Abstract
The chromosomal region 10p13 has been linked to paucibacillary leprosy in two independent studies. The MRC1 gene, encoding the human mannose receptor (MR), is located in the 10p13 region and non-synonymous SNPs in exon 7 of the gene have been suggested as leprosy susceptibility factors. We determined that G396S is the only non-synonymous exon 7-encoded polymorphism in 396 unrelated Vietnamese subjects. This SNP was genotyped in 490 simplex and 90 multiplex leprosy families comprising 704 patients (47% paucibacillary; 53% multibacillary). We observed significant under-transmission of the serine allele of the G396S polymorphism with leprosy per se (P = 0.036) and multibacillary leprosy (P = 0.034). In a sample of 384 Brazilian leprosy cases (51% paucibacillary; 49% multibacillary) and 399 healthy controls, we observed significant association of the glycine allele of the G396S polymorphism with leprosy per se (P = 0.016) and multibacillary leprosy (P = 0.023). In addition, we observed a significant association of exon 7 encoded amino acid haplotypes with leprosy per se (P = 0.012) and multibacillary leprosy (P = 0.004). Next, we tested HEK293 cells over-expressing MR constructs (293-MR) with three exon 7 haplotypes of MRC1 for their ability to bind and internalize ovalbumin and zymosan, two classical MR ligands. No difference in uptake was measured between the variants. In addition, 293-MR failed to bind and internalize viable Mycobacterium leprae and BCG. We propose that the MR–M. leprae interaction is modulated by an accessory host molecule of unknown identity.
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Acknowledgments
We are grateful to all patients and their families who participated in this study. We thank J.L. Casanova, M. Behr and K. Morgan for helpful discussions and A. Montpetit and A. Bélisle for assistance with high-throughput genotyping. Fresh nu/nu mouse derived M. leprae were supplied by Dr. R. Truman and Dr. L. Adams of the National Hansen’s Disease Program Laboratory Research Branch, Baton Rouge, LA. Funding for this service was provided by the American Leprosy Missions. We thank Dr. J.J. He (Indiana University, IN) for providing the MRC1 cDNA. This study was supported by a grant from the Canadian Institutes of Health Research (CIHR) to E.S. and MAGRALEPRE from l’Ordre de Malte to Al.A. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from The Rockefeller University Center for Clinical and Translational Science grant number 5UL1RR024143-03 and The Rockefeller University. An.A. holds a graduate studentship from the Natural Science and Engineering Research Council of Canada (NSERC). Al.A. and L.A. are supported by the Assistance Publique-Hôpitaux de Paris, Programme de Recherche Fondamentale en Microbiologie Maladies Infectieuses et Parasitaires (PRFMMIP), and the Agence Nationale de la Recherche (ANR) of the Ministère Français de l’Éducation Nationale de la Recherche et de la Technologie. E.S. is a Chercheur National du Fonds de la Recherche en Santé du Québec and an International Research Scholar of the Howard Hughes Medical Institute.
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A. Alter, L. de Léséleuc contributed equally to this work.
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Identification of coding SNPs with minor allele frequencies >5% in MRC1 by direct sequencing in 23 unrelated Vietnamese individuals (DOC 36 kb)
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Alter, A., de Léséleuc, L., Van Thuc, N. et al. Genetic and functional analysis of common MRC1 exon 7 polymorphisms in leprosy susceptibility. Hum Genet 127, 337–348 (2010). https://doi.org/10.1007/s00439-009-0775-x
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DOI: https://doi.org/10.1007/s00439-009-0775-x