Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection. (2nd August 2016)

• Record Type: Journal Article
• Authors: Horne, David J.; Graustein, Andrew D.; Shah, Javeed A.; Peterson, Glenna; Savlov, Meg; Steele, Sergio; Narita, Masahiro; Hawn, Thomas R.
• Is Part Of: Journal of infectious diseases. Volume 214:Number 8(2016:Oct. 15)
• Page Start: 1260
• Page End: 1267
• Publication Date: 2016-08-02
• Subjects: autophagy -- candidate gene analysis -- single nucleotide polymorphism -- genetic susceptibility -- tuberculosi; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiw347
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract: Background. Unlike tuberculosis, few studies have evaluated a host genetic basis for variability in susceptibility to latent Mycobacterium tuberculosis infection (LTBI). We performed a candidate gene association study of autophagy-related genes and LTBI. Methods. We enrolled close contacts of individuals with pulmonary tuberculosis, assessed LTBI status, and determined clinical and sociodemographic risk factors for LTBI. In participants who self-identified as Asian or black, we compared haplotype-tagging single-nucleotide polymorphisms (SNPs) in ULK1 and GABARAP between cases (n = 143) and controls (n = 106). Using CRISPR/Cas9 in U937 monocytes, we investigated the effect of ULK1 deficiency on cytokine expression, autophagy, and M. tuberculosis replication. Results. In Asian participants, we identified 2 ULK1 SNPs (rs12297124 and rs7300908) associated with LTBI. After adjustment for population admixture and clinical risk for LTBI, each rs12297124 minor allele conferred 80% reduction in LTBI risk (odds ratio, 0.18; 95% confidence interval, .07–.46). Compared with controls, ULK1-deficient cells exhibited decreased tumor necrosis factor secretion after stimulation with Toll-like receptor ligands and M. tuberculosis whole-cell lysate, increased M. tuberculosis replication, and decreased selective autophagy. Conclusions. These results demonstrate a strong association of rs12297124, a noncoding ULK1 SNP, with LTBI and a role for ULK1 regulation of TNF secretion, nonspecific and M. tuberculosis– induced autophagy, and M. tuberculosis replication in monocytes.