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

Furen Zhang, Hong Liu, Shumin Chen, Huiqi Low, Liangdan Sun, Yong Cui, Tongsheng Chu, Yi Li, Xi'an Fu, Yongxiang Yu, Gongqi Yu, Benqing Shi, Hongqing Tian, Dianchang Liu, Xiulu Yu, Jinghui Li, Nan Lu, Fangfang Bao, Chunying Yuan, Jian Liu, Huaxu Liu, Lin Zhang, Yonghu Sun, Mingfei Chen, Qing Yang et al.

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.