Tuberculosis infection and risk of diabetes mellitus and cardiovascular disease: Epigenetic and cardiometabolic trajectories after TB infection

Emory University, Atlanta GA

Investigators

Abstract

The intersection of tuberculosis (TB) with diabetes mellitus and cardiovascular disease (CVD) is a critical clinical and public health obstacle. Global diabetes incidence and prevalence is expanding rapidly, particularly in the United States where latent tuberculosis infection (LTBI) affects >13 million people. At the same time CVD is the leading cause of death, including in the US and globally. An expanding body of data bidirectionally link TB to both diabetes and CVD: previous theories suggested that diabetes and CVD only predisposed persons to becoming infected with TB; however, emerging information clearly demonstrates that TB disease increases the risk of both diabetes and CVD. But to date, the notion that LTBI may increase the risk of cardiometabolic diseases like diabetes and CVD has not been well explored. This study will determine the extent to which LTBI impacts indicators of diabetes and CVD incidence. We will also assess epigenetic signatures of LTBI and whether they impact cardiometabolic disease risk. This research will improve understanding of burdens of LTBI and non-communicable disease and inform treatment guidelines for management of LTBI and prevention of cardiometabolic disease. The long-term objective of this research is to generate an evidence base to help determine whether persons with LTBI would benefit from preventive interventions for diabetes and CVD. The specific aims of this proposal are to: (1) estimate the relationship between LTBI and indicators of diabetes and CVD; (2) determine whether established DNA methylation patterns of diabetes and CVD incidence are also associated with LTBI; and (3) explore longitudinal changes in DNA methylation patterns associated with recent LTBI. The aims of this project will be achieved by enrolling a cohort of participants with and without LTBI. We will determine LTBI status among participants at enrollment and follow them prospectively for 24-months. At enrollment and follow up time points we will measure insulin resistance, glycated hemoglobin, visceral adiposity index, pulse wave velocity, blood pressure, and endothelial function. We will also measure DNA methylation at enrollment and in a subset at follow up. The analyses will include multiple modeling strategies to assess the relationship between patient and host factors and the risk of cardiometabolic disease incidence. This proposal will directly address clinical and mechanistic uncertainties related to the growing global concern of intersecting TB with diabetes and CVD epidemics. The study will characterize the extent that LTBI contributes to diabetes and CVD risk and will identify which epigenetic signatures are related to both LTBI and cardiometabolic disease risk. Elucidating mechanistic linkages between LTBI and cardiometabolic disease risk will allow our group to evaluate the utility of using existing therapies aimed at lowering diabetes and CVD risk and identify new pathways that could be targeted to improve clinical outcomes for persons with LTBI.