CPT1A methylation is associated with plasma adiponectin

Abstract

Background and Aims Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood. Methods and Results We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n= 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression coefficient ± SE= 0.01 ± 0.001, P=3.4x10−13) between plasma adiponectin levels and methylation of a CpG site in CPT1A, a key player in fatty acid metabolism. The association was replicated (n=474, P=0.0009) in whole blood samples from the Amish participants of the Heredity and Phenotype Intervention (HAPI) Heart Study as well as White (n=592, P=0.0005) but not Black (n=243, P=0.18) participants of the Bogalusa Heart Study (BHS). The association remained significant upon adjusting for BMI and smoking in GOLDN and HAPI but not BHS. We also identified associations between methylation loci in RNF145 and UFM1 and plasma adiponectin in GOLDN and White BHS participants, although the association was not robust to adjustment for BMI or smoking. Conclusion We have identified and replicated associations between several biologically plausible loci and plasma adiponectin. These findings support the importance of epigenetic processes in metabolic traits, laying the groundwork for future translational applications.

Methylome-Wide Association Study of Central Adiposity Implicates Genes Involved in Immune and Endocrine Systems

“…Methylation at cg00574958 in the 5' region of CPT1A (carnitine palmitoyltransferase 1A), associated with WHRadjBMI and WCHTadjBMI in the current study, has been previously associated with a number of cardiometabolic traits, including BMI, obesity, central obesity, WC unadjusted for BMI, lipid levels, lipoproteins, blood pressure, T2D, and plasma adiponectin [11,12,16,43,53,[61][62][63][64]. Also, a recent study has shown that blood pressure is causally associated with methylation at this site and methylation at this CpG influences expression of CPT1A [43].…”

DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts

“…Associations of CPT1A with anthropometric traits [ 32 , 38 ] and triglyceride levels [ 39 ] were directionally consistent with previous studies in blood. Other associations with cg00574958 in CPT1A have been identified in EWAS of fasting blood lipids [ 39 – 41 ], adiponectin [ 42 ], the metabolic syndrome[ 43 ], and cardiovascular disease (CVD) risk [ 44 ]. Using the BIOS QTL browser, we identified an eQTM in blood associated with cg00574958 in CPT1A , indicating that DNAm at this site was inversely associated with expression of a transcript in the same gene, in line with findings by Irvin et al .…”

Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study

“…Interleukin-6 (IL6), interleukin-2 soluble receptor alpha (IL2sRα), tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1 (MCP1) were measured using quantitative sandwich enzyme immunoassays (ELISA kit assays, R&D Systems Inc., Minneapolis, MN) as described in previous publications [ 18 , 19 ]. Adiponectin was measured using an ELISA kit from R&D Systems (Minneapolis, MN) [ 20 ].…”