BACKGROUND The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS We observed a significant association (P<1.00×10 −10) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P = 5.10×10 −5) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae.

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.

Bladder cancer (BC) is one of the most commonly occurring cancers, with a high recurrence rate and poor outcomes in cases of relapsed metastatic disease. Here, we analyzed the markers and significance of myeloid-derived suppressor cells (MDSCs) for BC development and progression. MDSC markers were examined in peripheral blood from 113 BC patients and 20 healthy volunteers. We identified CD11b+CD33lowHLA-DR− CD3− cells as markers of MDSCs in peripheral blood from BC patients. We also demonstrated that MDSC numbers are higher in BC patients than healthy donors, and that MDSC numbers correlate with the clinical grade, stage, and poor prognosis. In addition, serum IL-6 levels are decreased in BC patients with higher MDSC counts. IL-6 blockade increases induction of MDSCs in vitro. Low IL-6 levels inhibit activation of Stat3, resulting in the increased formation of MDSCs in BC. These results indicate that the MDSCs numbers may serve as a novel prognostic marker in BC patients, and that targeting IL-6 signaling may be a promising strategy for BC treatment.

It is increasingly clear that microRNAs (miRNAs) play an important role in many diseases, including tumorigenesis. However, the mechanisms by which miRNAs regulate bladder cancer development remain poorly understood. Here, we evaluated the expression of microRNA‐203 (miR‐203) in bladder cancer tissues using real‐time PCR, and defined the target genes and biologically functional effect using luciferase reporter assay, flow cytometry and western blot analysis. We first verified that the expression of miR‐203 was decreased in bladder cancer tissues. Moreover, ectopic expression of miR‐203 promoted the apoptosis of human bladder cancer cell lines and inhibited cell proliferation, whereas its depletion increased cell growth. We further verified that miR‐203 directly targeted 3′‐untranslated region of the bcl‐w gene, and decreased its expression in vitro and in vivo. Western blot analysis also showed that the expression level of miR‐203 was negatively correlated with bcl‐w level in tumor tissues. These data suggest an important role for miR‐203 in the molecular etiology of bladder cancer and implicate the potential application of miR‐203 in bladder cancer therapy.