The Liver, Metabolic Syndrome, and Increased CVD risk among African American World Trade Center General Responders

The liver, metabolic syndrome, and increased CVD risk among non-Hispanic Black World Trade Center (WTC) General Responders. This discovery-oriented R21 project has the following premise: In addition to tra- ditional cardiometabolic risk factors, upstream drivers of cardiovascular disease (CVD) in members of the WTC General Responder Cohort include: Aim I: Pleiotropic genetic variants that effect both liver metabolism and CVD, and Aim II: Social determinants of health (SDoH). The proposed studies address a critical problem. More intense exposure to the WTC dust cloud increases CVD. CVD diagnoses are especially high in non-Hispanic (NH) Black female WTC General Responders and mortality from CVD is about 2-fold higher in NH Black than in NH White WTC rescue and recovery workers. CVD often develops in the setting of a systemic abnormality called cardio- vascular-kidney metabolic syndrome (CKM-S). Liver steatosis and MASLD are the hepatic manifestations of CKM-S. CKM-S can lead to oxidative stress and altered liver metabolism. These changes affect CVD risk, as the liver produces key CVD risk modifiers (LDL, HDL triglycerides). Our goal is to achieve a deeper understand- ing of CVD drivers, including the genomic architecture of liver-related CVD risk factors and actionable SDoH. Aim I. Hypothesis: Pleiotropic genetic variants that affect MASLD risk (up or down) and that increase CVD risk have a higher frequency in NH Black General Responders and other NH Black populations than in NH Whites. Approach: To test the hypothesis and investigate the pathways and clinical consequences associated with these variants we will: [1] Analyze results of publicly available GWAS studies that identify single nucleotide polymor- phisms (SNPs) associated with MASLD and CVD and select SNPs with genome-wide significant pleiotropic signals, i.e., significant effect sizes (βs) for both liver and cardiovascular abnormalities; [2] Determine the burden of these variants across populations and use them to estimate a Polygenic Score (PGS) to test the association between their cumulative effect and clinical phenotypes in two large multiethnic biobanks, BioMe and All of Us cohorts. [3] Analyze the risk alleles and apply the PGS to data of WTC General Responders enrolled in BioMe. Aim II. Hypothesis: NH Black General Responders have a higher burden of SDoH than NH White General Re- sponders and SDoH contribute to disparities in CVD risk, as estimated by PREVENT equations of the American Heart Association (AHA); to increased CVD events; and to early age of CVD on-set. Approach: [1] Differences in the burden of SDoH will be compared between NH Black and NH White General Responders, both men and women; [2] CVD risk will be estimated using AHA PREVENT equations and compared among groups, with adjustment for age at the time of risk calculation; [3] If differences in CVD risk are found, the percentage of the disparity mediated by SDoH will be determined; [4] Hazard ratios for CVD diagnosis (total and by CVD subtype) and the age at first CVD diagnosis will be compared between NH Black and NH White General Responders and the percentage of any disparity mediated by SDoH will be determined for men and women.