03060nas a2200457   4500000000100000008004100001260001300042653001500055653001000070653003900080653000900119653002200128653004000150653001100190653003800201653001300239653001100252653001200263653001200275653002500287653000900312653001600321653003600337653003000373653001600403100001200419700001600431700001400447700001700461700001200478700001600490700001800506700001100524700001300535700002300548245007400571300001000645490000700655520192600662022001402588       2013                            d  c2013 Jan10aAdolescent10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10agenotype10aHumans10aLectins10aleprosy10aLeprosy, lepromatous10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aPromoter Regions, Genetic10aYoung Adult1 aBoldt A1 aSanchez MIN1 aStahlke E1 aSteffensen R1 aThiel S1 aJensenius J1 aPrevedello FC1 aMira M1 aKun JF J1 aMessias-Reason LJT00aSusceptibility to leprosy is associated with M-ficolin polymorphisms.  a210-90 v333 a<p><b>PURPOSE: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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).</p><p><b>CONCLUSIONS: </b>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.</p>  a1573-2592