Human Genetics

, Volume 132, Issue 6, pp 629–640 | Cite as

Genetic variants of complement genes Ficolin-2, Mannose-binding lectin and Complement factor H are associated with leprosy in Han Chinese from Southwest China

  • Deng-Feng Zhang
  • Xian-Qiong Huang
  • Dong Wang
  • Yu-Ye Li
  • Yong-Gang Yao
Original Investigation


The complement system plays multiple roles in host defense against infection and is supposed to confer genetic susceptibility to leprosy. We aimed to examine whether genetic variants of the Ficolin-2 (FCN2), Mannose-binding lectin (MBL2) and Complement factor H (CFH) genes, which are involved in activation and regulation of the complement system, are associated with leprosy in Han Chinese from Southwest China. 527 leprosy patients and 583 matched controls were recruited from Yunnan Province, China, and were analyzed in this study. We sequenced the promoter region of the FCN2 and MBL2 genes and exon 8 of the FCN2 gene and genotyped three tag SNPs of the CFH gene. Association analysis was performed to discern potential effect of these three genes with leprosy and its subtypes. Luciferase assay was used to characterize the role of different promoter alleles of the FCN2 and MBL2 genes. Genetic variants of FCN2 (rs3811140 and rs7851696), MBL2 (rs11003125, rs7100749, rs11003124 and rs7096206) and CFH (rs1065489 and rs3753395) were significantly associated with leprosy and its subtypes. Haplotypes/genotypes representing low FCN2 and MBL2 transcriptional activity conferred risk to paucibacillary leprosy. Our data confirmed the expected positive association of complement genes with leprosy susceptibility and clinical outcomes in Han Chinese.



We thank all the participants in this study and Mr. Mei-Sheng Xiao and Miss Ling Xu for assistance with luciferase assay. This study was supported by the National Natural Science Foundation of China (31271346, 30925021 and 81260237), Top Talents Program of Yunnan Province (2009CI119) and the Chinese Academy of Sciences.

Conflict of interest

All authors declare no potential conflicts.

Supplementary material

439_2013_1273_MOESM1_ESM.doc (484 kb)
Supplementary material 1 (DOC 484 kb)


  1. Alter A, Grant A, Abel L, Alcais A, Schurr E (2011) Leprosy as a genetic disease. Mamm Genome 22:19–31PubMedCrossRefGoogle Scholar
  2. Bandelt HJ, Forster P, Rohl A (1999) Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol 16:37–48PubMedCrossRefGoogle Scholar
  3. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRefGoogle Scholar
  4. Bochud PY, Hawn TR, Siddiqui MR, Saunderson P, Britton S, Abraham I, Argaw AT, Janer M, Zhao LP, Kaplan G, Aderem A (2008) Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J Infect Dis 197:253–261PubMedCrossRefGoogle Scholar
  5. Boon CJ, Klevering BJ, Hoyng CB, Zonneveld-Vrieling MN, Nabuurs SB, Blokland E, Cremers FP, den Hollander AI (2008) Basal laminar drusen caused by compound heterozygous variants in the CFH gene. Am J Hum Genet 82:516–523PubMedCrossRefGoogle Scholar
  6. Britton WJ, Lockwood DN (2004) Leprosy. Lancet 363:1209–1219PubMedCrossRefGoogle Scholar
  7. Caprioli J, Castelletti F, Bucchioni S, Bettinaglio P, Bresin E, Pianetti G, Gamba S, Brioschi S, Daina E, Remuzzi G, Noris M (2003) Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum Mol Genet 12:3385–3395PubMedCrossRefGoogle Scholar
  8. Carroll MV, Lack N, Sim E, Krarup A, Sim RB (2009) Multiple routes of complement activation by Mycobacterium bovis BCG. Mol Immunol 46:3367–3378PubMedCrossRefGoogle Scholar
  9. Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR, Wheeler PR, Honoré N, Garnier T, Churcher C, Harris D, Mungall K, Basham D, Brown D, Chillingworth T, Connor R, Davies RM, Devlin K, Duthoy S, Feltwell T, Fraser A, Hamlin N, Holroyd S, Hornsby T, Jagels K, Lacroix C, Maclean J, Moule S, Murphy L, Oliver K, Quail MA, Rajandream MA, Rutherford KM, Rutter S, Seeger K, Simon S, Simmonds M, Skelton J, Squares R, Squares S, Stevens K, Taylor K, Whitehead S, Woodward JR, Barrell BG (2001) Massive gene decay in the leprosy bacillus. Nature 409:1007–1011PubMedCrossRefGoogle Scholar
  10. Cooper NR (1985) The classical complement pathway: activation and regulation of the first complement component. Adv Immunol 37:151–216PubMedCrossRefGoogle Scholar
  11. Davila S, Wright VJ, Khor CC, Sim KS, Binder A, Breunis WB, Inwald D, Nadel S, Betts H, Carrol ED, de Groot R, Hermans PW, Hazelzet J, Emonts M, Lim CC, Kuijpers TW, Martinon-Torres F, Salas A, Zenz W, Levin M, Hibberd ML (2010) Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat Genet 42:772–776PubMedCrossRefGoogle Scholar
  12. de Messias-Reason IJ, Boldt AB, MoraesBraga AC, von Rosen Seeling Stahlke E, Dornelles L, Pereira-Ferrari L, Kremsner PG, Kun JF (2007) The association between mannan-binding lectin gene polymorphism and clinical leprosy: new insight into an old paradigm. J Infect Dis 196:1379–1385PubMedCrossRefGoogle Scholar
  13. de Messias-Reason I, Kremsner PG, Kun JF (2009) Functional haplotypes that produce normal ficolin-2 levels protect against clinical leprosy. J Infect Dis 199:801–804PubMedCrossRefGoogle Scholar
  14. Dommett RM, Klein N, Turner MW (2006) Mannose-binding lectin in innate immunity: past, present and future. Tissue Antigens 68:193–209PubMedCrossRefGoogle Scholar
  15. Dornelles LN, Pereira-Ferrari L, Messias-Reason I (2006) Mannan-binding lectin plasma levels in leprosy: deficiency confers protection against the lepromatous but not the tuberculoid forms. Clin Exp Immunol 145:463–468PubMedCrossRefGoogle Scholar
  16. Endo Y, Takahashi M, Fujita T (2006) Lectin complement system and pattern recognition. Immunobiology 211:283–293PubMedCrossRefGoogle Scholar
  17. Faik I, Oyedeji SI, Idris Z, de Messias-Reason IJ, Lell B, Kremsner PG, Kun JF (2011) Ficolin-2 levels and genetic polymorphisms of FCN2 in malaria. Hum Immunol 72:74–79PubMedCrossRefGoogle Scholar
  18. Ferguson JS, Weis JJ, Martin JL, Schlesinger LS (2004) Complement protein C3 binding to Mycobacterium tuberculosis is initiated by the classical pathway in human bronchoalveolar lavage fluid. Infect Immun 72:2564–2573PubMedCrossRefGoogle Scholar
  19. Fitness J, Floyd S, Warndorff DK, Sichali L, Mwaungulu L, Crampin AC, Fine PE, Hill AV (2004) Large-scale candidate gene study of leprosy susceptibility in the Karonga district of northern Malawi. Am J Trop Med Hyg 71:330–340PubMedGoogle Scholar
  20. Garred P, Larsen F, Seyfarth J, Fujita R, Madsen HO (2006) Mannose-binding lectin and its genetic variants. Genes Immun 7:85–94PubMedCrossRefGoogle Scholar
  21. Garred P, Honoré C, Ma YJ, Munthe-Fog L, Hummelshøj T (2009) MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement. Mol Immunol 46:2737–2744PubMedCrossRefGoogle Scholar
  22. Garred P, Honoré C, Ma YJ, Rorvig S, Cowland J, Borregaard N, Hummelshøj T (2010) The genetics of ficolins. J Innate Immun 2:3–16PubMedCrossRefGoogle Scholar
  23. Gauderman WJ (2002) Sample size requirements for matched case-control studies of gene-environment interaction. Stat Med 21:35–50PubMedCrossRefGoogle Scholar
  24. George Priya Doss C, Nagasundaram N, Srajan J, Chiranjib C (2012) LSHGD: a database for human leprosy susceptible genes. Genomics 100:162–166PubMedCrossRefGoogle Scholar
  25. Gomes GI, Nahn EP Jr, Santos RK, Da Silva WD, Kipnis TL (2008) The functional state of the complement system in leprosy. Am J Trop Med Hyg 78:605–610PubMedGoogle Scholar
  26. Hummelshoj T, Munthe-Fog L, Madsen HO, Fujita T, Matsushita M, Garred P (2005) Polymorphisms in the FCN2 gene determine serum variation and function of ficolin-2. Hum Mol Genet 14:1651–1658PubMedCrossRefGoogle Scholar
  27. Li Y–Y, Li X-A, He L, Wang D, Chen W-Y, Chen L, Lu JB, Yao Y-G (2011) Trends in new leprosy case detection over 57 years (1952–2008) in Yuxi, Yunnan Province of Southwest China. Lepr Rev 82:6–16PubMedGoogle Scholar
  28. Madsen HO, Garred P, Kurtzhals JA, Lamm LU, Ryder LP, Thiel S, Svejgaard A (1994) A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein. Immunogenetics 40:37–44PubMedCrossRefGoogle Scholar
  29. Madsen HO, Garred P, Thiel S, Kurtzhals JA, Lamm LU, Ryder LP, Svejgaard A (1995) Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol 155:3013–3020PubMedGoogle Scholar
  30. Madsen HO, Satz ML, Hogh B, Svejgaard A, Garred P (1998) Different molecular events result in low protein levels of mannan-binding lectin in populations from southeast Africa and South America. J Immunol 161:3169–3175PubMedGoogle Scholar
  31. Misch EA, Berrington WR, Vary JC Jr, Hawn TR (2010) Leprosy and the human genome. Microbiol Mol Biol Rev 74:589–620PubMedCrossRefGoogle Scholar
  32. Modlin RL (2010) The innate immune response in leprosy. Curr Opin Immunol 22:48–54PubMedCrossRefGoogle Scholar
  33. Munthe-Fog L, Hummelshøj T, Hansen BE, Koch C, Madsen HO, Skjødt K, Garred P (2007) The impact of FCN2 polymorphisms and haplotypes on the ficolin-2 serum levels. Scand J Immunol 65:383–392PubMedCrossRefGoogle Scholar
  34. Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11:785–797PubMedCrossRefGoogle Scholar
  35. Rodríguez de Córdoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sánchez-Corral P (2004) The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 41:355–367PubMedCrossRefGoogle Scholar
  36. Rooijakkers SH, van Strijp JA (2007) Bacterial complement evasion. Mol Immunol 44:23–32PubMedCrossRefGoogle Scholar
  37. Saha K, Chakraborty AK (1977) Serum complement profile in human leprosy and its comparison with immune complex diseases. Int J Lepr Mycobact Dis 45:327–337Google Scholar
  38. Saha K, Sharma V, Chakrabarty AK, Sehgal VN (1983) Breakdown product of factor B as an index of complement activation in lepromatous leprosy and its relation with bacillary load. Scand J Immunol 17:37–43PubMedCrossRefGoogle Scholar
  39. Sapkota BR, Macdonald M, Berrington WR, Misch EA, Ranjit C, Siddiqui MR, Kaplan G, Hawn TR (2010) Association of TNF, MBL, and VDR polymorphisms with leprosy phenotypes. Hum Immunol 71:992–998PubMedCrossRefGoogle Scholar
  40. Sato S, Imi M (1968) The surface structure of M. leprae. Int J Lepr Mycobact Dis 36:303–308Google Scholar
  41. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989PubMedCrossRefGoogle Scholar
  42. Thakkinstian A, Han P, McEvoy M, Smith W, Hoh J, Magnusson K, Zhang K, Attia J (2006) Systematic review and meta-analysis of the association between complement factor H Y402H polymorphisms and age-related macular degeneration. Hum Mol Genet 15:2784–2790PubMedCrossRefGoogle Scholar
  43. Vasconcelos LR, Fonseca JP, do Carmo RF, de Mendonca TF, Pereira VR, Lucena-Silva N, Pereira LM, Moura P, Cavalcanti Mdo S (2011) Mannose-binding lectin serum levels in patients with leprosy are influenced by age and MBL2 genotypes. Int J Infect Dis 15: e551–557Google Scholar
  44. Vogl G, Lesiak I, Jensen DB, Perkhofer S, Eck R, Speth C, Lass-Flörl C, Zipfel PF, Blom AM, Dierich MP, Würzner R (2008) Immune evasion by acquisition of complement inhibitors: the mould Aspergillus binds both factor H and C4b binding protein. Mol Immunol 45:1485–1493PubMedCrossRefGoogle Scholar
  45. Wang D, Feng J-Q, Li Y–Y, Zhang D-F, Li X-A, Li Q-W, Yao Y-G (2012a) Genetic variants of the MRC1 gene and the IFNG gene are associated with leprosy in Han Chinese from Southwest China. Hum Genet 131:1251–1260PubMedCrossRefGoogle Scholar
  46. Wang D, Su L-Y, Zhang A-M, Li Y–Y, Li X-A, Chen L–L, Long H, Yao Y-G (2012b) Mitochondrial DNA copy number, but not haplogroup, confers a genetic susceptibility to leprosy in Han Chinese from Southwest China. PLoS ONE 7:e38848PubMedCrossRefGoogle Scholar
  47. Wong SH, Gochhait S, Malhotra D, Pettersson FH, Teo YY, Khor CC, Rautanen A, Chapman SJ, Mills TC, Srivastava A, Rudko A, Freidin MB, Puzyrev VP, Ali S, Aggarwal S, Chopra R, Reddy BS, Garg VK, Roy S, Meisner S, Hazra SK, Saha B, Floyd S, Keating BJ, Kim C, Fairfax BP, Knight JC, Hill PC, Adegbola RA, Hakonarson H, Fine PE, Pitchappan RM, Bamezai RN, Hill AV, Vannberg FO (2010) Leprosy and the adaptation of human toll-like receptor 1. PLoS Pathog 6:e1000979PubMedCrossRefGoogle Scholar
  48. Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y, Cui Y, Yan XX, Yang HT, Yang RD, Chu TS, Zhang C, Zhang L, Han JW, Yu GQ, Quan C, Yu YX, Zhang Z, Shi BQ, Zhang LH, Cheng H, Wang CY, Lin Y, Zheng HF, Fu XA, Zuo XB, Wang Q, Long H, Sun YP, Cheng YL, Tian HQ, Zhou FS, Liu HX, Lu WS, He SM, Du WL, Shen M, Jin QY, Wang Y, Low HQ, Erwin T, Yang NH, Li JY, Zhao X, Jiao YL, Mao LG, Yin G, Jiang ZX, Wang XD, Yu JP, Hu ZH, Gong CH, Liu YQ, Liu RY, Wang DM, Wei D, Liu JX, Cao WK, Cao HZ, Li YP, Yan WG, Wei SY, Wang KJ, Hibberd ML, Yang S, Zhang XJ, Liu JJ (2009) Genomewide association study of leprosy. N Engl J Med 361:2609–2618PubMedCrossRefGoogle Scholar
  49. Zipfel PF, Mihlan M, Skerka C (2007) The alternative pathway of complement: a pattern recognition system. Adv Exp Med Biol 598:80–92PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Deng-Feng Zhang
    • 1
    • 3
  • Xian-Qiong Huang
    • 2
  • Dong Wang
    • 1
    • 3
  • Yu-Ye Li
    • 2
  • Yong-Gang Yao
    • 1
  1. 1.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan ProvinceKunming Institute of ZoologyKunmingChina
  2. 2.Department of DermatologyThe First Affiliated Hospital of Kunming Medical UniversityKunmingChina
  3. 3.University of Chinese Academy of SciencesBeijingChina

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