Abstract
Leprosy is caused by infection with Mycobacterium leprae and is classified clinically into paucibacillary (PB) or multibacillary (MB) subtypes based on the number of skin lesions and the bacillary index detected in skin smears. We previously identified a major PB susceptibility locus on chromosome region 10p13 in Vietnamese families by linkage analysis. In the current study, we conducted high-density association mapping of the 9.5 Mb linkage peak on chromosome region 10p13 covering 39 genes. Using leprosy per se and leprosy subtypes as phenotypes, we employed 294 nuclear families (303 leprosy cases, 63 % MB, 37 % PB) as a discovery sample and 192 nuclear families (192 cases, 55 % MB, 45 % PB) as a replication sample. Replicated significant association signals were revealed in the genes for cubilin (CUBN) and nebulette (NEBL). In the combined sample, the C allele (frequency 0.26) at CUBN SNP rs10904831 showed association [p = 1 × 10−5; OR 0.52 (0.38–0.7)] with MB leprosy only. Likewise, allele T (frequency 0.42) at NEBL SNP rs11012461 showed association [p = 4.2 × 10−5; OR 2.51 (1.6–4)] with MB leprosy only. These associations remained valid for the CUBN signal when taking into account the effective number of tests performed (type I error significance threshold = 2.4 × 10−5). We used the results of our analyses to propose a new model for the genetic control of polarization of clinical leprosy.
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References
Abel L, Demenais F (1988) Detection of major genes for susceptibility to leprosy and its subtypes in a Caribbean island: Desirade Island. Am J Hum Genet 42:256–266
Alcaïs A, Alter A, Antoni G et al (2007) Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy. Nat Genet 39:517–522. doi:10.1038/ng2000
Alter A, de Léséleuc L, Van Thuc N et al (2010) Genetic and functional analysis of common MRC1 exon 7 polymorphisms in leprosy susceptibility. Hum Genet 127:337–348. doi:10.1007/s00439-009-0775-x
Alter A, Grant A, Abel L et al (2011a) Leprosy as a genetic disease. Mamm Genome 22:19–31. doi:10.1007/s00335-010-9287-1
Alter A, Huong NT, Singh M et al (2011b) Human leukocyte antigen class I region single-nucleotide polymorphisms are associated with leprosy susceptibility in Vietnam and India. J Infect Dis 203:1274–1281. doi:10.1093/infdis/jir024
Alter A, Fava VM, Huong NT et al (2013) Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy. Hum Genet 132:107–116. doi:10.1007/s00439-012-1227-6
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265. doi:10.1093/bioinformatics/bth457
Behr MA, Schurr E (2013) Cell biology: a table for two. Nature 501:498–499. doi:10.1038/nature12555
Casanova J-L, Abel L (2002) Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol 20:581–620. doi:10.1146/annurev.immunol.20.081501.125851
Christensen EI, Birn H, Storm T et al (2012) Endocytic receptors in the renal proximal tubule. Physiology (Bethesda) 27:223–236. doi:10.1152/physiol.00022.2012
Cochran WG (1954) The combination of estimates from different experiments. Biometrics 10:101–129
De Bakker PIW, Yelensky R, Pe’er I et al (2005) Efficiency and power in genetic association studies. Nat Genet 37:1217–1223. doi:10.1038/ng1669
De Souza VNB, de Malaspina TS, Campanelli AP et al (2012) Increased hepcidin expression in multibacillary leprosy. Mem Inst Oswaldo Cruz 107 Suppl 1:183–189
Deng XA, Norris A, Panaviene Z, Moncman CL (2008) Ectopic expression of LIM-nebulette (LASP2) reveals roles in cell migration and spreading. Cell Motil Cytoskeleton 65:827–840. doi:10.1002/cm.20304
Gauderman WJ (2002) Sample size requirements for matched case–control studies of gene–environment interaction. Stat Med 21:35–50
Gopinath K, Venclovas C, Ioerger TR et al (2013) A vitamin B12 transporter in Mycobacterium tuberculosis. Open Biol 3:120175. doi:10.1098/rsob.120175
Gorodezky C, Alaez C, Munguía A et al (2004) Molecular mechanisms of MHC linked susceptibility in leprosy: towards the development of synthetic vaccines. Tuberculosis (Edinb) 84:82–92
Grant AV, Alter A, Huong NT et al (2012) Crohn’s disease susceptibility genes are associated with leprosy in the Vietnamese population. J Infect Dis. doi:10.1093/infdis/jis588
Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560. doi:10.1136/bmj.327.7414.557
Horvath S, Xu X, Laird NM (2001) The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 9:301–306. doi:10.1038/sj.ejhg.5200625
Katoh M, Katoh M (2003) Identification and characterization of LASP2 gene in silico. Int J Mol Med 12:405–410
Li J, Ji L (2005) Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity (Edinb) 95:221–227. doi:10.1038/sj.hdy.6800717
Mägi R, Morris AP (2010) GWAMA: software for genome-wide association meta-analysis. BMC Bioinform 11:288. doi:10.1186/1471-2105-11-288
Manzanillo PS, Ayres JS, Watson RO et al (2013) The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501:512–516. doi:10.1038/nature12566
McLaren CE, McLachlan S, Garner CP et al (2012) Associations between single nucleotide polymorphisms in iron-related genes and iron status in multiethnic populations. PLoS ONE 7:e38339. doi:10.1371/journal.pone.0038339
Merle CSC, Cunha SS, Rodrigues LC (2010) BCG vaccination and leprosy protection: review of current evidence and status of BCG in leprosy control. Expert Rev Vaccines 9:209–222. doi:10.1586/erv.09.161
Midroni G, Bilbao JM (1995) Leprous neuropathy. Biopsy diagnosis of peripheral neuropathy
Mira MT, Alcaïs A, Van Thuc N et al (2003) Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet 33:412–415. doi:10.1038/ng1096
Mira MT, Alcaïs A, Nguyen VT et al (2004) Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427:636–640. doi:10.1038/nature02326
Misch EA, Berrington WR, Vary JC Jr, Hawn TR (2010) Leprosy and the human genome. Microbiol Mol Biol Rev 74:589–620. doi:10.1128/MMBR.00025-10
Mostowy S, Cossart P (2011) Autophagy and the cytoskeleton: new links revealed by intracellular pathogens. Autophagy 7:780–782
Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769. doi:10.1086/383251
Ovunc B, Otto EA, Vega-Warner V et al (2011) Exome sequencing reveals cubilin mutation as a single-gene cause of proteinuria. J Am Soc Nephrol 22:1815–1820. doi:10.1681/ASN.2011040337
Pappas CT, Bliss KT, Zieseniss A, Gregorio CC (2011) The Nebulin family: an actin support group. Trends Cell Biol 21:29–37. doi:10.1016/j.tcb.2010.09.005
Patin E, Kutalik Z, Guergnon J, et al. (2012) Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection. Gastroenterology. doi:10.1053/j.gastro.2012.07.097
Ridley DS, Jopling WH (1966) Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 34:255–273
Sales AM, Ponce de Leon A, Düppre NC et al (2011) Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 5:e1013. doi:10.1371/journal.pntd.0001013
Sarno EN, Duppre NC, Sales AM et al (2012) Leprosy exposure, infection and disease: a 25-year surveillance study of leprosy patient contacts. Mem Inst Oswaldo Cruz 107:1054–1059
Schaid DJ, Rowland C (1998) Use of parents, sibs, and unrelated controls for detection of associations between genetic markers and disease. Am J Hum Genet 63:1492–1506. doi:10.1086/302094
Schurr E, Gros P (2009) A common genetic fingerprint in leprosy and Crohn’s disease? N Engl J Med 361:2666–2668. doi:10.1056/NEJMe0910690
Scollard DM, Adams LB, Gillis TP et al (2006) The continuing challenges of leprosy. Clin Microbiol Rev 19:338–381. doi:10.1128/CMR.19.2.338-381.2006
Seetharam B, Levine JS, Ramasamy M, Alpers DH (1988) Purification, properties, and immunochemical localization of a receptor for intrinsic factor-cobalamin complex in the rat kidney. J Biol Chem 263:4443–4449
Seetharam B, Christensen EI, Moestrup SK et al (1997) Identification of rat yolk sac target protein of teratogenic antibodies, gp280, as intrinsic factor-cobalamin receptor. J Clin Invest 99:2317–2322. doi:10.1172/JCI119411
Siddiqui MR, Meisner S, Tosh K et al (2001) A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat Genet 27:439–441. doi:10.1038/86958
Wang D, Feng J-Q, Li Y–Y et al (2012) Genetic variants of the MRC1 gene and the IFNG gene are associated with leprosy in Han Chinese from Southwest China. Hum Genet 131:1251–1260. doi:10.1007/s00439-012-1153-7
Wong SH, Hill AVS, Vannberg FO, India-Africa-United Kingdom Leprosy Genetics Consortium (2010) Genomewide association study of leprosy. N Engl J Med 362:1446–1447 (author reply 1447–1448). doi:10.1056/NEJMc1001451
Zhang F-R, Huang W, Chen S-M et al (2009) Genomewide association study of leprosy. N Engl J Med 361:2609–2618. doi:10.1056/NEJMoa0903753
Zhang F, Liu H, Chen S et al (2011) Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nat Genet 43:1247–1251. doi:10.1038/ng.973
Acknowledgments
We thank all the family members who participated in this study. This study was supported by grants from the Canadian Institutes of Health Research (CIHR) to ES, MALTALEP from l’Ordre de Malte to AA and ES, the Agence Nationale de la Recherche (ANR) to AA and the Heiser Fondation to LA. AVG was supported by the Fondation Pour la Recherche Médicale (FRM). AC was the recipient of a Banting postdoctoral fellowship from the Government of Canada.
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A. Alcaïs and E. Schurr contributed equally.
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Grant, A.V., Cobat, A., Van Thuc, N. et al. CUBN and NEBL common variants in the chromosome 10p13 linkage region are associated with multibacillary leprosy in Vietnam. Hum Genet 133, 883–893 (2014). https://doi.org/10.1007/s00439-014-1430-8
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DOI: https://doi.org/10.1007/s00439-014-1430-8