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Susceptibility to Leprosy is Associated with M-ficolin Polymorphisms.

Abstract
PURPOSE: 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.

More information

Type
Journal Article
Author
Boldt A
Sanchez MIN
Stahlke E
Steffensen R
Thiel S
Jensenius J
Prevedello FC
Mira M
Kun JF J
Messias-Reason LJT

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