Abstract 16605: Alterations of a Cellular Cholesterol Metabolism Network is a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease
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.
Methods: Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis participants (age: 55-94; 47% Cau, 21% AA, 32% His; 51% female), we quantified the transcriptome (using Illumina HumanHT-12 v4 BeadChip). Coronary artery calcium (CAC) was scored using the Agatston method. Analysis was adjusted for age, sex, race, and study sites.
Results: We discovered that alterations in a network of co-expressed cholesterol metabolism genes are a signature feature of obesity (p: 1.6 x10-18) and inflammatory stress (interleukin-6, p: 2.0x10-7). 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 (p: 5.1x10-10) and CAC (p: 2.0x10-3). This network significantly mediated the associations between obesity and T2D/CAC (p: 9.3x10-4/p: 0.015, respectively). The associations remained significant after further adjustment for serum lipids and other cardiometabolic factors and were qualitatively consistent across sex or race. Several genes in the network harbored CpG dinucleotides (e.g. ABCG1/cg06500161) which overlapped ENCODE-annotated regulatory regions, and had methylation profiles that significantly mediated the associations between BMI/inflammation and expression of their cognate genes. Internal validation using mRNA sequencing (N=374) and pyrosequencing technologies (N=176) and external validation using monocyte expression data from 1,285 German men and women from the Gutenberg Heart Study corroborated most of the findings.
Conclusions: Taken together with several lines of experimental evidence, these data suggest that an increase in intracellular cholesterol in monocytes, indicated by alterations of the cholesterol metabolism gene network, represents a molecular link between obesity/inflammation and T2D/CVD.
Author Disclosures: J. Ding: None. L.M. Reynolds: None. T. Zeller: None. C. Muller: None. K. Lohman: None. Z. Huang: None. A. de la Fuente: None. N. Soranzo: None. R.E. Settlage: None. C. Chuang: None. T. Howard: None. N. Xu: None. M.O. Goodarzi: None. Y. Chen: None. J.I. Rotter: None. D.S. Siscovick: None. J.S. Parks: None. S. Murphy: None. D.R. Jacobs, Jr.: None. W. Post: None. R.P. Tracy: None. P.S. Wild: None. S. Blackenberg: None. I. Hoeschele: None. D. Herrington: None. C. McCall: None. Y. Liu: None.
- © 2014 by American Heart Association, Inc.