A large-scale genome-wide association and meta-analysis identified four novel susceptibility loci for leprosy

Abstract

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.

Discovery of 4 exonic and 1 intergenic novel susceptibility loci for leprosy

“…In addition, rs1465788, which is found in the upstream region of the ZFP36L1 gene, showed consistent associations between the discovery and validation samples, but was barely below the genome‐wide significance threshold level ( P = 7.81 × 10 −6 , OR = 0.88, Table ). We also checked the association results of variants located in the LD region of variant rs1465788 against our previously imputed GWAS dataset, which included 2743 leprosy cases and 3573 healthy controls . The rs1465788 variant was found to be the top variant in the LD locus with a P value of 1.02 × 10 −4 (Figure S3).…”

“…We also checked the association results of variants located in the LD region of variant rs1465788 against our previously imputed GWAS dataset, which included 2743 leprosy cases and 3573 healthy controls. 8 The rs1465788 variant was found to be the top variant in the LD locus with a P value of 1.02 × 10 −4 ( Figure S3). The transcription factor CCCTC-Binding factor (CTCF) was predicted to bind at the rs1465788 site and was subsequently co-transfected with reporter vectors to determine whether the effect of the risk allele on the binding capacity of the transcription factor caused decreased promoter activity.…”

Precision Medicine in Critical Illness: Sepsis and Acute Respiratory Distress Syndrome

“…Because these were all retrospective studies and many were subgroup analyses, a prospective validation study is needed before altering clinical care SRS sepsis response signature, PEEP positive end-expiratory pressure, IV intravenous T-cell, natural killer cell, neutrophil) to combined immunodeficiencies, autoimmune diseases, or autoinflammatory disorders. Some syndromes present as an inherited susceptibility to one particular type of infection, such as mycobacteria, fungi, or certain bacteria, and thus, elucidation of the respective genetic underpinnings has helped to pinpoint critical host responses to specific pathogens [42][43][44][45][46]. Further, the identification of monogenic conditions causing auto-inflammatory conditions that mimic the clinical features of sepsis while remaining culture-negative [47][48][49] highlight the primacy of host response in driving shock and organ failure.…”

Meta-Analysis Identifies Major Histocompatiblity Complex Loci in or Near HLA-DRB1, HLA-DQA1, HLA-C as Associated with Leprosy in Chinese Han Population

“…In order to identify specific HLA variants potentially underlying leprosy in the Han Chinese population, we conducted a large-scale fine-mapping study of leprosy risk by imputing class I and II HLA genes and their corresponding amino acid variation sites using a previously described HLA reference panel specifically for the Han Chinese population (Zhou et al, 2016). We utilized genotyping data from a total of 2,901 leprosy cases and 3,801 healthy controls from previously published three-stage leprosy genome-wide association studies data sets (Liu et al, 2015;Wang et al, 2016;Wong et al, 2010) (please note the details of available data through GEO database, https://www.ncbi.nlm.nih.gov/geo/info/ datasets.html, GEO accession number: GSE119367), which were divided into four groups according to ethnicity (Supplementary Table S1 online). We then performed imputation to fine-map leprosy-related major histocompatibility complex variants.…”