Susceptibility to tuberculosis is associated with the ASAP1 gene that regulates dendritic cell migration. Y. Luo1, J. Curtis2, H. L. Zenner2, D. Cuchet-Lourenco2, C. Wu2, K. Lo3, M. Maes2, A. Alisaac2, E. Stebbings2, J. Z. Liu1, O. Ignatyeva4,5, Y. Balabanova4,5, V. Nikolayevskyy5, P. Nürnberg6, R. Horstmann7, F. Drobniewski4, V. Plagnol3, J. C. Barrett1, S. Nejentsev2 1) Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK; 2) Department of Medicine, University of Cambridge, Cambridge, UK; 3) UCL Genetics Institute, UCL, London, UK; 4) Samara Oblast Tuberculosis Dispensary, Samara, Russia; 5) Health Protection Agency National Mycobacterium Reference Laboratory and Clinical TB and HIV Group, Institute for Cell and Molecular Sciences, Barts and the London School of Medicine, Queen Mary, University of London, London, UK; 6) Cologne Center for Genomics, University of Cologne, Cologne, Germany; 7) Department of Molecular Medicine, Bernhard Nocht Institute for Topical Medicine, Hamburg, Germany.

   Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis, remains a major threat to public health, with two billion people estimated to be infected with the pathogen worldwide. Despite its high infection rate, only ~10% of infected individuals eventually develop active TB. Early case observations, twin studies and mouse models indicate that host genetic factors are important in determining susceptibilities to M. tuberculosis. Recent Genome-wide association studies (GWAS) have identified two loci on chromosomes 11p13 and 18q11 in two African populations. However, pathophysiological mechanisms underpinning these associations, as well as their role in other TB endemic regions, remain unknown. In this study, we conducted the largest TB GWAS to date of 5,914 patients with active pulmonary TB and 6,022 healthy adult controls from Russia using Affymetrix Genome-Wide Human SNP array 6.0, and then imputed genotypes at ~7.6 million SNPs using the 1000 Genome reference panel. Our study identified a new TB-associated locus on chromosome 8q24, where 11 SNPs located in introns of the ASAP1 gene reached the genome-wide significant level (P 5 x 10-8). Among the most significantly associated SNPs, 7 were selected for replication in the combined cohort of 15,087 subjects and showed strong association with TB (P = 2.6 x 10-11). We also see association in one of the two previously reported TB GWAS loci at 11p13 (rs2057178, P = 0.00068), but did not detect any signal at the 18q11 locus, suggesting that it may be population-specific. To advance our understanding of the pathophysiological mechanisms underpinning the ASAP1 associations, we further studied the expression of ASAP1 in dendritic cells (DCs). DCs are essential in the formation and maintenance of granulomas -- structures that are characteristic of human TB. DCs had high ASAP1 expression, which was reduced after M. tuberculosis infection. We found that the TB-associated SNP was also associated with the level of reduction of ASAP1 expression after M. tuberculosis infection (P = 4.6 x 10-3). After knockdown of ASAP1 expression, DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis-infected DCs may lead to their impaired migration and predispose to TB. Our study highlights a novel functional mechanism, indicating that the ASAP1-mediated pathways are involved in mycobacterial infection and TB pathogenesis.

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