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Variation in FCN1 Affects Biosynthesis of Ficolin-1 and Is Associated With

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Variation in FCN1 Affects Biosynthesis of Ficolin-1 and Is Associated With Genes and Immunity (2012) 13, 515–522 & 2012 Macmillan Publishers Limited All rights reserved 1466-4879/12 www.nature.com/gene ORIGINAL ARTICLE Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation L Munthe-Fog1, T Hummelshoj1, C Honore´ 1, ME Moller1, MO Skjoedt1, I Palsgaard1, N Borregaard2, HO Madsen1 and P Garred1 Ficolin-1 is a recognition molecule of the lectin complement pathway. The ficolin-1 gene FCN1 is polymorphic, but the functional and clinical consequences are unknown.The concentration of ficolin-1 in plasma and FCN1 polymorphisms in positions À 1981 (rs2989727), À 791 (rs28909068), À 542 (rs10120023), À 271 (rs28909976), À 144 (rs10117466) and þ 7918 (rs1071583) were determined in 100 healthy individuals. FCN1 expression by isolated monocytes and granulocytes and ficolin-1 levels in monocyte culture supernatants were assessed in 21 FCN1-genotyped individuals. FCN1 polymorphisms were determined in a cohort of 251 patients with systemic inflammation. High ficolin-1 plasma levels were significantly associated with the minor alleles in position À 542 and À 144. These alleles were also significantly associated with high FCN1 mRNA expression. The level of ficolin-1 in culture supernatants was significantly higher in individuals homozygous for the minor alleles at positions À 542 and À 144. Homozygosity for these alleles was significantly associated with fatal outcome in patients with systemic inflammation. None of the other investigated polymorphisms were associated with FCN1 and ficolin-1 expression, concentration or disease outcome. Functional polymorphic sites in the promoter region of FCN1 regulate both the expression and synthesis of ficolin-1 and are associated with outcome in severe inflammation. Genes and Immunity (2012) 13, 515–522; doi:10.1038/gene.2012.27; published online 7 June 2012 Keywords: Ficolin-1; FCN1; complement lectin pathway; monocyte; inflammation; innate immunity INTRODUCTION responsible for ligand recognition.3–5 Although the ficolins share An emerging role of the ficolins in innate immune defence has a common preference for acetylated compounds, each ficolin recently been appreciated.1 Three ficolins, ficolin-1, -2 and -3 (also displays distinct ligand specificities. Ficolin-2 binds to a wide range known as M-, L- and H-ficolin) have been identified in humans. of pathogens, such as bacteria, fungi and viruses, whereas only a 1 These are encoded by the FCN1, FCN2 and FCN3 genes, few bacterial ligands have been identified for ficolin-3. Both 6–8 respectively. Polymorphisms in the FCN2 and FCN3 genes are ficolin-2 and -3 have been shown to bind to apoptotic cells. 9 known to influence synthesis, function and structure of the Ficolin-1 has a preference for sialic acid and binds to sialic- corresponding proteins and disease associations have been acid-containing structures present on living monocytes and 10 described, but the influence of FCN1 polymorphisms are largely granulocytes. unknown.2 A highly conserved cysteine residue in the collagen-like domain FCN1 and FCN2 are genes located on chromosome 9 and FCN3 enables all three ficolins to form complexes with the mannose- is sequestered on chromosome 1. All the three FCN genes have a binding lectin/ficolin-associated serine proteases named MASPs similar locus organization encoding a short N-terminal cysteine and hence to activate the complement cascade through the lectin region, followed by a collagen-like domain and a linker region, pathway.1 However, the potential to activate complement differs which is further connected to a C-terminal fibrinogen-like domain. among the ficolins, ficolin-3 being the most potent, ficolin-2 FCN2 and FCN3 contain eight exons, whereas FCN1 has an intermediate and ficolin-1 displaying least complement activation additional exon in the collagen-like domain encoding four extra potential.11 Gly–Xaa–Yaa repeats.2 The ficolin polypeptide chains consist of Each FCN gene exhibits a unique expression profile.11 FCN2 299–326 amino acids. Ficolin-1 and -2 are highly homologous expression is limited to hepatocytes and is secreted to the blood molecules (80%), whereas the degree of homology with ficolin-3 is stream.12–14 FCN3 is expressed both in the liver and lungs, but the lower (48%). The similar locus organization of the FCN genes is FCN3 expression in the alveolar tissue exceeds the hepatic reflected in the structure of the corresponding proteins. The expression.11 In accordance, ficolin-3 is found in plasma and proteins are assembled from 4–6 subunits, each subunit consisting bronchoalveolar lavage fluid.15 Lower FCN3 expression is found in of three identical polypeptides. Disulfide bonding further heart, kidney, spleen, pancreas and placenta.11 assembles these subunits into the characteristic higher FCN1 is predominantly expressed by cells derived from the oligomeric forms that resemble a bouquet.3 The C-terminal end myeloid lineage in the bone marrow and is found in the peripheral of the molecule, the globular fibrinogen-like domain, is circulation in monocytes and granulocytes, but not in cells of 1Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health Sciences, University Hospital of Copenhagen, Copenhagen, Denmark and 2The Granulocyte Research Laboratory, Department of Haematology, Rigshospitalet, Faculty of Health Sciences, University Hospital of Copenhagen, Copenhagen, Denmark. Correspondence: Dr P Garred, Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health Sciences, University Hospital of Copenhagen, 2100 Copenhagen, Denmark. Email: [email protected] Received 31 January 2012; revised 12 April 2012; accepted 4 May 2012; published online 7 June 2012 FCN1 expression and disease L Munthe-Fog et al 516 lymphoid origin.16–19 In addition, ficolin-1 may be expressed in the lungs.20 Both neutrophils and monocytes secrete ficolin-1 to the surroundings where it may have a role in local immune defence.10,17,18,21 The FCN1 gene is well conserved between invertebrates, mouse and human, suggesting crucial and fundamental roles of ficolin-1.2,22 Several polymorphisms have been described both in the promoter and coding region when the FCN1 gene has been thoroughly sequenced.13,23 To date, no or only limited information exists whether variations in FCN1 influence the expression, the synthesis or plasma level of ficolin-1 and whether such may be of clinical importance. We therefore wanted to determine the genetic impact of the FCN1 polymorphisms described in Caucasians on the FCN1 gene expression, ficolin-1 synthesis and Figure 1. Serial dilution of EDTA plasma (–) and EDTA plasma plasma level of ficolin-1. Furthermore, based on the putative role depleted for ficolin-2 (---) analyzed by ficolin-2 ELISA (a) and ficolin-1 ELISA (b). As ficolin-2 was removed from plasma, as shown in panel of ficolin-1 in host defence and inflammation, we hypothesized a, no difference in the ficolin-1 signal was observed (b). Hence, that functional FCN1 variant alleles may have an impact on ficolin-2 did not contribute to the obtained optical density values in outcome in patients with systemic inflammatory response the ficolin-1 ELISA. syndrome (SIRS) and sepsis. RESULTS Establishing a ficolin-1-specific enzyme-linked immunosorbent assay (ELISA) The specificity of the ficolin-1 ELISA was assessed by determining the ficolin-1 level in EDTA plasma samples before and after the removal of ficolin-2. No reduction was observed in the optical density values obtained in the ficolin-1 ELISAs (Figure 1). Similarly, adding recombinant ficolin (rficolin)-2 to the depleted plasma samples did not change the read-out of the ficolin-1 ELISA. Thus, the ficolin-1 ELISA demonstrated no cross-reactivity with ficolin-2. Figure 2. Ficolin-1 EDTA plasma levels in 100 Danish blood donors. The concentration ranged 0.01–1.89 mgmlÀ 1 with a median À 1 Plasma levels of ficolin-1 concentration of 0.30 mgml . The concentration of ficolin-1 ranged 0.01–1.89 mgmlÀ 1 with a median concentration of 0.3 mgmlÀ 1 determined in 100 Danish blood donors (Figure 2). No correlation was observed with gender, À 271 (rs28909976), À 144 (rs10117466) and þ 7918 (rs1071583) age or with the levels of ficolin-2 (data not shown). It has been (Table 1). All the polymorphisms adhered to the Hardy–Weinberg expectations and the allele frequencies obtained were in good shown that neutrophils might be the primary source of ficolin-1 13,23 in the blood,21 thus we determined the level of neutrophil agreement with the allele frequencies observed before. As gelatinase-associated lipocalin (NGAL) and gelatinase, which previously reported, the promoter polymorphism at position 24,25 À 1981 and the polymorphism in position þ 7918 in exon 9 were reflects the pool of circulating neutrophils. No correlation 2 26 was observed with either NGAL or gelatinase (data not shown). near complete linkage disequilibrium (r ¼ 0.98, Po0.0001); the major allele from both polymorphisms segregated together in all individuals apart from one (Figure 3). Further, linkage disequili- Validation of the ficolin-1 plasma concentration brium, although to a lesser degree (r2 ¼ 0.71, Po0.001), was To ensure the validity of the newly established ficolin-1 ELISA, the observed for À 542 with À 144. Linkage disequilibrium between ficolin-1 concentration was determined in plasma samples from 21 any of the other polymorphisms was not observed. additional donors and the levels were compared with the concentrations obtained with a commercially available ficolin-1 ELISA kit (E90786Hu; Uscn Life Science Inc, Whhan, China). The FCN1 variation associated with the ficolin-1 plasma level median ficolin-1 concentration observed with the newly estab- We investigated the association of the FCN1 polymorphisms with lished ELISA in the 21 additional donors was 0.37 mgmlÀ 1 the ficolin-1 plasma concentration in the 100 blood donors.
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