Exercise effects on DNA methylation in EVL, CDKN2A (p14, ARF), and ESR1 in colon tissue from healthy men and women

Figures & data

Table 1. Baseline characteristics of APPEAL study participants with DNA methylation data.

		Control			Exercise			All participants
		N	Mean	SD	N	Mean	SD	N	Mean	SD
Age (years)	Men	47	56.20	7.04	50	56.00	6.49	97	56.10	6.73
	Women	51	53.69	5.65	49	54.42	7.07	100	54.05	6.36
Weight (kg)	Men	47	96.64	16.05	50	94.68	14.97	97	95.63	15.45
	Women	51	77.94	12.79	49	78.04	17.75	100	77.99	15.34
BMI (kg/m^2)	Men	47	29.98	4.70	50	29.71	3.76	97	29.84	4.22
	Women	51	28.52	4.80	49	28.89	5.48	100	28.70	5.12
Waist to hip ratio	Men	47	0.97	0.06	50	0.96	0.06	97	0.96	0.06
	Women	51	0.78	0.07	49	0.79	0.06	100	0.79	0.07
Waist circumference (cm)	Men	47	104.0	11.70	50	102.8	9.88	97	103.4	10.76
	Women	51	85.25	11.40	49	87.54	13.62	100	86.37	12.52
Fat (%)	Men	47	29.84	6.05	48	31.47	6.50	95	30.66	6.30
	Women	50	43.03	6.80	49	43.28	7.18	99	43.15	6.95
Total lean (g)	Men	47	63,430	7684	48	60,677	7275	95	62,039	7568
	Women	50	40,689	3864	49	40,112	4926	99	40,404	4408
Calories	Men	46	1654	564.0	46	1645	555.7	92	1649	556.8
	Women	50	1583	554.6	49	1543	720.1	99	1563	638.9
Vigorous to moderate physical activity	Men	47	75.39	87.30	50	67.41	115.4	97	71.27	102.3
	Women	51	45.40	80.65	49	43.24	59.89	100	44.34	70.89
Average steps/day	Men	45	6084	3215	49	6004	2794	94	6042	2987
	Women	51	6640	2926	49	5959	2567	100	6306	2763
VO2max	Men	47	30.79	6.08	50	30.21	5.95	97	30.49	5.99
	Women	51	24.81	4.34	49	23.84	5.09	100	24.34	4.72
		N	%		N	%		N	%
Race/Ethnicity Non-Latino White	Men	44	93.6		47	94.0		91	93.8
	Women	47	92.2		42	85.7		89	89.0
Education College degree/higher	Men	27	57.4		33	66.0		60	61.9
	Women	34	66.7		28	57.1		62	62.0
Non-smoker	Men	43	91.5		46	92.0		89	91.8
	Women	50	98.0		47	95.9		97	97.0
First degree relative with colon cancer	Men	17	36.2		14	28.0		31	32.0
	Women	19	37.3		21	42.9		40	40.0
Endoscopy History of adenomatous polyps	Men	27	57.4		29	58.0		56	57.7
	Women	12	23.5		15	30.6		27	27.0

Table 2. Twelve-month change in DNA methylation patterns.

		Control							Exercise							P-value*
		Baseline			12 Month			Difference %	Baseline			12 Month			Difference %
Gene	Sex	N	GM	95% CI	N	GM	95% CI		N	GM	95% CI	N	GM	95% CI		P_un	P^[Citation1]	P^[Citation2]
ESR1	Men	47	3.410	(2.840, 4.0927	43	3.131	(2.516, 3.897)	−0.278 –8.16%	50	3.774	(3.124, 4.559)	44	3.985	3.249 4.887	0.211 5.54%	0.62	0.61	0.99
	Women	51	2.760	(2.197, 3.467)	46	3.066	(2.394, 3.926)	0.306 11.10%	48	2.451	(1.959, 3.066)	43	2.191	1.704 2.817	−0.259 –10.58%	0.05	0.06	0.07
	P interaction															0.06	0.05	0.12
EVL	Men	47	0.270	(0.181, 0.405)	43	0.225	(0.158, 0.318)	−0.047 –17.25%	50	0.284	(0.206, 0.392)	44	0.336	0.238 0.474	0.052 18.21%	0.17	0.14	0.58
	Women	51	0.286	(0.203, 0.404)	46	0.340	(0.247, 0.494)	0.063 21.90%	48	0.266	(0.201, 0.352)	43	0.280	0.204 0.383	0.014 5.26%	0.63	0.67	0.60
	P interaction															0.09	0.09	0.29
p14ARF	Men	47	0.016	(0.011, 0.024)	43	0.015	(0.010, 0.021)	−0.001 –7.03%	50	0.021	(0.015, 0.029)	44	0.016	0.011 0.023	−0.004 –21.04%	0.46	0.24	0.46
	Women	51	0.014	(0.010, 0.021)	46	0.017	(0.012, 0.025)	0.003 20.63%	48	0.010	(0.007, 0.013)	43	0.015	0.011 0.021	0.005 54.92%	0.38	0.33	0.38
	P interaction															0.82	0.86	0.82

P_un: P-value based on GEE models comparing the 12-months changes in the DNA methylation between Controls versus participants in the Exercise group within each stratum of gender, unadjusted.

P¹: P-value based on GEE models comparing the 12-months changes in the DNA methylation between Controls versus participants in the Exercise group within each stratum of gender, adjusted for age and baseline BMI (continuous).

P²: P-value based on GEE models comparing the 12-months changes in the DNA methylation between Controls versus participants in the Exercise group within each stratum of gender, adjusted for age, baseline BMI (continuous), history of adenomatous polyps, history of adenomatous polyps, folate, and vitamin B2, B6, and B12 intakes.

P Interaction is the P-value obtained from GEE model comparing the intervention effect on the DNA methylation between men and women.

Table 3. Correlations between baseline (log-transformed) DNA methylation patterns and baseline variables in women.

	ESR1			EVL			p14ARF
	N	Rho	P	N	Rho	P	N	Rho	P
Bax density
Crypt bottom	97	0.123	0.23	97	0.084	0.41	97	0.192	0.06
Crypt middle	97	0.126	0.22	97	0.109	0.28	97	0.211	0.04
Crypt top	97	0.126	0.22	97	0.065	0.52	97	0.217	0.03
Crypt whole	97	0.129	0.21	97	0.087	0.39	97	0.215	0.03
Crypt height	97	0.015	0.89	97	0.036	0.74	97	0.067	0.51
Bcl-2 density
Crypt bottom	96	0.027	0.79	96	0.144	0.16	96	0.093	0.37
Crypt middle	96	−0.057	0.58	96	0.040	0.70	96	−0.041	0.70
Crypt top	96	0.112	0.27	96	0.192	0.06	96	0.205	0.05
Crypt whole	96	0.043	0.68	96	0.146	0.15	96	0.111	0.28
Crypt height	96	−0.062	0.55	96	0.054	0.60	96	0.125	0.23
Bax/bcl-2
Crypt bottom	96	−0.111	0.28	96	0.01	0.76	96	−0.130	0.20
Crypt middle	96	−0.162	0.11	96	−0.062	0.55	96	−0.224	0.02
Crypt top	96	−0.001	0.99	96	0.136	0.19	96	0.012	0.91
Crypt whole	96	−0.091	0.38	96	0.049	0.63	96	−0.113	0.28
Crypt height	97	−0.023	0.821	97	0.047	0.647	97	0.104	0.310
Ki67+ cells
Average cell height	97	0.092	0.37	97	0.138	0.18	97	−0.041	0.69
Median cell height	97	0.092	0.37	97	0.138	0.18	97	−0.041	0.69
75^th percentile cell height	97	0.117	0.25	97	0.118	0.25	97	−0.083	0.42
Weighted average cell height	97	0.102	0.32	97	0.109	0.29	97	−0.114	0.26
Average crypt height from KI67 slice	97	0.096	0.34	97	0.126	0.22	97	0.049	0.63
Average percent cell height	97	0.102	0.32	97	0.120	0.24	97	−0.090	0.38
Median percent cell height	97	0.099	0.33	97	0.104	0.31	97	−0.028	0.78
75^th percentile percent cell height	97	0.134	0.19	97	0.092	0.37	97	−0.148	0.14
Cytokeratin-18	98	0.021	0.84	98	0.040	0.69	98	−0.045	0.66
Circulating biomarkers
Insulin	99	0.113	0.27	99	0.125	0.21	99	0.028	0.78
Glucose	99	0.061	0.55	99	0.119	0.24	99	0.133	0.19
HOMA (Homoeostatic Model Assessment)	99	0.104	0.30	99	0.130	0.19	99	0.045	0.66
CRP (C-Reactive Protein)	97	0.053	0.60	97	0.031	0.76	97	−0.114	0.26
Testosterone	99	0.021	0.84	99	0.023	0.82	99	0.112	0.27
Free testosterone	99	0.080	0.43	99	0.088	0.39	99	0.095	0.35
SHBG (Sex Steroid Hormone Binding Globulin)	99	0.006	0.95	99	0.035	0.72	99	0.008	0.93

Table 4. Correlations between baseline (log-transformed) DNA methylation patterns and baseline variables in men.

	ESR1			EVL			p14ARF
	N	Rho	P	N	Rho	P	N	Rho	P
Bax density
Crypt bottom	94	−0.116	0.26	94	−0.118	0.26	94	−0.112	0.29
Crypt middle	94	−0.140	0.18	94	−0.124	0.24	94	−0.107	0.30
Crypt top	94	−0.138	0.18	94	−0.104	0.32	94	−0.097	0.35
Crypt whole	94	−0.137	0.19	94	−0.118	0.26	94	−0.108	0.30
Crypt height	94	0.091	0.39	94	0.013	0.90	94	−0.039	0.70
Bcl-2 density
Crypt bottom	94	−0.123	0.236	94	−0.094	0.367	94	−0.146	0.16
Crypt middle	94	−0.141	0.176	94	−0.068	0.515	94	−0.190	0.07
Crypt top	94	−0.117	0.261	94	−0.043	0.681	94	−0.053	0.60
Crypt whole	94	−0.140	0.180	94	−0.072	0.492	94	−0.134	0.19
Crypt height	94	0.033	0.750	94	−0.073	0.486	94	−0.113	0.28
Bax/bcl-2
Crypt bottom	92	−0.009	0.93	92	0.030	0.78	92	−0.009	0.93
Crypt middle	92	0.004	0.97	92	0.063	0.55	92	−0.060	0.57
Crypt top	92	0.027	0.79	92	0.061	0.56	92	0.054	0.61
Crypt whole	92	0.012	0.91	92	0.061	0.57	92	0.003	0.98
Crypt height	96	0.066	0.52	96	−0.037	0.72	96	−0.085	0.41
Ki67+ cells
Average cell height	96	0.008	0.94	96	−0.097	0.35	96	−0.119	0.25
Median cell height	96	0.014	0.89	96	−0.116	0.26	96	−0.104	0.31
75^th percentile cell height	96	0.017	0.87	96	−0.074	0.47	96	−0.099	0.34
Weighted average cell height	96	0.028	0.79	96	−0.069	0.50	96	0.010	0.92
Average crypt height from KI67 slice	96	−0.013	0.89	96	−0.080	0.44	96	−0.189	0.07
Average percent cell height	96	0.042	0.69	96	−0.047	0.65	96	0.023	0.82
Median percent cell height	96	0.036	0.73	96	−0.075	0.47	96	0.024	0.81
75^th percentile percent cell height	96	0.044	0.67	96	−0.024	0.82	96	0.051	0.62
Cytokeratin-18	97	0.045	0.66	97	0.043	0.68	97	−0.085	0.41
Circulating biomarkers
Insulin	97	−0.100	0.330	97	−0.088	0.39	97	−0.008	0.95
Glucose	97	0.027	0.795	97	−0.023	0.82	97	−0.044	0.67
HOMA (Homoeostatic Model Assessment)	97	−0.094	0.359	97	−0.089	0.39	97	−0.013	0.89
CRP (C-reactive Protein)	93	−0.070	0.502	93	−0.097	0.36	93	−0.055	0.60
Testosterone	97	−0.196	0.055	97	−0.125	0.22	97	−0.100	0.33
Free testosterone	97	−0.227	0.026	97	−0.097	0.35	97	−0.109	0.29
SHBG (Sex Steroid Hormone Binding Globulin)	97	−0.089	0.387	97	−0.132	0.20	97	−0.065	0.50
DHT (5α-dihydrotestosterone)	97	−0.087	0.40	97	−0.065	0.52	97	−0.085	0.41

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