Abstract
Leprosy is a complex disease with phenotypes strongly influenced by genetic variation. A Chinese genome-wide association study (GWAS) depicted novel genes and pathways associated with leprosy susceptibility, only partially replicated by independent studies in different ethnicities. Here, we describe the results of a validation and replication study of the Chinese GWAS in Brazilians, using a stepwise strategy that involved two family-based and three independent case–control samples, resulting in 3,614 individuals enrolled. First, we genotyped a family-based sample for 36 tag single-nucleotide polymorphisms (SNPs) of five genes located in four different candidate loci: CCDC122-LACC1, NOD2, TNFSF15 and RIPK2. Association between leprosy and tag SNPs at NOD2 (rs8057431) and CCDC122-LACC1 (rs4942254) was then replicated in three additional, independent samples (combined ORAA = 0.49, P = 1.39e−06; ORCC = 0.72, P = 0.003, respectively). These results clearly implicate the NOD2 pathway in the regulation of leprosy susceptibility across diverse populations.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alcais A 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, Grant A, Abel L, Alcais A, Schurr E (2011) Leprosy as a genetic disease. Mamm Genome 22:19–31. doi:10.1007/s00335-010-9287-1
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
Berrington WR et al (2010) Common polymorphisms in the NOD2 gene region are associated with leprosy and its reactive states. J Infect Dis 201:1422–1435. doi:10.1086/651559
Britton WJ, Lockwood DN (2004) Leprosy. Lancet 363:1209–1219. doi:10.1016/S0140-6736(04)15952-7
Cardoso CC et al (2011a) TNF-308G>A single nucleotide polymorphism is associated with leprosy among Brazilians: a genetic epidemiology assessment, meta-analysis, and functional study. J Infect Dis 204:1256–1263. doi:10.1093/infdis/jir521
Cardoso CC, Pereira AC, de Sales Marques C, Moraes MO (2011b) Leprosy susceptibility: genetic variations regulate innate and adaptive immunity, and disease outcome. Future Microbiol 6:533–549. doi:10.2217/fmb.11.39->
CdS Marques et al (2013) Toll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection. J Infect Dis 208:120–129. doi:10.1093/infdis/jit133
Cooney R et al (2010) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 16:90–97. doi:10.1038/nm.2069
Grant AV et al (2012) Crohn’s disease susceptibility genes are associated with leprosy in the Vietnamese population. J Infect Dis 206:1763–1767. doi:10.1093/infdis/jis588
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
International HapMap C (2005) A haplotype map of the human genome. Nature 437:1299–1320. doi:10.1038/nature04226
John SW, Weitzner G, Rozen R, Scriver CR (1991) A rapid procedure for extracting genomic DNA from leukocytes. Nucleic Acids Res 19:408
Kazeem GR, Farrall M (2005) Integrating case–control and TDT studies. Ann Hum Genet 69:329–335. doi:10.1046/j.1529-8817.2005.00156.x
Lake SL, Blacker D, Laird NM (2000) Family-based tests of association in the presence of linkage. Am J Hum Genet 67:1515–1525
Lazaro FP et al (2010) A major gene controls leprosy susceptibility in a hyperendemic isolated population from north of Brazil. J Infect Dis 201:1598–1605. doi:10.1086/652007
Liu H et al (2012) Identification of IL18RAP/IL18R1 and IL12B as leprosy risk genes demonstrates shared pathogenesis between inflammation and infectious diseases. Am J Hum Genet 91:935–941. doi:10.1016/j.ajhg.2012.09.010
Manry J, Quintana-Murci L (2013) A genome-wide perspective of human diversity and its implications in infectious disease. Cold Spring Harb Perspect Med 3:a012450. doi:10.1101/cshperspect.a012450
Mira MT 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 et al (2004) Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427:636–640. doi:10.1038/nature02326
Monot M et al (2009) Comparative genomic and phylogeographic analysis of Mycobacterium leprae. Nat Genet 41:1282–1289. doi:10.1038/ng.477
Orlova M, Di Pietrantonio T, Schurr E (2011) Genetics of infectious diseases: hidden etiologies and common pathways. Clin Chem Lab Med 49:1427–1437. doi:10.1515/CCLM.2011.620
Pereira AC et al (2009) Genetic, epidemiological and biological analysis of interleukin-10 promoter single-nucleotide polymorphisms suggests a definitive role for −819C/T in leprosy susceptibility. Genes Immun 10:174–180. doi:10.1038/gene.2008.97
R Development Core team (2013) R: a language and environment for statistical computing. http://www.R-project.org/. Accessed 02 May 2014
Ridley DS, Jopling WH (1966) Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 34:255–273
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
Schenk M et al (2012) NOD2 triggers an interleukin-32-dependent human dendritic cell program in leprosy. Nat Med 18:555–563. doi:10.1038/nm.2650
Schuenemann VJ et al (2013) Genome-wide comparison of medieval and modern Mycobacterium leprae. Science 341:179–183. doi:10.1126/science.1238286
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
Siddiqui MR et al (2001) A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat Genet 27:439–441. doi:10.1038/86958
Trabzuni D et al (2013) Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. PLoS One 8:e70724. doi:10.1371/journal.pone.0070724
Werneck RI et al (2011) A major gene effect controls resistance to caries. J Dent Res 90:735–739. doi:10.1177/0022034510397614
WHO (2014) Global leprosy update, 2013; reducing disease burden. Wkly Epidemiol Rec 89:389–400
Wong SH, Hill AV, Vannberg FO, India–Africa–United Kingdom Leprosy Genetics C (2010) Genomewide association study of leprosy. N Engl J Med 362:1446–1447. doi:10.1056/NEJMc1001451 (author reply 1447–1448)
Zhang FR et al (2009) Genomewide association study of leprosy. N Engl J Med 361:2609–2618. doi:10.1056/NEJMoa0903753
Zhang F 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 families, affected and unaffected volunteers for agreeing to participate in this study. This study was supported by a grant from the Brazilian Departamento de Ciências e Tecnologia, Conselho Nacional de Desenvolvimento Científico, Ministério da Saúde/Tecnologia de Insumos Estratégicos (DECIT/CNPq/MS/SCTIE, Process Number 576051/2008-0).
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
C. Sales-Marques and H. Salomão share first authorship.
M. T. Mira and A. C. Pereira share senior authorship.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Sales-Marques, C., Salomão, H., Fava, V.M. et al. NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians. Hum Genet 133, 1525–1532 (2014). https://doi.org/10.1007/s00439-014-1502-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-014-1502-9