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

James Curtis, Yang Luo, Helen L Zenner, Delphine Cuchet-Lourenço, Changxin Wu, Kitty Lo, Mailis Maes, Ali Alisaac, Emma Stebbings, Jimmy Z Liu, Liliya Kopanitsa, Olga Ignatyeva, Yanina Balabanova, Vladyslav Nikolayevskyy, Ingelore Baessmann, Thorsten Thye, Christian G Meyer, Peter Nürnberg, Rolf D Horstmann, Francis DrobniewskiVincent Plagnol, Jeffrey C Barrett, Sergey Nejentsev

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)523-527
Number of pages5
JournalNature Genetics
Volume47
Issue number5
DOIs
Publication statusPublished - May 2015

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