Abstract
Background. Data suggest that the tuberculosis (TB) – diabetes mellitus (DM) interaction is bidirectional with comorbidity being associated with unfavorable outcomes for both diseases. Epigenetic changes may influence the interaction between infectious diseases and non-communicable diseases. We defined TB infection (TBI) as having a positive QuantiFERON (QFT), an interferon-Ɣ release assay in response to TB antigens. Methods. We performed a cross-sectional epigenome wide association study of 75 contacts of active TB cases. We compared those with and without TBI to evaluate 1) if patients with TBI have differentially methylated DNA, and 2) if methylation patterns are similar to signatures associated with DM incidence, immune exhaustion, and/or accelerated aging. Participants were >18 years of age, normoglycemic, HIV-negative, and without signs/symptoms of active TB disease. We used a linear model where CpG methylation was the outcome and QFT results (categorical and continuous) were the primary exposure. We adjusted for age, sex, and white blood cell types. Results. Seventy-five individuals were included in the analysis. Thirty-eight had a positive QFT (presumed TBI) compared to 37 with a negative QFT test. Persons with a positive QFT had differentially methylated DNA, measured as “effect” of QFT positivity on the proportion of methylation on each of the 935,000 CpG sites. The strongest effect was elucidated at CpG site cg08369130, located on chromosome 5 and linked to the GABRB3 gene that encodes the gamma-aminobutyric acid (GABA) A receptor. Its mean methylation was 21.69% lower among those with positive QFT compared to those with negative QFT. Our analysis also suggests that QFT positivity is associated with 3.76 years of accelerated aging. Cg20784591 and cg24678869, associated with increased incident DM, and cg02026773, associated with immune exhaustion in TB disease, were found to be differentially methylated in persons with asymptomatic QFT positivity. Conclusion. We found an association between DNA methylation and immune response to TB antigens, a process that could help re-define TBI as a dynamic infectious state, rather than a simple latent reservoir for future TB disease cases. Finally, QFT positivity was associated with age acceleration, a potentially impactful finding in a condition affecting around 23% of the World population.
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