DISCOVERY AND VALIDATION OF A NOVEL NEUTROPHIL ACTIVATION MARKER ASSOCIATED WITH OBESITY

Abstract

Obesity and its related comorbidities such as cardiovascular disease (CVD) have imposed a huge burden on public health worldwide. Identification of the mechanistic pathways by which obesity impacts cardiovascular health is urgently needed to provide new targets for prevention of obesity and its associated CVDs. Low-grade systemic inflammation accompanies obesity and etiologically contributes to obesity-induced CVD. Neutrophils represent the most abundant type of leukocytes in humans and neutrophil activation is a fundamental process in the inflammatory response. Growing evidence supports that neutrophils are most likely to be the target peripheral leukocyte subtype initiating the adipose tissue inflammatory cascade in response to obesity. As depleting neutrophils is not a choice in humans, identification of obesity induced neutrophil activation markers becomes a prerequisite to develop targeted treatment. Therefore, our central hypothesis is that there are neutrophil activation markers that can specifically respond to obesity status and mediate obesity’s effect on CVD risks. The goal of this study is to identify these markers and their roles on CVD risk using a step-wise approach including an unbiased omic step (i.e. the discovery phase) and a target step (i.e. the validation phase). To achieve this goal, we used the biological samples of 688 subjects from multiple cohorts that generally have neutrophils, white blood cells, and plasma stored. CVD risk factors including blood pressure, insulin resistance, lipid profile, and pulse wave velocity have been measured. In the discovery phase, genome wide DNA methylation, RNA-sequencing and quantitative proteomics were obtained from the purified neutrophils. A significant difference was found for one gene, ALPL, across 3 omics platforms. In the validation phase, ALPL expression and the cellular protein levels were found to be higher in obese compared with lean subjects. Within the obese population, we observed ALPL expression level positively associated with CVD risk factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), carotid intima–media thickness (IMT), triglycerides (TG), and fasting insulin. This study identified one novel marker of neutrophil activation in response to obesity and provided evidence that obesity induced changes in ALPL expression were associated with CVD risk factors.