G6PD Deficiency and Atherosclerosis

Glucose-6-phosphate dehydrogenase deficiency (G6PD-d) is the most common enzymopathy, affecting approximately 5% of humans, or half a billion individuals worldwide. While the majority of data centers around the erythrocyte phenotype in G6PD-d with hemolysis being a notable and impactful result of G6PD-d, this deficiency exists in all cell types. Recent epidemiological data suggest that G6PD-d in humans may be associated with increased risk of CVD. Yet whether G6PD-d plays a causal role in atherosclerosis development is unknown. Our preliminary data, utilizing a novel humanized mouse which expresses a human G6PD gene with a common G6PD-d mutation (Med-), revealed a significant increase in diet-induced atherosclerosis in the G6PD-d mice compared to the canonical control. Intriguingly, immune cell profiling of these mice revealed a significant reduction in atheroprotective B-1b cells and the IgM to oxidation specific epitopes (OSE) that they make. In mice, B-1b cells protect against atherosclerosis largely through production of IgM antibodies that block these pro-inflammatory OSE on LDL (IgMOSE). Humans with high levels of IgM to OSE have less coronary artery disease (CAD) and fewer CV events. Yet, the factors that regulate these atheroprotective IgM producing cells are largely unknown. Accordingly, we propose to test the hypothesis that G6PD- d promotes atherosclerosis, at least in part, through B cell intrinsic effects of G6PD-d on B cell subset number and production of IgM to OSE.