Methylation ofSOCS3is inversely associated with metabolic syndrome in an epigenome-wide association study of obesity

Abstract

Epigenetic mechanisms, including DNA methylation, mediate the interaction between gene and environment and may play an important role in the obesity epidemic. We assessed the relationship between DNA methylation and obesity in peripheral blood mononuclear cells (PBMCs) at 485,000 CpG sites across the genome in family members (8-90 y of age) using a discovery cohort (192 individuals) and a validation cohort (1,052 individuals) of Northern European ancestry. After Bonferroni-correction (Pα=0.05 = 1.31 × 10−7) for genome-wide significance, we identified 3 loci, cg18181703 (SOCS3), cg04502490 (ZNF771), and cg02988947 (LIMD2), where methylation status was associated with body mass index percentile (BMI%), a clinical index for obesity in children, adolescents, and adults. These sites were also associated with multiple metabolic syndrome (MetS) traits, including central obesity, fat depots, insulin responsiveness, and plasma lipids. The SOCS3 methylation locus was also associated with the clinical definition of MetS. In the validation cohort, SOCS3 methylation status was found to be inversely associated with BMI% (P = 1.75 × 10−6), waist to height ratio (P = 4.18 × 10−7), triglycerides (P = 4.01 × 10−4), and MetS (P = 4.01 × 10−7), and positively correlated with HDL-c (P = 4.57 × 10−8). Functional analysis in a sub cohort (333 individuals) demonstrated SOCS3 methylation and gene expression in PBMCs were inversely correlated (P = 2.93 × 10−4) and expression of SOCS3 was positively correlated with status of MetS (P = 0.012). We conclude that epigenetic modulation of SOCS3, a gene involved in leptin and insulin signaling, may play an important role in obesity and MetS.

Epigenetics: from the past to the present

“…Similar studies with remarkable findings in the investigation of a variety of diseases as type 2 diabetes mellitus (Soriano-Tarraga et al 2016), psoriasis (Zhou et al 2016), schizophrenia (Montano et al 2016), metabolic syndrome/obesity (Ali et al 2016) and many others have been recently published. It is expected that the new technologies that make possible this type of works and the technologies that will come allow epigenetic epidemiology to reach major objectives as the complete description of the epigenetic processes shaping the development of organisms, the interactions gene-epigene and epigene-environment, the establishment of the role of epigenetics in risk and emergence of diseases, as marker of disease or exposure, and the mechanisms of the inheritance of epigenetic changes over generations in humans (Bollati & Baccarelli 2010;Bakulski & Fallin 2014).…”

Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

“…The majority of BMI-related CpGs (65%-85% of CpGs depending on the cohort) had mean sample CpG methylation levels between 20% and 80% (S4 Table). Fifty of the 83 replicated differentially methylated CpGs have not been previously reported in microarraybased EWASs of BMI [28][29][30][31][32][33][34][35][36] (Table 3). Age and sex interactions among the BMI EWAS findings.…”

The Omics of Obesity

“…A study by Ali et al (2016) used a discovery approach in 192 subjects from seven families from the Take off Pounds Sensibly Family Study of Epigenetics (TFSE), and then validated the initial differential methylation marks in an extended cohort of 1,052 subjects [39]. They identified and replicated three loci where methylation status was associated with BMI%, and these were located in the body of suppressor of cytokine signalling (SOCS3), 3′ untranslated region of the zinc finger protein 771 (ZNF771) and at the transcription start site of LIM domain containing 2 (LIMD2) gene.…”

“…They identified and replicated three loci where methylation status was associated with BMI%, and these were located in the body of suppressor of cytokine signalling (SOCS3), 3′ untranslated region of the zinc finger protein 771 (ZNF771) and at the transcription start site of LIM domain containing 2 (LIMD2) gene. Functional analyses were then performed in 330 subjects from the methylation analyses [39].…”

“…Targeted lipidomics involves the combination of liquid chromatography and stable isotope or non-physiological internal standards to provide quantification to hundreds of lipids. While untargeted lipidomics refers to the combination of liquid chromatography with high mass analysis to detect lipid species [39]. Numerous studies have investigated the lipidomic signature that is associated with increased fat mass in animal and human models.…”