Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

• Published in: Nature genetics Vol. 47; no. 5; pp. 523 - 527
• Main Authors: Curtis, James, Luo, Yang, Zenner, Helen L, Cuchet-Lourenço, Delphine, Wu, Changxin, Lo, Kitty, Maes, Mailis, Alisaac, Ali, Stebbings, Emma, Liu, Jimmy Z, Kopanitsa, Liliya, Ignatyeva, Olga, Balabanova, Yanina, Nikolayevskyy, Vladyslav, Baessmann, Ingelore, Thye, Thorsten, Meyer, Christian G, Nürnberg, Peter, Horstmann, Rolf D, Drobniewski, Francis, Plagnol, Vincent, Barrett, Jeffrey C, Nejentsev, Sergey
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2015; Nature Publishing Group
• Subjects: 14/1; 14/34; 14/63; 45/43; 631/208/205; 692/699/255/1856; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adult; Agriculture; Animal Genetics and Genomics; Biomedical research; Biomedicine; Cancer Research; Case-Control Studies; Cell Movement; Cells, Cultured; Data analysis; Datasets; Dendritic Cells - physiology; Deoxyribonucleic acid; Disease; Disease susceptibility; DNA; Female; Gene Expression; Gene Function; Genetic aspects; Genetic factors; Genetic Predisposition to Disease; Genetic testing; Genetic variance; Genetic variation; Genome-Wide Association Study; Genomes; Health aspects; Human Genetics; Humans; Identification and classification; Infections; Inflammatory bowel disease; Introns; letter; Logistics; Male; Middle Aged; Polymorphism, Single Nucleotide; Protein Transport; Proteins; Risk factors; Studies; Tuberculosis; Tuberculosis, Pulmonary - genetics; Russia
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3248

Sergey Nejentsev and colleagues identify intronic variants in ASAP1 that associate with susceptibility to tuberculosis. They show that ASAP1 is downregulated in dendritic cells infected with Mycobacterium tuberculosis , impairing their migration and matrix degradation abilities. Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 ( P = 2.6 × 10 −11 for rs4733781; P = 1.0 × 10 −10 for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted 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, suggesting a potential mechanism of predisposition to TB.