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Am J Respir Crit Care Med. 2018 Apr 6. doi: 10.1164/rccm.201711-2340OC. [Epub ahead of print]

Four-gene Pan-African Blood Signature Predicts Progression to Tuberculosis.

Author information

1
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine & Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
2
The Center for Infectious Diseases Research, Seattle, Washington, United States.
3
Vaccines and Immunity, Medical Research Council Unit, Fajara, Gambia.
4
Max-Planck-Institut fur Infektionsbiologie, 28260, Berlin, Germany.
5
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine & Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, Western Cape, South Africa.
6
Case Western Reserve University, Cleveland, Ohio, United States.
7
Center for Infectious Diseases Research, Seattle, Washington, United States.
8
University of Otago, 2495, Preventive and Social Medicine, Dunedin, New Zealand.
9
DST/NRF Centre of Excellence for Biomedical TB Research and MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Heath Sciences, Stellenbosch University, Cape Town, South Africa.
10
Medical Research Council (UK) Laboratories, Bacterial Diseases Programme, Banjul, Gambia.
11
Medical Research Council Unit, Disease Control and Elimination Theme, Banjul, Gambia.
12
Immunology Unit, Armauer Hansen Research Institute, Addid Ababa, Ethiopia.
13
Makerere University, 58588, Kampala, Kampala, Uganda.
14
Case Western Reserve University School of Medicine, 12304, Cleveland, Ohio, United States.
15
London School of Tropical Medicine and Hygiene, Infectious and Tropical Diseases, London, United Kingdom of Great Britain and Northern Ireland.
16
Leiden University Medical Center, Leiden, Netherlands.
17
Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany.
18
The Center for Infectious Disease Research, Seattle, Washington, United States.
19
DST/NRF Centre of Excellence for Biomedical TB Research and MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Heath Sciences, Stellenbosch University, Cape Town, South Africa ; gwalzl@sun.ac.za.

Abstract

RATIONALE:

Contacts of tuberculosis (TB) patients constitute an important target population for preventative measures as they are at high risk of infection with Mycobacterium tuberculosis and progression to disease.

OBJECTIVES:

We investigated biosignatures with predictive ability for incident tuberculosis.

METHODS:

In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, polymerase chain reaction (PCR) and the Pair Ratio algorithm in a training/test set approach. Overall, 79 progressors, who developed tuberculosis between 3 and 24 months following exposure, and 328 matched non-progressors, who remained healthy during 24 months of follow-up, were investigated.

MEASUREMENTS AND MAIN RESULTS:

A four-transcript signature (RISK4), derived from samples in a South African and Gambian training set, predicted progression up to two years before onset of disease in blinded test set samples from South Africa, The Gambia and Ethiopia with little population-associated variability and also validated on an external cohort of South African adolescents with latent Mycobacterium tuberculosis infection. By contrast, published diagnostic or prognostic tuberculosis signatures predicted on samples from some but not all 3 countries, indicating site-specific variability. Post-hoc meta-analysis identified a single gene pair, C1QC/TRAV27, that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events.

CONCLUSIONS:

Collectively, we developed a simple whole blood-based PCR test to predict tuberculosis in household contacts from diverse African populations, with potential for implementation in national TB contact investigation programs.

KEYWORDS:

Biomarkers; Gene expression; Tuberculosis

PMID:
29624071
PMCID:
PMC6019933
[Available on 2019-05-01]
DOI:
10.1164/rccm.201711-2340OC

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