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Grant Abstract: Role of Glycine Metabolism in Cardiovascular Disease

Grant Number: 5R01HL133169-02
PI Name: Allayee
Project Title: Role of Glycine Metabolism in Cardiovascular Disease

Abstract: Our recent metabolomics and genetic analyses led to the discovery of an amino acid variant in carbamoyl-phosphate synthase 1 (CPS1) that was strongly associated with 12% reduced risk of cardiovascular disease (CVD) in women (p=6.3x10-5) but not men (p=0.95). Since this cardio-protective allele is the major genetic determinant of increased plasma glycine levels in humans, we proposed a series of integrative clinical, genetics, bioinformatics, and dietary approaches to investigate the role of glycine metabolism in CVD, which was recently funded through NHLBI grant (R01HL133169). Based on prior evidence from the literature, one of our hypotheses was that dietary glycine feeding in mice would attenuate atherosclerosis through anti-inflammatory mechanisms. As part of the studies proposed in R01HL133169, we conducted a 16-week feeding study in apolipoprotein-E deficient (ApoE-/-) mice, which resulted in 2-fold increased plasma glycine levels, and are currently in the process of completing the molecular, metabolomics, and atherosclerosis-related experiments. Of note, the same CPS1 variant was also recently reported as being associated with reduced platelet count, suggesting that decreased thrombotic potential could be another athero-protective consequence of genetically elevated glycine levels in humans. Therefore, we first characterized the mice from our feeding study for hematological traits, which revealed that elevation of plasma glycine through dietary supplementation not only reduced platelets, but surprisingly also led to decreased white blood cell counts and alterations in red blood cell parameters. We confirmed the physiological relevance of these observations to humans using bioinformatics analyses with publicly available genetic data, which revealed that subjects carrying the CPS1 glycine-raising allele had both decreased vitamin B12 levels and exhibited the same pattern of hematological perturbations observed in glycine-fed mice. Interestingly, these pleiotropic hematological effects resemble the clinical manifestations of prolonged vitamin B12 deficiency, particularly those observed in pernicious anemia. Taken together, these exciting new results have led our project in a new direction that suggest another potential atheroprotective mechanism of glycine is through lowering of platelets and leukocytes, which could be mediated through a mechanism involving vitamin B12-availability/absorption. This administrative supplement seeks to address this question through another 16-week mouse glycine feeding study, whereby blood counts and plasma vitamin B12 levels will be measured on a weekly basis, followed by quantification of hepatic vitamin B12 content at the end of the dietary study. Plasma levels of gastric intrinsic factor (GIF) will also be measured weekly in parallel, followed by tissue levels in the stomach, small intestine, and liver, to determine whether altered vitamin B12 levels is due to impaired absorption as a result of reduced GIF availability. Thus, these new proposed experiments will provide mechanistic insight into whether the athero-protective properties of glycine involve a widely used vitamin supplement and address the research objectives of PAR 17-307 “Administrative Supplements for Research on Dietary Supplements.”

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