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Lancet. 2016 Jun 4;387(10035):2312-2322. doi: 10.1016/S0140-6736(15)01316-1. Epub 2016 Mar 24.

A blood RNA signature for tuberculosis disease risk: a prospective cohort study.

Author information

1
The Center for Infectious Disease Research, Seattle, WA, USA.
2
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine & Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.
3
KNCV Tuberculosis Foundation, The Hague, Netherlands.
4
Vaccines & Immunity, Medical Research Council Unit, Fajara, The Gambia.
5
Immunology Unit, Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
6
Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, UK.
7
Tuberculosis Research Unit, Case Western Reserve University, Cleveland, OH, USA.
8
Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.
9
Department of Medicine and Department of Microbiology, Makerere University, Kampala, Uganda.
10
Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, UK; Karonga Prevention Study, Chilumba, Malawi.
11
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
12
DST/NRF Centre of Excellence for Biomedical TB Research and MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Tygerberg, South Africa.
13
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine & Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa. Electronic address: willem.hanekom@gatesfoundation.org.

Abstract

BACKGROUND:

Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat the tuberculosis epidemic. We aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease.

METHODS:

In this prospective cohort study, we followed up healthy, South African adolescents aged 12-18 years from the adolescent cohort study (ACS) who were infected with M tuberculosis for 2 years. We collected blood samples from study participants every 6 months and monitored the adolescents for progression to tuberculosis disease. A prospective signature of risk was derived from whole blood RNA sequencing data by comparing participants who developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex quantitative real-time PCR (qRT-PCR), the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. Participants of the independent cohorts were household contacts of adults with active pulmonary tuberculosis disease.

FINDINGS:

Between July 6, 2005, and April 23, 2007, we enrolled 6363 participants from the ACS study and 4466 from independent South African and Gambian cohorts. 46 progressors and 107 matched controls were identified in the ACS cohort. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% CI 63·2-68·9) and a specificity of 80·6% (79·2-82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA sequencing and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6-64·3) and a specificity of 82·8% (76·7-86) in the 12 months preceding tuberculosis.

INTERPRETATION:

The whole blood tuberculosis risk signature prospectively identified people at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease.

FUNDING:

Bill & Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union, and the South African Medical Research Council.

PMID:
27017310
PMCID:
PMC5392204
DOI:
10.1016/S0140-6736(15)01316-1
[Indexed for MEDLINE]
Free PMC Article

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