title: Susceptibility to leprosy is associated with M-ficolin polymorphisms.
abstract: OBJECTIVE
  Mycobacterium leprae exploits complement activation and opsonophagocytosis to infect phagocytes. M-ficolin is encoded by the FCN1 gene and initiates the lectin pathway on monocyte surfaces. We investigated FCN1 promoter polymorphisms that could be responsible for the high interindividual variability of M-ficolin levels and for modulating leprosy susceptibility.
  
  
  METHODS
  We genotyped rs2989727 (-1981 G > A), rs28909068 (-791 G > A), rs10120023 (-542 G > A), rs17039495 (-399 G > A), rs28909976 (-271IndelT), rs10117466 (-144C > A) and rs10858293 (+33 T > G) in 400 controls and 315 leprosy patients from Southern Brazil, and in 296 Danish healthy individuals with known M-ficolin levels.
  
  
  RESULTS
  Ten haplotypes were identified with sequence-specific PCR and/or haplotype-specific sequencing. We found evidence for a protective codominant additive effect of FCN1*-542A-144C with leprosy in Euro-Brazilians (P=0.003, PBf =0.021, OR=0.243 [CI95% =0.083-0.71]), which was independent of age, ethnic group and gender effects (P=0.029). There was a trend for a positive association of the -399A variant in Afro-Brazilians (P=0.022, PBf =0.154, OR=4.151 [CI95% =1.115-15.454], as well as for a negative association of the FCN1*3A haplotype with lepromatous leprosy, compared with less severe forms of the disease (P=0.016, PBf =0.112, OR=0.324 [CI95% =0.123-0.858]). Danish individuals with this haplotype presented M-ficolin levels higher than the population average of circa 1,000 ng/ml, and -542A-144C, which is able to modify the recognition of transcription factors in silico, occurred in individuals with levels under the 25 percentil (P=0.031).
  
  
  CONCLUSIONS
  Our data provide the first evidence that FCN1 polymorphisms are associated with leprosy. M-ficolin may represent a novel key to understand the immunopathogenesis of M. leprae infection.
authors.affiliation: Laboratório de Imunopatologia Molecular - Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil.
authors.forename: Angelica B W
authors.initials: AB
authors.lastname: Boldt
authors.forename: Maria Iolanda N
authors.initials: MI
authors.lastname: Sanchez
authors.forename: Ewalda R S
authors.initials: ER
authors.lastname: Stahlke
authors.forename: Rudi
authors.initials: R
authors.lastname: Steffensen
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.forename: Jens C
authors.initials: JC
authors.lastname: Jensenius
authors.forename: Flávia Costa
authors.initials: FC
authors.lastname: Prevedello
authors.forename: Marcelo Távora
authors.initials: MT
authors.lastname: Mira
authors.forename: Jürgen F J
authors.initials: JF
authors.lastname: Kun
authors.forename: Iara J T
authors.initials: IJ
authors.lastname: Messias-Reason
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044383:Black People; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D037102:Lectins / Q000235:genetics*; D007918:Leprosy / Q000208:ethnology / Q000235:genetics* / Q000276:immunology*; D015440:Leprosy, Lepromatous / Q000208:ethnology / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D044465:White People; D055815:Young Adult; D000097604:Ficolins
chemical_list: D037102:Lectins; D000097604:Ficolins