Abstract Body (Do not enter title and authors here): Background: Mfge8 is an integrin ligand and a major exosome (EV) protein known to mediate inflammation and atherosclerosis in type 2 diabetes mellitus (T2DM) in animal research. The pathophysiological relevance of this protein in T2DM and cardiovascular disease (CVD) remains contentious and is less explored in humans. Earlier, we reported a rare population-specific missense variant (rs371227978; Arg148His) in the MFGE8 gene, associated with increased circulating Mfge8 and T2DM in Asian Indians (AIs).
Method: The role of MFGE8 with T2DM risk in additional AIs (n=4917) and Europeans and multiethnic cohorts from UK Biobank (UKBB) (n=455,808) and the US (n=1150) was investigated. We evaluated the exposure of Mfge8-enriched human EVs in zebrafish (ZF) and human cells and examined Mfge8 protein levels in adipose, aortal, muscle, and blood tissues obtained from patients with CVD to assess its impact on the cardiometabolic organ system.
Result: Most individual carriers of the variant had high circulating Mfge8 and showed positive correlation with glucose (r=0.42; p=4.9x10^-04), while non-carriers showed negative correlation (r=-0.38; p=0.001) in AIs. However, the same variant was monomorphic in Europeans and other ethnic groups of UKBB and the US cohorts. In absence of Arg148His variant, serum Mfge8 correlated significantly with glucose in other non-Asian (r=0.47; p=2.2x10^-13). The exposure of Mfge8-enriched human EVs in ZF larvae developed fatty liver disease, heart hypertrophy, redundant growth, and poor muscular architecture with and without high-fat diet (HFD). The control group developed fatty liver disease and heart hypertrophy only after HFD. A 5-fold increase was reported in IL-6 and IL-8 in the cells treated by Mfge8-enriched EVs compared to untreated cells and using a positive control of recombinant Mfge8.
Discussion: The Mfge8 protein concentration varied in a tissue-specific manner showing highest expression levels in aortic tissues compared to muscle and lowest in adipose tissues in all CAD patients with T2DM. These results align with animal studies, which have shown that higher levels of Mfge8 are detected in the aortas of rats with T2DM. Our findings suggest that circulating Mfge8 may serve as a potential biomarker for assessing the risk of vascular disease in patients with T2DM.
Funding: The AIDHS/SDS was supported by NIH grants R01DK082766 and R01DK118427(NIDDK), COMAA, PHF, Leinbach Foundation grants, and Dr. Geoffrey Altshuler Endowment funds.