Cardiometabolic risk factors and type 2 diabetes (T2D) impart a substantial and growing morbidity and mortality burden that disproportionally affects racial/ethnic minorities, including Hispanic/Latinos (H/L). The population burden, established disparities, and limited availability of T2D treatments to reverse progression or prevent long- term complications underscore an urgent need to clarify mechanistic pathways that may serve as novel targets for prevention and treatment. Chronic low-grade inflammation is a widely recognized common pathological feature underling cardiometabolic risk factors and T2D, particularly in H/L when compared to other racial/ethnic groups; identifying specific mediators of chronic low-grade inflammation could greatly enhance efforts to tailor existing agents or develop of novel therapies, especially in populations at highest risk. Prior attempts to examine specific mediators of chronic low-grade inflammation have been limited by a focus on downstream markers, including C-reactive protein, which are less likely to be causal or are difficult to reliably measure. Upstream regulation of systemic inflammation is in turn mediated by fatty acid derived lipid mediators termed eicosanoids. Although select eicosanoids have been associated with cardiometabolic risk factors and T2D, prior studies have only assessed a handful of the most abundant eicosanoids in humans. We propose to address this major research gap by leveraging advances in analytical mass spectrometry (MS) that now enable the rapid and accurate quantification of >150 eicosanoids spanning major biosynthetic pathways. Eicosanoids will be assayed in the deeply-phenotyped population-based Hispanic Community Health Study/Study of Latinos (SOL) cohort, enabling cost-effective testing of study hypotheses in a H/L population with established cardiometabolic risk factor and T2D disparities. Specifically, we will identify known and novel eicosanoids associated with cardiometabolic risk factors and T2D, as well as leverage existing genomics data to conduct causal inference studies and evaluate mechanistic frameworks for key eicosanoids. This work will shed insight into the mechanisms underlying cardiometabolic disease in H/L, identify potential sources of health disparities in a genetically admixed cohort, and provide an essential foundation for future studies of inflammatory-modulating therapies aimed at reducing the burden of cardiometabolic disease in the population at large.

Public Health Relevance

Type 2 diabetes (T2D) and adverse cardiometabolic risk factor profiles impart major and growing public health burdens that are disproportionately shouldered by racial/ethnic minorities, including Hispanic/Latinos. Chronic low-grade inflammation is a common pathologic feature underling adverse cardiometabolic risk factors and T2D, particularly in Hispanic/Latinos. Our proposal to examine the role of upstream inflammatory mediators in the development of cardiometabolic risk factors and T2D will offer insights into cardiometabolic disease mechanisms, sources of health disparities, and potential future therapeutic targets for reducing this major disease burden.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Kidney, Nutrition, Obesity and Diabetes Study Section (KNOD)
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Coady, Sean
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University of North Carolina Chapel Hill
Public Health & Prev Medicine
Schools of Public Health
Chapel Hill
United States
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