The Genetics of Ficolins

Garred, Peter; Honoré, Christian; Jie, Ying; Rørvig, Sara; Cowland, Jack B.; Borregaard, Niels; Hummelshøj, Tina

doi:10.1159/000242419

Cited by 108 publications

(105 citation statements)

References 134 publications

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“…We found variabilities in ficolin-2 binding among the different donors (Fig. 1A), as reported previously (17,18). Interestingly though, we also found striking variabilities in ficolin-2 binding within blood samples from each donor collected in the different tube types.…”

Section: Resultssupporting

confidence: 89%

Blood Collection Tubes Influence Serum Ficolin-1 and Ficolin-2 Levels

Brady¹,

Spencer²,

Falsey³

et al. 2013

Clin. Vaccine Immunol.

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The ficolins are members of a recently discovered family of host innate opsonins that can activate the lectin pathway of complement. The ficolins bind many ligands, although they are typically described as binding acetylated sugars. Ficolin-1 (M-ficolin) and ficolin-2 (L-ficolin) are known to bind Streptococcus pneumoniae serotypes 19C and 11A, respectively. While studying the binding of ficolins to pneumococci, we found variations in ficolin-2 binding among serum samples collected in different types of blood collection tubes. Plastic tubes, which contain a silica clot activator, yielded sera with reduced ficolin-2 binding and apparent ficolin-2 levels. We found that the silica clot activator eluted from plastic red-top tubes inhibited ficolin-2 ligand binding, while other related proteins, like mannose-binding lectin (MBL) and ficolin-1, were not affected. These tube types did not affect the concentrations of other related opsonins (C1q, MBL, or ficolin-3 [H-ficolin]). Interestingly, we also found that ficolin-1 levels were increased 2-to 3-fold in plastic serum separator tubes compared to the increases in other tube types. These findings have implications for future ficolin-1 and ficolin-2 studies, as proper sample collection and handling are essential.

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Section: Resultssupporting

confidence: 89%

Blood Collection Tubes Influence Serum Ficolin-1 and Ficolin-2 Levels

Brady¹,

Spencer²,

Falsey³

et al. 2013

Clin. Vaccine Immunol.

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“…A patient who was homozygous for this mutation had recurrent infections (Munthe-Fog et al, 2009). Along with MASP1 (MASP-1/3 and MAp44 proteins) and MASP2 (MASP-2 and MAp19 proteins), a number of SNPs have been described for FCNs (Garred et al, 2010;Degn et al, 2011). However, the importance of ficolins in general and the genetic variations in FCN genes in particular remain largely unknown.…”

Section: Components Of the Lectin Pathwaymentioning

confidence: 99%

Complement genetics, deficiencies, and disease associations

Mayilyan

2012

Protein Cell

148

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The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

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“…FCN2 and FCN3 contain eight exons, whereas FCN1 has an additional exon in the collagen-like domain encoding four extra Gly-Xaa-Yaa repeats. 2 The ficolin polypeptide chains consist of 299-326 amino acids. Ficolin-1 and -2 are highly homologous molecules (80%), whereas the degree of homology with ficolin-3 is lower (48%).…”

mentioning

confidence: 99%

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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The Genetics of Ficolins

Cited by 108 publications

References 134 publications

Blood Collection Tubes Influence Serum Ficolin-1 and Ficolin-2 Levels

Blood Collection Tubes Influence Serum Ficolin-1 and Ficolin-2 Levels

Complement genetics, deficiencies, and disease associations

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

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