genes S100A8, S100A9, and S100A12 (strongest association: rs1560833; P=5.3×10-15). The minor allele of rs1560833 was inversely associated with CVD (odds ratio [95% confidence interval]: 0.90 [0.82-0.99]; P=0.032) and the time to incident CVD event (hazard ratio [95% confidence interval]: 0.91 [0.84-0.99]; P=0.032) in men but not in women. CONCLUSIONS: According to our results, the activation of the alternative pathway of the complement system strongly contributes to serum MMP-8 concentration. Genetic polymorphism in S100A9-S100A12-S100A8 locus affects serum and plasma MMP-8 and shows a suggestive association with the risk of CVDs. Our results show that genetic variation determines a significant portion of circulating MMP-8 concentrations.
BACKGROUND:Matrix metalloproteinase 8 (MMP-8) is a proinflammatory enzyme expressed mainly by neutrophils. Elevated serum and plasma concentrations of MMP-8 are associated with the risk for and outcome of cardiovascular diseases (CVDs). The origin of circulating MMP-8 is not completely clear. METHODS AND RESULTS: We performed a genome-wide association study of serum MMP-8 levels in 2 populations comprising altogether 6049 individuals. Moreover, we studied whether MMP-8-associated variants are linked to increased risk of CVDs and overall mortality in >20 000 subjects. The strongest association with serum MMP-8 was found in locus 1q31.3, containing the gene for complement factor H (lead single nucleotide polymorphism: rs800292; P=2.4×10-35). In functional experiments, activation of the alternative pathway of complement in the carriers of rs800292 minor allele (Ile62 in factor H) led to decreased release of MMP-8 from neutrophils compared with the major allele (Val62 in factor H). Another association was detected in 1q21.3, containing genes S100A8, S100A9, and S100A12 (strongest association: rs1560833; P=5.3×10-15). The minor allele of rs1560833 was inversely associated with CVD (odds ratio [95% confidence interval]: 0.90 [0.82-0.99]; P=0.032) and the time to incident CVD event (hazard ratio [95% confidence interval]: 0.91 [0.84-0.99]; P=0.032) in men but not in women. CONCLUSIONS: According to our results, the activation of the alternative pathway of the complement system strongly contributes to serum MMP-8 concentration. Genetic polymorphism in S100A9-S100A12-S100A8 locus affects serum and plasma MMP-8 and shows a suggestive association with the risk of CVDs. Our results show that genetic variation determines a significant portion of circulating MMP-8 concentrations.
Authors: Elena A Goncharova; Tatiana V Kudryashova; Giovanni Maroli; Soni S Pullamsetti Journal: Am J Respir Crit Care Med Date: 2021-12-15 Impact factor: 21.405
Authors: Sivan Livson; Seppo Virtanen; A Inkeri Lokki; Tiina Holster; Leena Rahkonen; Ilkka Kalliala; Pekka Nieminen; Anne Salonen; Seppo Meri Journal: Front Immunol Date: 2022-07-25 Impact factor: 8.786