ABSTRACT
To date, genome-wide association studies (GWASs) have discovered 35 susceptible loci of leprosy; however, the cumulative effects of these loci can only partially explain the overall risk of leprosy, and the causal variants and genes within these loci remain unknown. Here, we conducted out new GWASs in two independent cohorts of 5007 cases and 4579 controls and then a meta-analysis in these newly generated and multiple previously published (2277 cases and 3159 controls) datasets were performed. Three novel and 15 previously reported risk loci were identified from these datasets, increasing the known leprosy risk loci of explained genetic heritability from 23.0 to 38.5%. A comprehensive fine-mapping analysis was conducted, and 19 causal variants and 14 causal genes were identified. Specifically, manual checking of epigenomic information from the Epimap database revealed that the causal variants were mainly located within the immune-relevant or immune-specific regulatory elements. Furthermore, by using gene-set, tissue, and cell-type enrichment analyses, we highlighted the key roles of immune-related tissues and cells and implicated the PD-1 signaling pathways in the pathogenetic mechanism of leprosy. Collectively, our study identified candidate causal variants and elucidated the potential regulatory and coding mechanisms for genes associated with leprosy.
ABSTRACT
BACKGROUND: A few new leprosy cases still can be seen in Shandong province after elimination. In post-elimination era, government commitments dwindled and active case-finding activities were seldom done. Most of the cases were detected by passive modes and advanced cases with longer delay and visible disability were common. MATERIALS AND METHODS: Comprehensive measures including health promotion, personnel training, reward-offering, symptom surveillance and a powerful referral center were implemented in the past decade. The diagnosis of leprosy was mainly based on three cardinal clinical signs. Two-group classification system developed by the WHO was used and cases were classified into multibacillary (MB) type or paucibacillary (PB) type. Cases detected during period 2007-2017 were analyzed and associated factors of grade 2 disability (G2D) were explored. RESULTS: 231 new leprosy cases detected during 2007-2017 were analyzed. The mean age at diagnosis is 51.7±16.0 years and the number of males, peasants, illiterates, MB cases, G2D cases and immigrants were 130(56.3%), 221(95.7%), 73(31.6%), 184(79.7%), 92(39.8%) and 40(17.3%) respectively. 181(78.4%) cases were reported by skin clinics and 152 (65.8%) cases came from formerly high endemic counties/districts. The annual number of new cases showed a decreasing trend, from 42 cases in 2008 to 13 cases in 2017. 92 (39.8%) cases presented with G2D at diagnosis. The annual proportion of new cases with G2D declined from 50% in 2008 to 23% in 2017. PB type (OR = 2.76, 95% CI, 1.43-5.32), >12 months of patient delay (OR = 2.40, 95% CI, 1.38-4.19), >24 months of total delay (OR = 4.35, 95% CI, 2.33-8.11), detected by non skin-clinic (OR = 3.21, 95% CI, 1.68-6.14), known infectious source (OR = 1.77, 95% CI, 1.01-3.12) were associated with G2D. CONCLUSION: A few scattered cases still can be seen in post-elimination era and some kind of leprosy control program is still necessary. Government commitments including adequate financial security and strong policy support are vital. Comprehensive case-finding measures including health promotion, personnel training, reward-offering, with an emphasis on former high or middle endemic areas, are necessary to improve early presentation of suspected cases and to increase suspicion and encourage participation of all relevant medical staff. Symptom surveillance based on a powerful transfer center may play an important role in the early detection of new cases in post-elimination era.
Subject(s)
Leprosy/diagnosis , Leprosy/epidemiology , Adult , Aged , China/epidemiology , Early Diagnosis , Female , Humans , Male , Middle AgedABSTRACT
Leprosy, a chronic infectious disease, results from the uncultivable pathogen Mycobacterium leprae (M. leprae), and usually progresses to peripheral neuropathy and permanent progressive deformity if not treated. Previously published genetic studies have identified 18 gene/loci significantly associated with leprosy at the genome-wide significant level. However as a complex disease, only a small proportion of leprosy risk could be explained by those gene/loci. To further identify more susceptibility gene/loci, we hereby performed a three-stage GWAS comprising 8,156 leprosy patients and 15,610 controls of Chinese ancestry. Four novel loci were identified including rs6807915 on 3p25.2 (P=1.94 × 10-8, OR=0.89), rs4720118 on 7p14.3 (P=3.85 × 10-10, OR=1.16), rs55894533 on 8p23.1 (P=5.07 × 10-11, OR=1.15) and rs10100465 on 8q24.11 (P=2.85 × 10-11, OR=0.85). Altogether, these findings have provided new insight and significantly expanded our understanding of the genetic basis of leprosy.