The Impact of <i>FCN2</i> Polymorphisms and Haplotypes on the Ficolin‐2 Serum Levels

Munthe-Fog, Lea; Hummelshøj, Tina; Hansen, Bo Moelholm; Koch, Claus; Madsen, Hans O.; Skjødt, Karsten; Garred, Peter

doi:10.1111/j.1365-3083.2007.01915.x

Cited by 152 publications

(168 citation statements)

References 22 publications

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“…[12][13][14] FCN3 is expressed both in the liver and lungs, but the FCN3 expression in the alveolar tissue exceeds the hepatic expression. 11 In accordance, ficolin-3 is found in plasma and bronchoalveolar lavage fluid.…”

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confidence: 99%

“…14,24,25 Briefly, EDTA plasma samples were applied to microtiter wells coated with either anti-ficolin-2 antibody, rabbit-anti-NGAL or rabbitanti-gelatinase, respectively. Following incubation, the wells were washed, and bound ficolin-2, NGAL or gelatinase was detected using biotinylated anti-ficolin-2 antibody, anti-NGAL or anti-gelatinase, respectively, and subsequently with horseradish peroxidase-conjugated streptavidin.…”

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confidence: 99%

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Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation

et al. 2012

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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.

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Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation

et al. 2012

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“…The ficolins are multimeric macromolecules, structurally and functionally related to collectins. Ficolin-1, ficolin-2, and ficolin-3 are found in serum (15)(16)(17), with ficolin-1 being the least abundant (15). Ficolins primarily recognize acetylated compounds via the fibrinogen-like domain, such as N-acetyl-D-glucosamine (GlcNAc) and acetylated BSA (AcBSA) (18,19).…”

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Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Pilely

Rosbjerg

Genster

et al. 2016

The Journal of Immunology

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Cholesterol crystals (CC) play an essential role in the formation of atherosclerotic plaques. CC activate the classical and the alternative complement pathways, but the role of the lectin pathway is unknown. We hypothesized that the pattern recognition molecules (PRMs) from the lectin pathway bind CC and function as an upstream innate inflammatory signal in the pathophysiology of atherosclerosis. We investigated the binding of the PRMs mannose-binding lectin (MBL), ficolin-1, ficolin-2, and ficolin-3, the associated serine proteases, and complement activation products to CC in vitro using recombinant proteins, specific inhibitors, as well as deficient and normal sera. Additionally, we examined the deposition of ficolin-2 and MBL in human carotid plaques by immunohistochemistry and fluorescence microscopy. The results showed that the lectin pathway was activated on CC by binding of ficolin-2 and MBL in vitro, resulting in activation and deposition of complement activation products. MBL bound to CC in a calcium-dependent manner whereas ficolin-2 binding was calcium-independent. No binding was observed for ficolin-1 or ficolin-3. MBL and ficolin-2 were present in human carotid plaques, and binding of MBL to CC was confirmed in vivo by immunohistochemistry, showing localization of MBL around CC clefts. Moreover, we demonstrated that IgM, but not IgG, bound to CC in vitro and that C1q binding was facilitated by IgM. In conclusion, our study demonstrates that PRMs from the lectin pathway recognize CC and provides evidence for an important role for this pathway in the inflammatory response induced by CC in the pathophysiology of atherosclerosis.

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“…Plasma concentrations of mannose‐binding lectin (MBL), ficolin‐1 (FCN1), ficolin‐2 (FCN2), and ficolin‐3 (FCN3) were determined by sandwich enzyme‐linked immunosorbent assays using specific in‐house produced monoclonal antibodies as previously described 21, 22, 23, 24…”

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Acute heart failure following myocardial infarction: complement activation correlates with the severity of heart failure in patients developing cardiogenic shock

et al. 2018

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AimsHeart failure (HF) is an impending complication to myocardial infarction. We hypothesized that the degree of complement activation reflects severity of HF following acute myocardial infarction.Methods and resultsThe LEAF trial (LEvosimendan in Acute heart Failure following myocardial infarction) evaluating 61 patients developing HF within 48 h after percutaneous coronary intervention‐treated ST‐elevation myocardial infarction herein underwent a post hoc analysis. Blood samples were drawn from inclusion to Day 5 and at 42 day follow‐up, and biomarkers were measured with enzyme immunoassays. Regional myocardial contractility was measured by echocardiography as wall motion score index (WMSI). The cardiogenic shock group (n = 9) was compared with the non‐shock group (n = 52). Controls (n = 44) were age‐matched and sex‐matched healthy individuals. C4bc, C3bc, C3bBbP, and sC5b‐9 were elevated in patients at inclusion compared with controls (P < 0.01). The shock group had higher levels compared with the non‐shock group for all activation products except C3bBbP (P < 0.05). At Day 42, all products were higher in the shock group (P < 0.05). In the shock group, sC5b‐9 correlated significantly with WMSI at baseline (r = 0.68; P = 0.045) and at Day 42 (r = 0.84; P = 0.036). Peak sC5b‐9 level correlated strongly with WMSI at Day 42 (r = 0.98; P = 0.005). Circulating endothelial cell activation markers sICAM‐1 and sVCAM‐1 were higher in the shock group during the acute phase (P < 0.01), and their peak levels correlated with sC5b‐9 peak level in the whole HF population (r = 0.32; P = 0.014 and r = 0.30; P = 0.022, respectively).ConclusionsComplement activation discriminated cardiogenic shock from non‐shock in acute ST‐elevation myocardial infarction complicated by HF and correlated with regional contractility and endothelial cell activation, suggesting a pathogenic role of complement in this condition.

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The Impact of FCN2 Polymorphisms and Haplotypes on the Ficolin‐2 Serum Levels

Cited by 152 publications

References 22 publications

Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation

Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Acute heart failure following myocardial infarction: complement activation correlates with the severity of heart failure in patients developing cardiogenic shock

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