title: Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.
abstract: BACKGROUND
  The innate immune system encompasses various recognition molecules able to sense both exogenous and endogenous danger signals arising from pathogens or damaged host cells. One such pattern-recognition molecule is M-ficolin, which is capable of activating the complement system through the lectin pathway. The lectin pathway is multifaceted with activities spanning from complement activation to coagulation, autoimmunity, ischemia-reperfusion injury and embryogenesis. Our aim was to explore associations between SNPs in FCN1, encoding M-ficolin and corresponding protein concentrations, and the impact of non-synonymous SNPs on protein function.
  
  
  RESULTS
  We genotyped 26 polymorphisms in the FCN1 gene and found 8 of these to be associated with M-ficolin levels in a cohort of 346 blood donors. Four of those polymorphisms were located in the promoter region and exon 1 and were in high linkage disequilibrium (r(2)≥0.91). The most significant of those were the AA genotype of -144C>A (rs10117466), which was associated with an increase in M-ficolin concentration of 26% compared to the CC genotype. We created recombinant proteins corresponding to the five non-synonymous mutations encountered and found that the Ser268Pro (rs150625869) mutation lead to loss of M-ficolin production. This was backed up by clinical observations, indicating that an individual homozygote of Ser268Pro would be completely M-ficolin deficient. Furthermore, the Ala218Thr (rs148649884) and Asn289Ser (rs138055828) were both associated with low M-ficolin levels, and the mutations crippled the ligand-binding capability of the recombinant M-ficolin, as indicated by the low binding to Group B Streptococcus.
  
  
  CONCLUSIONS
  Overall, our study interlinks the genotype and phenotype relationship concerning polymorphisms in FCN1 and corresponding concentrations and biological functions of M-ficolin. The elucidations of these associations provide information for future genetic studies in the lectin pathway and complement system.
authors.affiliation: Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark. c.ammitz@gmail.com
authors.forename: Christian Gytz
authors.initials: CG
authors.lastname: Ammitzbøll
authors.forename: Troels Rønn
authors.initials: TR
authors.lastname: Kjær
authors.forename: Rudi
authors.initials: R
authors.lastname: Steffensen
authors.forename: Kristian
authors.initials: K
authors.lastname: Stengaard-Pedersen
authors.forename: Hans Jørgen
authors.initials: HJ
authors.lastname: Nielsen
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.forename: Martin
authors.initials: M
authors.lastname: Bøgsted
authors.forename: Jens Christian
authors.initials: JC
authors.lastname: Jensenius
mesh_terms: D000367:Age Factors; D005260:Female; D005838:Genotype; D006801:Humans; D037102:Lectins / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D012737:Sex Factors; D000097604:Ficolins
chemical_list: D037102:Lectins; D000097604:Ficolins