Methylation of SOCS3 is 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 (P_α=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.

KEYWORDS:

• BMI
• childhood obesity
• CpG methylation
• EWAS
• epigenetics
• family study
• metabolic syndrome
• obesity

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We acknowledge the contribution of Jacqueline Marks (Medical College of Wisconsin) for her supervision of all biochemical procedures and Ruth Gielow (TOPS Club, Inc.) and her assistants in the recruitment process and finally to all the members of TOPS Club, Inc. and their families who volunteered for this study.

Accession numbers

The NCBI Gene Expression Omnibus accession number for the methylation data generated from the 192 samples reported in this paper is under the Gene Series GSE60132.

Funding

This work is supported by grants from the NIH (DK071895-03 and DK65598-01) for A.H.K. and in part with federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201100014C (OA and YZ). Quantitative genetic methods development and analysis was supported in part by NIH-National Mental Health Institute grant MH059490 (JB). This work has been also supported by grants by TOPS Club, Inc. to A.H.Kissebah and Y. Zhang. The late Dr. Ahmed H. Kissebah was the principal investigator on the various NIH funded studies that led to the collection of this unique family-based cohort.