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.
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Acknowledgments
The subjects of this investigation were informed about the aims of the study and their consent to participate is gratefully acknowledged. We are also thankful to the medical staff of the Hospital de Clínicas of the Federal University of Paraná and of the Sanitary and Dermatologic Hospital of Paraná for patient recruitment, to the staff of the Laboratório de Imunopatologia Molecular in Curitiba and of the Department of Clinical Immunology in Aalborg for assistance in the DNA extraction, to Rubia Zem, Andressa Chequin, Bianca Oliveira and Caroline Grisbach for valuable help in the FCN1 genotyping. We are grateful to Andrea Weierich and Viola Galinat from Tübingen for DNA sequencing, as well as for the excellent technical assistance from Annette Hansen, Louise Jakobsen and Lisbeth Jensen in Aarhus. This work was supported by a PRODOC grant of CAPES (Coordenação de Aperfeiçoamento de Pessoal Superior) and by CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil) grants for ABW Boldt and IJT Messias-Reason, as well as by a grant of the Bundesministerium für Bildung und Forschung (BMBF) for JFJ Kun and of the Danish Research Council and Novo Nordic Foundation for S Thiel and JC Jensenius.
Conflict of interest
Dr. Thiel and Dr. Jensenius have financial interest in NatImmune A/S, a biotech company exploring the possibilities of therapy with proteins of the innate immune system. Dr. Boldt, Ms. Neves Sanchez, Dr. Steffensen, Dr. Mira, Dr. Stahlke and Dr. Messias-Reason declare no potential conflict of interest.
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In memorian (28.04.2011). We miss Prof. Jürgen F. J. Kun as a wonderful friend and excellent scientist.
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Boldt, A.B.W., Sanchez, M.I.N., Stahlke, E.R.S. et al. Susceptibility to Leprosy is Associated with M-ficolin Polymorphisms. J Clin Immunol 33, 210–219 (2013). https://doi.org/10.1007/s10875-012-9770-4
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DOI: https://doi.org/10.1007/s10875-012-9770-4