Genome-wide association study reveals a novel tuberculosis susceptibility locus in multiple East Asian and European populations
Rattachement africain : sg, us, au, gb, vn. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Abstract Background Tuberculosis (TB) continues to be a leading cause of morbidity and mortality worldwide. Although numerous genome-wide association studies (GWAS) have explored TB susceptibility across various ethnic groups, multi-population replication of findings has been very limited, particularly outside the HLA region, and a significant portion of TB heritability remains unexplained. Methods We conducted GWAS in the Singapore Chinese and Vietnamese, followed by a comprehensive meta-analysis incorporating 4 independent East Asian datasets (N = 11,841 cases; N = 197,373 controls). The transferability of any identified association was assessed using summary statistics from independent European populations. Potential candidate genes were prioritized using gene-based association testing and integrative bioinformatic database mining, followed by functional validation through assessment of Mycobacterium marinum (M.marinum) infection burden in CRISPR-Cas9-edited zebrafish embryos. Results We identified a novel susceptibility locus for pulmonary TB (PTB) at 22q12.2 in East Asians [rs6006426, OR (95%Cl) = 1.097(1.066, 1.130), Pmeta=3.31 × 10− 10]. The association was further validated in Europeans [OR (95%Cl) = 1.101(1.002, 1.211), P = 0.046] and was strengthened in the combined meta-analysis including a total of 12,736 PTB cases and 673,864 controls [OR (95%Cl) = 1.098 (1.068, 1.129); Pmeta=4.33 × 10− 11]. Gene-based association test identified Oncostatin M (OSM) to be significantly associated with PTB (ZSTAT = 5.013; P = 2.68 × 10− 7; Padj=0.005). The lead SNP rs6006426 affected Splicing factor 3a subunit 1 (SF3A1) expression in various immune cells (P from 0.003 to 6.17 × 10− 18) and OSM expression in monocytes post lipopolysaccharide stimulation (P = 5.57 × 10− 4) as reported in the eQTL Catalogue. CRISPR-Cas9 edited zebrafish embryos with osm depletion resulted in decreased burden of M.marinum in infected embryos (P = 0.047). Conclusions Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.
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National University of Singapore pays non établi dans la noticeUniversité ou école supérieure
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University Health System pays non établi dans la noticeÉtablissement de santé
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Peter Doherty Institute pays non établi dans la noticeStructure de recherche
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National University Health System pays non établi dans la noticeUniversité ou école supérieure
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Tan Tock Seng Hospital pays non établi dans la noticeÉtablissement de santé
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Nanyang Technological University pays non établi dans la noticeUniversité ou école supérieure
National University of Singapore, University Health System et Peter Doherty Institute, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.