THE ROLE OF THE DUFFY ANTIGEN RECEPTOR FOR CHEMOKINES (DARC) IN ETHNIC SUSCEPTIBILITY TO CARDIOMETABOLIC DISEASE

Abstract

Cardiometabolic disease is a cluster of pathologies relating to obesity and cardiovascular diseases with many shared risk factors and are hallmarked by chronic inflammation mediated by the aberrant production of cytokines and chemokines. Cardiometabolic disease risk is highly stratified by ethnicity. African Americans have a higher prevalence of metabolic syndrome, vascular stiffness and hypertension compared to Caucasians. Concomitantly, African Americans typically have elevated levels of circulating IL-6 and c reactive protein, both of which have been implicated in the progression of cardiometabolic disease. Conversely, the incidence of abdominal aortic aneurysms (AAA) and coronary artery calcification, pathologies that are also mechanistically linked to inflammation, are markedly reduced in African Americans compared to Caucasians. These disparate findings in cardiometabolic disease rates among ethnic populations suggest that the relationship between obesity, cardiovascular disease, and inflammation is complex and is likely not explained solely on the basis of conventional risk factors. Interestingly, mutations in the Duffy antigen receptor for chemokines (DARC) are highly prevalent in African American, Asian, and Hispanic populations as a result of negative selection pressure imposed by P. vivax malaria. Indeed, up to 80% of African Americans harbor a mutation in the DARC resulting in complete loss of expression on erythrocytes. DARC is prominently expressed on the surface of erythrocytes and is a promiscuous non-signaling chemokine receptor whose function has been described as a chemokine ‘buffer-sink’. Loss of functional DARC is associated with dysregulation of its ligands, including MCP-1. In the present study, we investigate the role of DARC in inflammatory driven cardiometabolic diseases employing a mouse that is genetically deficient in DARC. We found that mice deficient in DARC are more prone to the development of metabolic syndrome in the setting of diet induced obesity, reduced incidence of AAA, but increased hypertension. Our findings in mice deficient in DARC mirror disparities in cardiometabolic disease observed in human populations expressing allelic variants of DARC suggesting a role for DARC in ethnic disparities of cardiometabolic disease.