Genome-Wide Analysis of Protein-Coding Variants in Leprosy.

Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1.71 × 10-9, odds ratio [OR] = 4.35) and rs149308743 in CARD9 (P = 2.09 × 10-8, OR = 4.75); three low-frequency variants: rs76418789 in IL23R (P = 1.03 × 10-10, OR = 1.36), rs146466242 in FLG (P = 3.39 × 10-12, OR = 1.45), and rs55882956 in TYK2 (P = 1.04 × 10-6, OR = 1.30); and two common variants: rs780668 in SLC29A3 (P = 2.17 × 10-9, OR = 1.14) and rs181206 in IL27 (P = 1.08 × 10-7, OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases.

Bacteriological results and leprosy reactions among MB leprosy patients treated with uniform multidrug therapy in China.

OBJECTIVES: To investigate the changes of bacteriological index and leprosy reactions among Multi-bacillary (MB) patients treated with uniform multi-drug therapy (UMDT). METHODS: Newly diagnosed leprosy patients were recruited after taking informed consent in three districts in Guizhou Province and one district in Yunnan Province China during November 2003 to June 2005 and were treated with Uniform Multidrug Therapy. All patients were followed up once a year for 3 years after completion of treatment. All data on bacteriological index (BI) and the frequencies of leprosy reaction were collected and analysed. RESULTS: A total of 166 patients were recruited for UMDT trial. Among them 114 patients had positive BI smear, and 83 patients had been followed up for 42 months. The mean BI of 83 patients decreased from 2.84 before treatment to 0.33 at the end of 42 months follow-up. At the end of this period, 61 patients (73.5%) had become BI negative. There were 13 (14.6%) patients who had a Type I reaction during 24 months of follow-up. One patient in the study group relapsed 13 months after stopping treatment of the UMDT. CONCLUSION: There was a significant decrease in the mean BI and 73.5% of patients treated with UMDT became BI negative during 3 years' follow-up. The frequency of Type I reaction seemed a little higher among patients treated with UMDT, but the numbers of patients enrolled were too few to determine statistical significance. Future studies on U-MDT should also study Type I reactions in these patients.

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

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.

[Historical comparisons on related features among newly registered leprosy patients in the endemic areas of Wenshan district, Yunnan province].

OBJECTIVE: To analyze the current situation and prevalence of leprosy in Wenshan district, Yunnan province. METHODS: To collect various data on leprosy reported by the health workers at the county level. RESULTS: The number of newly registered patients did not decrease significantly in 1989, 1999 and 2009, respectively. The mean age of patients at detection was 33 - 35 years old. Time of delay between the disease onset and being diagnosed was shortened from 35.2 months in 1989 to 15.9 months in 2009. However, the proportion of patients with more than 12 months of delay still accounted for nearly 50%. The proportion of Grade II disability fluctuated between 15.2% - 17.7% and the proportion of child cases increased from 8.1% in 1989 to 13.1% in 2009. Clinics for skin diseases were the main locations for case detection. The proportion of new cases detected through 'active case finding' program accounted for 44.3% in 1999 and 42.6% in 2009, both higher than 17.7% in 1989. CONCLUSION: The situation of leprosy in Wenshan district, Yunnan province, was still serious and the reason for the occurrence of new cases was related to the fact that the infectious source of leprosy had not been under full control.

Genomewide association study of leprosy.

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<1.00x10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P=5.10x10(-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.