Integration of genetic and transcriptional profiles of innate cells to decipher mechanisms of TB susceptibility
Sara Suliman1, Maria Arcelus-Gutierrez1,2,3,4,5, Samira Asgari1,2,3,4,5, Sarah K. Iwany1, Kattya Lopez Tamara1,6, Yang Luo1,2,3,4,5, Aparna Nathan1,2,3,4,5, Zibiao Zhang7, Segundo R León6, Roger I Calderon6, Leonid Lecca6, Megan B. Murray7, Ildiko Van Rhijn1,8, Soumya Raychaudhuri1,2,3,4,5,9, and D. Branch Moody1
1Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
2Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 3Broad Institute of MIT and Harvard, Cambridge, MA, USA; 4Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
5Center for Data Sciences, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; 6Socios En Salud Sucursal Peru, Lima, Peru; 7Department of Global Health and Social Medicine, and Division of Global Health Equity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
8Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
9Centre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
Most people infected with Mycobacterium tuberculosis (Mtb) never develop TB disease, suggesting host-specific risk factors for disease progression. Transcriptional profiling of samples from TB patients and Mtb-exposed controls identified innate pathways associated with progression to TB disease. However, few published studies integrate genetic variation with transcriptional profiles to decipher mechanisms of TB pathogenesis. We sought to determine how genetic polymorphisms influence expression of key innate response genes between individuals at high and low risk of progression to TB. From a prospective Peruvian cohort of household contacts of TB patients, we re-recruited fully genotyped former progressors (n=68) and non-progressors (n=67) and stored cryopreserved peripheral blood mononuclear cell samples. We generated monocyte-derived dendritic cells and macrophages by differentiating sorted monocytes in granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 4 (IL4), or macrophage colony-stimulating factor (M-CSF), respectively. Samples were analyzed by low-input RNA-sequencing and flow cytometry. We analyzed the impact of genetic polymorphisms on expression of key target genes in an expression quantitative trait loci (eQTL) study. We identified 433 and 355 eQTL events in DCs and macrophages, respectively, 76 of which were unique to one cell type. In addition, we identified a novel interaction between a single nucleotide polymorphism rs2562754 and TB status with expression of FAH, the gene encoding for Fumaryl Acetoacetate Hydrolase, which mediates tyrosine catabolism. This eQTL analysis highlights under-explored candidate TB susceptibility pathways, which are now being functionally validated using CRISPR-based gene editing.