In the Journals Plus

Four-gene signature predicts TB progression

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April 11, 2018

A genetic signature predicted the progression of tuberculosis in household contacts of active cases up to 2 years before disease onset, according to findings published in the American Journal of Respiratory and Critical Care Medicine.

“This simple, four-marker test could be translated into a simple, rapid and affordable point-of-care test for field application in resource-limited settings, where TB and [Mycobacterium tuberculosis] are endemic, to identify individuals at risk of developing TB,” Gerhard Walzl, MMed, PhD, head of the Stellenbosch University Immunology Research Group in Tygerberg, South Africa, and colleagues wrote. “High-risk TB contacts could then be prioritized for prophylactic interventions.”

WHO estimates that about one-quarter of the world's population is infected with M. tuberculosis. However, only 5% to 15% of patients develop active TB. Tuberculin skin tests (TSTs) and interferon-gamma release assays (IGRAs) are currently used to predict TB progression, but the positive predictive values (PPVs) of these tests are low, at 1.5% and 2.7%, respectively, according to the researchers. As a result, the number of patients who test positive with TSTs and IGRAs and require preventive treatment is “prohibitively high.”

Preventive treatment is several weeks long and has potential side effects,” Walzl said in a press release. “One wants to limit the number of people who have to undergo such treatment to those most likely to be at risk for developing active TB.”

To develop a more accurate test, Walzl and colleagues analyzed blood samples from patients in South Africa and Gambia infected with M. tuberculosis to identify gene expression signatures that can better predict TB progression. The researchers selected a genetic signature comprising four genes — GAS6, SEPT4, BLK and CD1C — that were upregulated (GAS6 and SEPT4) or downregulated (BLK and CD1C) in TB progressors vs. matched controls.

The accuracy of the four-gene signature, known as RISK4, was validated in 79 HIV-negative household contacts of patients with active TB in South Africa, Gambia and Ethiopia who developed active TB 3 to 24 months after exposure, as well as 328 matched nonprogressors. The RISK4 biomarker significantly predicted TB progression up to 2 years before diagnosis (area under the receiver operating characteristic curve [AUC] = 0.67), with little variability between countries (AUC = 0.66-0.72; P < .03). In contrast, previously identified genetic signatures have demonstrated cohort-specific variability, which limits their use to certain populations, according to the researchers. RISK4 also predicted TB in an external cohort of South African adolescents with latent infection, confirmed by TST and IGRA testing (AUC = 0.69).

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In healthy, asymptomatic participants, the sensitivity of RISK4 ranged from 50% to 81%, whereas the specificity ranged from 34% to 77%. Although RISK4 had lower positivity rates compared with TSTs and IGRAs, it had a similar poor PPV of 3%, which was due to lower sensitivity rates with higher specificity thresholds, the researchers reported.

Walzl and colleagues conducted a post-hoc meta-analysis to determine whether RISK4 could be reduced to a single gene pair. They found that up-regulation of the complement C1q C-chain (C1QC) and downregulation of T cell receptor alpha variable gene 27 (TRAV27) consistently predicted TB progression in most participants. However, it was less accurate in the cohort of South African adolescents, whose time of M. tuberculosis exposure was unknown.

“The next steps include assessment of the performance of RISK4 and the two-transcript C1QC/TRAV27 signature in other settings, including non-African populations, and to determine the feasibility of developing a near-patient test for targeted intervention,” the researchers concluded. – by Stephanie Viguers

Disclosures: Walzl reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.