Background
Understanding how pathogen genetic factors contribute to pathology in tuberculosis could enable tailored treatments to the most pathogenic and infectious strains. New strategies are needed to control drug-resistant tuberculosis which requires longer and costlier treatment. We hypothesized that the severity of radiological pathology on the chest radiograph in tuberculosis disease was associated with variants arising independently, multiple times (homoplasies) in the Mycobacterium tuberculosis genome.
Methods
We performed whole genome sequencing (Illumina HiSeq2000 platform) on M. tuberculosis isolates from 103 drug-resistant tuberculosis patients in Lima between 2010-2013. Variables including age, sex, HIV status, previous tuberculosis disease and the percentage of lung involvement on the pre-treatment chest radiograph were collected from health posts of the national tuberculosis program. Genomic variants were identified using standard pipelines.
Results
Two mutations were significantly associated with more widespread radiological pathology in a multivariable regression model controlling for confounding variables [Rv2828c.141, RR 1.3 95%CI 1.21-1.39, p<0.01; rpoC.1040 95%CI 1.77-2.16, RR 1.9, p<0.01]. The rpoB.450 mutation was associated with less extensive radiological pathology (RR 0.81 95%CI 0.69-0.94, p=0.03) suggestive of a bacterial fitness cost for this mutation in vivo. Patients with a previous episode of tuberculosis disease and those between 10-30 years of age also had significantly increased radiological pathology.
Conclusions
This study is the first to compare the M. tuberculosis genome to radiological pathology on the chest radiograph. We identified two variants significantly positively associated with more widespread radiological pathology, and one with reduced pathology. Prospective studies are warranted to determine whether mutations associated with increased pathology also predict the spread of drug-resistant tuberculosis
