title: 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 (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.
authors: a Department of Pediatrics , Medical College of Wisconsin , Milwaukee , WI , USA.
authors: Omar
authors: O
authors: Ali
authors: b TOPS Obesity and Metabolic Research Center, Department of Medicine, Medical College of Wisconsin , Milwaukee , WI , USA.|c Human and Molecular Genetics Center, Medical College of Wisconsin , Milwaukee , WI , USA.
authors: Diana
authors: D
authors: Cerjak
authors: d Department of Genetics , Texas Biomedical Research Institute , San Antonio , TX , USA.
authors: Jack W
authors: JW
authors: Kent
authors: b TOPS Obesity and Metabolic Research Center, Department of Medicine, Medical College of Wisconsin , Milwaukee , WI , USA.|c Human and Molecular Genetics Center, Medical College of Wisconsin , Milwaukee , WI , USA.
authors: Roland
authors: R
authors: James
authors: e South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley , Brownsville , TX , USA.
authors: John
authors: J
authors: Blangero
authors: d Department of Genetics , Texas Biomedical Research Institute , San Antonio , TX , USA.
authors: Melanie A
authors: MA
authors: Carless
authors: b TOPS Obesity and Metabolic Research Center, Department of Medicine, Medical College of Wisconsin , Milwaukee , WI , USA.|c Human and Molecular Genetics Center, Medical College of Wisconsin , Milwaukee , WI , USA.
authors: Yi
authors: Y
authors: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D016678:Genome; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein
keywords: BMI; CpG methylation; EWAS; childhood obesity; epigenetics; family study; metabolic syndrome; obesity