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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

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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.

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Figure 1: Regional association plots of rs3762318 and rs2275606.

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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–).

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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
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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.

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The authors declare no competing financial interests.

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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

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