title: Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medicine, University of Washington School of Medicine Firland Northwest TB Center, University of Washington.
authors.forename: David J
authors.initials: DJ
authors.lastname: Horne
authors.affiliation: Department of Medicine, University of Washington School of Medicine.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Graustein
authors.affiliation: Department of Medicine, University of Washington School of Medicine.
authors.forename: Javeed A
authors.initials: JA
authors.lastname: Shah
authors.affiliation: Department of Medicine, University of Washington School of Medicine.
authors.forename: Glenna
authors.initials: G
authors.lastname: Peterson
authors.affiliation: TB Control Program, Public Health-Seattle and King County, Washington.
authors.forename: Meg
authors.initials: M
authors.lastname: Savlov
authors.affiliation: TB Control Program, Public Health-Seattle and King County, Washington.
authors.forename: Sergio
authors.initials: S
authors.lastname: Steele
authors.affiliation: Department of Medicine, University of Washington School of Medicine Firland Northwest TB Center, University of Washington TB Control Program, Public Health-Seattle and King County, Washington.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Narita
authors.affiliation: Department of Medicine, University of Washington School of Medicine.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D051017:Apoptosis Regulatory Proteins; D044466:Asian People / Q000235:genetics; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D055985:Latent Tuberculosis / Q000235:genetics* / Q000382:microbiology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000382:microbiology*; D020298:U937 Cells
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C116741:GABARAP protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D000071189:Autophagy-Related Protein-1 Homolog; C484754:ULK1 protein, human
keywords: autophagy; candidate gene analysis; genetic susceptibility; single nucleotide polymorphism; tuberculosi