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Previous genome-wide association studies (GWASs) identified multiple susceptibility loci that have highlighted the important role of  TLR  (Toll-like receptor) and  CARD  (caspase recruitment domain) genes in leprosy. A large three-stage candidate gene-based association study of 30  TLR  and 47  CARD  genes was performed in the leprosy samples of Chinese Han. Of 4363 SNPs investigated, eight SNPs showed suggestive association ( P  &lt; 0.01) in our previously published GWAS datasets (Stage 1). Of the eight SNPs, rs2735591 and rs4889841 showed significant association ( P  &lt; 0.001) in an independent series of 1504 cases and 1502 controls (Stage 2), but only rs2735591 (next to  BCL10 ) showed significant association in the second independent series of 938 cases and 5827 controls (Stage 3). Rs2735591 showed consistent association across the three stages ( P  &gt; 0.05 for heterogeneity test), significant association in the combined validation samples (P corrected  = 5.54 × 10 −4  after correction for 4363 SNPs tested) and genome-wide significance in the whole GWAS and validation samples ( P  = 1.03 × 10 −9 , OR = 1.24). In addition, we demonstrated the lower expression of  BCL10  in leprosy lesions than normal skins and a significant gene connection between  BCL10  and the eight previously identified leprosy loci that are associated with NFκB, a major regulator of downstream inflammatory responses, which provides further biological evidence for the association. We have discovered a novel susceptibility locus on 1p22, which implicates  BCL10  as a new susceptibility gene for leprosy. Our finding highlights the important role of both innate and adaptive immune responses in leprosy.

An association study of TOLL and CARD with leprosy susceptibility in Chinese population