Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy

Nature Genetics volume 43, pages 1247–1251 (2011)Cite this article

Subjects

Abstract

We performed a genome-wide association study with 706 individuals with leprosy and 5,581 control individuals and replicated the top 24 SNPs in three independent replication samples, including a total of 3,301 individuals with leprosy and 5,299 control individuals from China. Two loci not previously associated with the disease were identified with genome-wide significance: rs2275606 (combined P = 3.94 × 10−14, OR = 1.30) on 6q24.3 and rs3762318 (combined P = 3.27 × 10−11, OR = 0.69) on 1p31.3. These associations implicate IL23R and RAB32 as new susceptibility genes for leprosy. Furthermore, we identified evidence of interaction between the NOD2 and RIPK2 loci, which is consistent with the biological association of the proteins encoded by these genes (NOD2-RIPK2 complex) in activating the NF-κB pathway as a part of the host defense response to infection. Our findings have expanded the biological functions of IL23R by uncovering its involvement in infectious disease susceptibility and suggest a potential involvement of autophagocytosis in leprosy pathogenesis. The IL23R association supports previous observations of the marked overlap of susceptibility genes for leprosy and Crohn's disease, implying common pathogenesis mechanisms.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Regional association plots of rs3762318 and rs2275606.

Similar content being viewed by others

References

  1. Davila, S. et al. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat. Genet. 42, 772–776 (2010).

    Article  CAS  Google Scholar 

  2. Thye, T. et al. Genome-wide association analyses identifies a susceptibility locus for tuberculosis chromosome 18q11.2. Nat. Genet. 42, 739–741 (2010).

    Article  CAS  Google Scholar 

  3. World Health Organization. Global leprosy situation, 2010. Wkly. Epidemiol. Rec. 85, 337–348 (2010).

  4. Shields, E.D., Russell, D.A. & Pericak-Vance, M.A. Genetic epidemiology of the susceptibility to leprosy. J. Clin. Invest. 79, 1139–1143 (1987).

    Article  CAS  Google Scholar 

  5. Zhang, F.R. et al. Genomewide association study of leprosy. N. Engl. J. Med. 361, 2609–2618 (2009).

    Article  CAS  Google Scholar 

  6. Wong, S.H. et al. Leprosy and the adaptation of human toll-like receptor 1. PLoS Pathog. 6, e1000979 (2010).

    Article  Google Scholar 

  7. Zhang, X.J. et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat. Genet. 41, 205–210 (2009).

    Article  CAS  Google Scholar 

  8. Quan, C. et al. Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nat. Genet. 42, 614–618 (2010).

    Article  CAS  Google Scholar 

  9. Han, J.W. et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234–1237 (2009).

    Article  CAS  Google Scholar 

  10. Sun, L.D. et al. Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. Nat. Genet. 43, 690–694 (2011).

    Article  CAS  Google Scholar 

  11. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  12. Plenge, R.M. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482 (2007).

    Article  CAS  Google Scholar 

  13. Mells, G.F. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat. Genet. 43, 329–332 (2011).

    Article  CAS  Google Scholar 

  14. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010).

    Article  CAS  Google Scholar 

  15. Hennessy, S. et al. Factors influencing the optimal control-to-case ratio in matched case-control studies. Am. J. Epidemiol. 149, 195–197 (1999).

    Article  CAS  Google Scholar 

  16. Sun, L.D. et al. Association analyses identify six new psoriasis susceptibility loci in the Chinese population. Nat. Genet. 42, 1005–1009 (2010).

    Article  CAS  Google Scholar 

  17. Sheng, Y.J. et al. Follow-up study identifies two novel susceptibility loci PRKCB and 8p11.21 for systemic lupus erythematosus. Rheumatology (Oxford) 50, 682–688 (2011).

    Article  CAS  Google Scholar 

  18. Strange, A. et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. 42, 985–990 (2010).

    Article  CAS  Google Scholar 

  19. Mizuki, N. et al. Genome-wide association studies identify IL23R–IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nat. Genet. 42, 703–706 (2010).

    Article  CAS  Google Scholar 

  20. McGovern, D.P. et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat. Genet. 42, 332–337 (2010).

    Article  CAS  Google Scholar 

  21. Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

    Article  CAS  Google Scholar 

  22. Brand, S. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut 58, 1152–1167 (2009).

    Article  CAS  Google Scholar 

  23. Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002).

    Article  CAS  Google Scholar 

  24. Ottenhoff, T.H., Verreck, F.A., Hoeve, M.A. & van de Vosse, E. Control of human host immunity to mycobacteria. Tuberculosis (Edinb.) 85, 53–64 (2005).

    Article  CAS  Google Scholar 

  25. Seto, S., Tsujimura, K. & Koide, Y. Rab GTPases regulating phagosome maturation are differentially recruited to mycobacterial phagosomes. Traffic 12, 407–420 (2011).

    Article  CAS  Google Scholar 

  26. Deretic, V. Autophagy in infection. Curr. Opin. Cell Biol. 22, 252–262 (2010).

    Article  CAS  Google Scholar 

  27. Browning, B.L. & Browning, S.R. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 84, 210–223 (2009).

    Article  CAS  Google Scholar 

  28. Mantel, N. & Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).

    CAS  Google Scholar 

  29. DerSimonian, R. & Laird, N. Meta-analysis in clinical trials. Control. Clin. Trials 7, 177–188 (1986).

    Article  CAS  Google Scholar 

  30. Yang, T.P. et al. Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. Bioinformatics 26, 2474–2476 (2010).

    Article  CAS  Google Scholar 

  31. Fujita, P.A. et al. The UCSC Genome Browser database: update 2010. Nucleic Acids Res. 38, D613–D619 (2010).

    Article  Google Scholar 

Download references

Acknowledgements

We thank the individuals who participated in this project. This work was funded by grants from the National Natural Science Foundation of China (81071288, 81072391), the Project of Research Foundation of the Shandong Provincial Institute of Dermatology and Venereology (2008.07–2011.07), the Shandong Provincial Leprosy Control Special Financial Support (2009–2011), the Anhui Provincial Special Scientific Program (2007.07–2011.07) and the Agency for Science, Technology, and Research of Singapore. Grant support was also provided by the Project of Taishan scholar (2008–) and the Project of Medical leading scholar of Shandong Province (2010–). F. Zhang was supported by funding from the Project of Taishan scholar award (2008–) and the Project of Medical Leading Scholar of Shandong Province award (2010–).

Author information

Authors and Affiliations

  1. Shandong Provincial Institute of Dermatology and Venereology, Provincial Academy of Medical Science, Jinan, China

    Furen Zhang, Hong Liu, Shumin Chen, Tongsheng Chu, Xi'an Fu, Yongxiang Yu, Gongqi Yu, Dianchang Liu, Xiulu Yu, Jinghui Li, Nan Lu, Fangfang Bao, Chunying Yuan, Jian Liu, Huaxu Liu, Lin Zhang, Yonghu Sun, Mingfei Chen, Qing Yang, Hong Liu, Fuguang Zuo, Haizhen Zhang & Jianjun Liu

  2. Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, China

    Furen Zhang, Benqing Shi & Hongqing Tian

  3. Shandong Provincial Key Lab for Dermatovenereology, Jinan, China

    Furen Zhang, Hong Liu, Shumin Chen, Tongsheng Chu, Xi'an Fu, Yongxiang Yu, Gongqi Yu, Dianchang Liu, Xiulu Yu, Jinghui Li, Nan Lu, Fangfang Bao, Chunying Yuan, Jian Liu, Huaxu Liu, Lin Zhang, Yonghu Sun, Mingfei Chen, Qing Yang, Hong Liu, Fuguang Zuo & Haizhen Zhang

  4. Shandong Provincial Medical Center for Dermatovenereology, Jinan, China

    Furen Zhang, Benqing Shi & Hongqing Tian

  5. Human Genetics, Genome Institute of Singapore, A*STAR, Singapore

    Huiqi Low, Yi Li, Chiea Chuen Khor, Martin L Hibberd & Jianjun Liu

  6. Institute of Dermatology and Department of Dermatology at No.1 hospital, Anhui Medical University, Hefei, China

    Liangdan Sun, Yong Cui, Sen Yang & Xuejun Zhang

  7. State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, China

    Liangdan Sun, Yong Cui, Sen Yang & Xuejun Zhang

  8. Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China

    Haitao Yang & Lianhua Zhang

  9. Wenshan Institute of Dermatology, Wenshan, China

    Rongde Yang

  10. Anhui Provincial Institute of Dermatology, Hefei, China

    Qiang Wang

  11. Center for Molecular Epidemiology, National University of Singapore, Singapore

    Chiea Chuen Khor & Jianjun Liu

  12. Department of Epidemiology and Public Health, National University of Singapore, Singapore

    Martin L Hibberd

  13. School of Life Sciences, Anhui Medical University, Hefei, China

    Jianjun Liu

Authors
  1. Furen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shumin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huiqi Low
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liangdan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tongsheng Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xi'an Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yongxiang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gongqi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Benqing Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hongqing Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Dianchang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xiulu Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jinghui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Nan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Fangfang Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Chunying Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Jian Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Huaxu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Lin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Yonghu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Mingfei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Qing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Haitao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Rongde Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Lianhua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Qiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Hong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Fuguang Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Haizhen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Chiea Chuen Khor
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Martin L Hibberd
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Sen Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Jianjun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Xuejun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F. Zhang, X.Z. and Jianjun Liu conceived of and designed the study. S.C., T.C., X.Y., Lin Zhang, D.L., R.Y., H.Y., Lianhua Zhang and Q.W. undertook recruitment and collected phenotype data. Hong Liu, X.F., G.Y., Y.Y., Q.L., F.B., N.L., C.Y., Y.S., M.C., Hong Liu, H.Z., F. Zuo and Q.Y. conducted sample selection and performed the genotyping of the validation study. Hong Liu, X.F., Jian Liu, B.S., H.T. and Huaxu Liu collected phenotype data, undertook related data handling and calculation, managed recruitment and obtained biological samples. Jianjun Liu, H. Low, Hong Liu and Y.L. undertook data checking, statistical analysis and bioinformatics analyses. S.Y., Hong Liu, L.S. and Y.C. were responsible for sample selection, genotyping and project management. C.C.K. and M.L.H. helped to revise the manuscript. All authors contributed to the final manuscript, with F. Zhang, Jianjun Liu, X.Z. and Hong Liu having key roles.

Corresponding author

Correspondence to Furen Zhang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–5 and Supplementary Figures 1-3 (PDF 560 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, F., Liu, H., Chen, S. et al. Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nat Genet 43, 1247–1251 (2011). https://doi.org/10.1038/ng.973

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.973

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing