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 Drobniewski; Vincent Plagnol; Jeffrey C. Barrett; Sergey Nejentsev

doi:10.1038/ng.3248

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

143 Citations (Scopus)

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 language	English
Pages (from-to)	523-527
Number of pages	5
Journal	Nature Genetics
Volume	47
Issue number	5
DOIs	https://doi.org/10.1038/ng.3248
Publication status	Published - 30 May 2015

Bibliographical note

Funding Information:
The study was supported by Wellcome Trust grants 088838/Z/09/Z (to S.N., J.C.B., F.D.) and 095198/Z/10/Z (to S.N.), EU Framework Programme 7 Collaborative grant 201483 (to S.N., F.D., R.D.H., P.N.), European Research Council Starting grant 260477 (to S.N.), and Royal Society grants UF0763346 (to S.N.) and RG090638 (to S.N.). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science and is also supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ng.3248

Cite this

Curtis, J., Luo, Y., Zenner, H. L., Cuchet-Lourenço, D., Wu, C., Lo, K., Maes, M., Alisaac, A., Stebbings, E., Liu, J. Z., Kopanitsa, L., Ignatyeva, O., Balabanova, Y., Nikolayevskyy, V., Baessmann, I., Thye, T., Meyer, C. G., Nürnberg, P., Horstmann, R. D., ... Nejentsev, S. (2015). Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration. Nature Genetics, 47(5), 523-527. https://doi.org/10.1038/ng.3248

@article{b5a5ef1a82d34b9fbcb422b53cf5c9c3,

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

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.",

author = "James Curtis and Yang Luo and Zenner, \{Helen L.\} and Delphine Cuchet-Louren{\c c}o and Changxin Wu and Kitty Lo and Mailis Maes and Ali Alisaac and Emma Stebbings and Liu, \{Jimmy Z.\} and Liliya Kopanitsa and Olga Ignatyeva and Yanina Balabanova and Vladyslav Nikolayevskyy and Ingelore Baessmann and Thorsten Thye and Meyer, \{Christian G.\} and Peter N{\"u}rnberg and Horstmann, \{Rolf D.\} and Francis Drobniewski and Vincent Plagnol and Barrett, \{Jeffrey C.\} and Sergey Nejentsev",

note = "Funding Information: The study was supported by Wellcome Trust grants 088838/Z/09/Z (to S.N., J.C.B., F.D.) and 095198/Z/10/Z (to S.N.), EU Framework Programme 7 Collaborative grant 201483 (to S.N., F.D., R.D.H., P.N.), European Research Council Starting grant 260477 (to S.N.), and Royal Society grants UF0763346 (to S.N.) and RG090638 (to S.N.). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science and is also supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355.",

year = "2015",

month = may,

day = "30",

doi = "10.1038/ng.3248",

language = "English",

volume = "47",

pages = "523--527",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

}

Curtis, J, Luo, Y, Zenner, HL, Cuchet-Lourenço, D, Wu, C, Lo, K, Maes, M, Alisaac, A, Stebbings, E, Liu, JZ, Kopanitsa, L, Ignatyeva, O, Balabanova, Y, Nikolayevskyy, V, Baessmann, I, Thye, T, Meyer, CG, Nürnberg, P, Horstmann, RD, Drobniewski, F, Plagnol, V, Barrett, JC & Nejentsev, S 2015, 'Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration', Nature Genetics, vol. 47, no. 5, pp. 523-527. https://doi.org/10.1038/ng.3248

TY - JOUR

T1 - Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

AU - Curtis, James

AU - Luo, Yang

AU - Zenner, Helen L.

AU - Cuchet-Lourenço, Delphine

AU - Wu, Changxin

AU - Lo, Kitty

AU - Maes, Mailis

AU - Alisaac, Ali

AU - Stebbings, Emma

AU - Liu, Jimmy Z.

AU - Kopanitsa, Liliya

AU - Ignatyeva, Olga

AU - Balabanova, Yanina

AU - Nikolayevskyy, Vladyslav

AU - Baessmann, Ingelore

AU - Thye, Thorsten

AU - Meyer, Christian G.

AU - Nürnberg, Peter

AU - Horstmann, Rolf D.

AU - Drobniewski, Francis

AU - Plagnol, Vincent

AU - Barrett, Jeffrey C.

AU - Nejentsev, Sergey

N1 - Funding Information: The study was supported by Wellcome Trust grants 088838/Z/09/Z (to S.N., J.C.B., F.D.) and 095198/Z/10/Z (to S.N.), EU Framework Programme 7 Collaborative grant 201483 (to S.N., F.D., R.D.H., P.N.), European Research Council Starting grant 260477 (to S.N.), and Royal Society grants UF0763346 (to S.N.) and RG090638 (to S.N.). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science and is also supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355.

PY - 2015/5/30

Y1 - 2015/5/30

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84929133989

U2 - 10.1038/ng.3248

DO - 10.1038/ng.3248

M3 - Article

C2 - 25774636

AN - SCOPUS:84929133989

SN - 1061-4036

VL - 47

SP - 523

EP - 527

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

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

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this