Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC.
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Acknowledgments. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions and thank Carole Grenier (Duke University, Durham, NC) for provision of technical support. A full list of participating MESA investigators and institutions can be found at http:// www.mesa-nhlbi.org. Funding. The MESA Epigenomics and Transcriptomics Study was funded by National Institutes of Health grant R01-HL-101250 to Wake Forest University Health Sciences. The weight-loss intervention study was supported by the National Institutes of Health grant R01-HL-093713 and the Wake Forest University Claude D. Pepper Older Americans Independence Center (P30-AG21332). This research was supported by National Heart, Lung, and Blood Institute contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 and by National Center for Research Resources grants UL1-RR-024156 and UL1-RR-025005. Duality of Interest. A provisional patent application relevant to this work has been filed. No other potential conflicts of interest relevant to this article were reported. Author Contributions. For MESA investigators: J.D. performed experiments, researched the data, and wrote the manuscript. L.M.R., R.P.T., I.H., D.H., and C.E.M. performed experiments, researched the data, and helped write the manuscript. K.L., B.J.N., S.B.K., Z.H., A.d.l.F., N.S., R.E.S., C.-C.C., T.H., J.S.P., S.M., D.R.J., and W.P. performed experiments and researched the data. N.X., M.O.G., Y.-D.I.C., J.I.R., and D.S.S. researched the data. Y.L. oversaw the study, carried out experiments, researched the data, and wrote the manuscript. For GHS investigators: T.Z. and P.S.W. acquired data. T.Z. and C.M. analyzed and interpreted data. T.Z., C.M., and S.B. reviewed and edited the manuscript. P.S.W. and S.B. obtained funding. T.Z. and S.B. supervised the study. Y.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.