Methylation of SOCS3 is inversely associated with metabolic syndrome in an epigenome-wide association study of obesity

Figures & data

Figure 1. Strength of associations of genome-wide autosomal CpG methylation status with BMI% in our TFSE cohort. Manhattan plot shows the significance level of each CpG locus with BMI-percentile. Each gray dot represents an individual CpG site. The red one depicts the genome-wide significance threshold after Bonferroni correction for multiple testing, P_α=0.05 = 1.31 × 10⁻⁷. Probes with associations of nominal significance (P < 0.05) are shown. Genes and associated CpG sites that exceed the significance threshold are labeled.

Table 1. TOPS Family Study of Epigenetics (TFSE) Cohort Characteristics.

	Children and Adolescents (mean ± SD)		Adults (mean ± SD)
Phenotype	Girls (n = 111)	Boys (n = 102)	Female (n = 509)	Male (n = 330)
Weight, kg	59.46 ± 22.20	62.23 ± 24.35	89.27 ± 24.92	97.76 ± 22.90
Height, cm	158.06 ± 13.52	162.67 ± 17.63	164.06 ± 7.06	177.74 ± 7.49
BMI%	67.25 ± 29.08	70.17 ± 29.28	67.37 ± 27.68	68.68 ± 27.10
BMI% > 85	41.4%	46.1%	35.0%	36.7%
Waist to Height Ratio	0.44 ± 0.10	0.42 ± 0.10	0.59 ± 0.14	0.56 ± 0.12
Waist to Hip Ratio	0.89 ± 0.13	0.94 ± 0.09	0.85 ± 0.10	0.97 ± 0.10
HOMA-IR	4.52 ± 5.34	3.69 ± 3.23	4.65 ± 8.44	4.08 ± 3.99
FG, mmol/l	82.16 ± 12.92	83.31 ± 9.13	88.39 ± 31.73	92.40 ± 35.27
HDL-c, mmol/l	47.61 ± 15.35	45.42 ± 16.29	42.75 ± 14.62	38.65 ± 15.24
LDL-c, mmol/l	89.02 ± 29.60	89.52 ± 29.53	129.31 ± 41.34	130.78 ± 48.53
TG, mmol/l	87.95 ± 79.89	83.62 ± 49.75	119.42 ± 77.89	138.17 ± 173.42
MetS, %	NA	NA	31.0%	31.8%

Table 2. Top BMI% CpGs with other MetS traits and MetS itself.

	cg18181703	cg04502490	cg02988947
	SOCS3 (body)	ZNF771 (3′UTR)	LIMD2 (TSS1500)
CpG	chr17: 73866216	chr16: 30337212	chr17: 59132545
Phenotype	P-value
BMI%	1.02 × 10^−8	2.70 × 10^−8	6.43 × 10^−8
Waist to Height	1.50 × 10^−8	0.001	1.26 × 10^-6
WHR	0.02	0.011	0.042
SubQ	0.0001	0.019	0.008
VF	0.001	0.072	0.017
HOMA-IR	0.002	0.0004	0.0004
FG	0.006	0.016	0.023
HDL-c	0.006	0.43	0.055
LDL-c	0.154	0.611	0.293
TG	0.0004	0.003	0.002
MetS	0.012	0.057	0.35

Figure 2. Boxplot of methylation β values at cg18181703 (SOCS3, body) against presence or absence of metabolic syndrome. The middle lines show the medians of the data, while the boxes show the 25^th to 75^th percentiles. The whiskers extend to include 99% of the data while circles represent outliers. The β values at this probe in individuals with and without MetS were significantly different (P = 4.01 × 10⁻⁷) when accounted for age, sex, and interactions of the two.

Table 3. Pyrosequencing of SOCS3 CpG site vs. traits.

Trait	Beta (SE)	P
BMI%	−0.15 (0.031)	1.75 × 10^−6
WHtR	−0.16 (0.031)	4.18 × 10^−7
HOMA-IR	−0.04 (0.032)	0.24
FG	−0.02 (0.031)	0.60
HDL-c	0.17 (0.031)	4.57 × 10^−8
LDL-c	−0.01 (0.034)	0.85
TG	−0.11 (0.031)	3.59 × 10^−4
MetS	−0.18 (0.034)	4.01 × 10^−7
SOCS3 expression	−0.20 (0.051)	2.93 × 10^−4
SOCS3 expression/MetS	0.16 (0.065)	1.17 × 10^−2