Four-gene signature predicted TB progression

A whole blood, four-gene polymerase chain reaction (PCR) signature predicted progression to tuberculosis disease up to 2 years after exposure, investigators reported.

The four-gene signature dubbed RISK4 performed similarly well in four diverse cohorts of HIV-negative household contacts of TB patients in sub-Saharan Africa, reported Sara Suliman, PhD, of the University of Cape Town, South Africa, and her associates. Testing for such a signature could be a cost-effective, point-of-care method to prioritize recipients of prophylactic treatment, the researchers said.

Worldwide, about 1.7 people are infected with M. tuberculosis, but only 5%-20% of these individuals develop TB. Finding a reliable biomarker for increased risk of progression would be “an important step forward towards better TB control,” especially in resource-strapped areas, the investigators said. Unfortunately, the predictive value of a positive tuberculin skin test or a positive interferon gamma release assay is too low to be useful for this purpose, they wrote in the American Journal of Respiratory and Critical Care Medicine.

Accordingly, the investigators searched for gene transcripts whose upregulation or downregulation reliably predicted progression to TB disease. To do so, they compared whole blood PCR test results from 79 cases (who developed TB after exposure to a household index case) and 328 controls (household contacts who did not progress to TB disease). Progressors developed TB disease within 3 to 24 months of exposure. Nonprogressors were matched by site, sex, age, and year of recruitment.

The RISK4 signature comprised four unique genes: GAS6 and SEPT4, which were upregulated in progressors compared with matched controls, and CD1C and BLK, which were downregulated, the researchers reported. For the overall data set, RISK4 predicted TB progression with an area under the curve (AUC) of 0.67 (95% confidence interval, 0.57 to 0.77; P = .0002). The AUC for individual sites ranged from 0.66 to 0.72 (P less than .03) and was 0.69 (P = .0004) among household contacts who were tested within 2 months of index case diagnosis. Furthermore, RISK4 performed comparably in an external cohort South African adolescents who tested positive on Interferon Gamma Release Assay (IGRA) or Tuberculin skin tests (AUC, 0.69; 95% CI, 0.62 to 0.76; P = .0003).

The groups in this study represented diverse genetic backgrounds, TB epidemiology, and circulating strains of M.tb, suggesting that RISK4 reliably predicts TB progression among household contacts across sub-Saharan Africa, the researchers said. Previously published TB signatures (which include DIAG3, DIAG4, and ACS COR) performed as well as RISK4 on the overall test cohort, but not at individual sites, they added.

In unblinded post hoc analyses, two of the four transcripts (SEPT4 and BLK) performed as well as the four-gene RISK4 signature, according to the investigators. Upregulation of the complement C1q C-chain (C1QC) with downregulation of T-cell receptor alpha variable gene 27 (TRAV27) predicted progression even more reliably, with AUCs exceeding 0.76 at all study sites. However, this transcript pair did not perform as well in the separate adolescent cohort (AUC = 0.57).

“Importantly, samples from household contact progressors were collected mostly at enrollment, immediately following exposure to the respective TB index cases, thus possibly representing a signature of recent M.tb exposure,” the researchers noted. “The next steps include assessment of the performance of RISK4 and the 2-transcript C1QC/TRAV27 signature in other settings, including non-African populations, and [determining] the feasibility of developing a near-patient test for targeted intervention.”

Funding sources included the Bill and Melinda Gates Foundation, the National Institutes of Health, the South African Medical Research Council, the Carnegie Corporation of New York, the South African National Research Foundation, and the Claude Leon Foundation. The researchers had no disclosures.

SOURCE: Am J Respir Crit Care Med. 2018 Apr 6. doi: 10.1164/rccm.201711-2340OC.