TABLE 3.

Baseline one-carbon nutrient intake and risk of colorectal cancer according to IGF2 DMR0 methylation level¹

	One-carbon nutrient intake
	First quintile	Second quintile	Third quintile	Fourth quintile	Fifth quintile	P-trend2	P-heterogeneity3
Vitamin B-6, mg/d
Person-years	651,952	645,266	641,446	637,991	630,330	—	—
All colorectal cancers							—
Cases, n	209	218	207	167	192	—
Age-adjusted HR (95% CI)	1 (referent)	0.97 (0.80, 1.18)	0.84 (0.69, 1.02)	0.68 (0.55, 0.83)	0.79 (0.64, 0.96)	0.010
Multivariable-adjusted HR (95% CI)	1 (referent)	1.04 (0.84, 1.27)	0.96 (0.76, 1.21)	0.83 (0.63, 1.10)	0.98 (0.74, 1.31)	0.75
IGF2 DMR0 methylation level						—	0.23
First quartile (≤25%)
Cases, n	50	52	53	46	46	—
Age-adjusted HR (95% CI)	1 (referent)	0.95 (0.64, 1.41)	0.86 (0.58, 1.27)	0.75 (0.50, 1.12)	0.76 (0.51, 1.13)	0.70
Multivariable-adjusted HR (95% CI)	1 (referent)	0.96 (0.64, 1.42)	0.89 (0.59, 1.34)	0.78 (0.50, 1.22)	0.82 (0.52, 1.30)	0.39
Second quartile (26–50%)
Cases, n	56	58	55	44	39	—
Age-adjusted HR (95% CI)	1 (referent)	0.98 (0.68, 1.42)	0.84 (0.58, 1.23)	0.68 (0.46, 1.02)	0.59 (0.39, 0.89)	0.15
Multivariable-adjusted HR (95% CI)	1 (referent)	0.99 (0.68, 1.44)	0.88 (0.59, 1.31)	0.72 (0.46, 1.12)	0.64 (0.40, 1.02)	0.87
Third quartile (51–75%)
Cases, n	53	61	47	46	41	—
Age-adjusted HR (95% CI)	1 (referent)	1.09 (0.75, 1.57)	0.76 (0.51, 1.13)	0.76 (0.51, 1.13)	0.67 (0.44, 1.01)	0.074
Multivariable-adjusted HR (95% CI)	1 (referent)	1.12 (0.77, 1.63)	0.80 (0.53, 1.21)	0.81 (0.52, 1.26)	0.74 (0.47, 1.18)	0.66
Fourth quartile (>75%)
Cases, n	50	47	52	31	66	—
Age-adjusted HR (95% CI)	1 (referent)	0.87 (0.58, 1.30)	0.86 (0.58, 1.28)	0.53 (0.34, 0.83)	1.11 (0.77, 1.61)	0.12
Multivariable-adjusted HR (95% CI)	1 (referent)	0.88 (0.58, 1.32)	0.90 (0.60, 1.36)	0.55 (0.34, 0.90)	1.21 (0.79, 1.86)	0.006
Vitamin B-12 (μg/d)
Person-years	780,801	547,678	574,728	661,972	641,806	—	—
All colorectal cancers							—
Cases, n	254	171	192	168	208	—
Age-adjusted HR (95% CI)	1 (referent)	0.86 (0.71, 1.05)	0.91 (0.75, 1.10)	0.68 (0.56, 0.82)	0.86 (0.71, 1.03)	0.11
Multivariable-adjusted HR (95% CI)	1 (referent)	0.89 (0.73, 1.09)	1.01 (0.82, 1.23)	0.78 (0.62, 0.97)	1.01 (0.79, 1.28)	0.81
IGF2 DMR0 methylation level							0.63
First quartile (≤25%)
Cases, n	67	44	47	35	54	—
Age-adjusted HR (95% CI)	1 (referent)	0.85 (0.58, 1.24)	0.84 (0.58, 1.22)	0.53 (0.35, 0.80)	0.81 (0.57, 1.17)	0.62
Multivariable-adjusted HR (95% CI)	1 (referent)	0.87 (0.59, 1.28)	0.93 (0.64, 1.36)	0.60 (0.39, 0.92)	0.94 (0.63, 1.39)	0.50
Second quartile (26–50%)
Cases, n	58	50	47	50	47	—
Age-adjusted HR (95% CI)	1 (referent)	1.12 (0.76, 1.63)	0.98 (0.67, 1.45)	0.90 (0.62, 1.32)	0.86 (0.58, 1.27)	0.91
Multivariable-adjusted HR (95% CI)	1 (referent)	1.16 (0.79, 1.70)	1.11 (0.75, 1.65)	1.02 (0.68, 1.52)	0.99 (0.65, 1.51)	0.30
Third quartile (51–75%)
Cases, n	64	43	47	43	51	—
Age-adjusted HR (95% CI)	1 (referent)	0.90 (0.61, 1.32)	0.92 (0.63, 1.35)	0.71 (0.48, 1.05)	0.87 (0.60, 1.27)	0.82
Multivariable-adjusted HR (95% CI)	1 (referent)	0.94 (0.64, 1.39)	1.03 (0.70, 1.51)	0.81 (0.54, 1.22)	1.02 (0.68, 1.53)	0.33
Fourth quartile (>75%)
Cases, n	65	34	51	40	56	—
Age-adjusted HR (95% CI)	1 (referent)	0.70 (0.46, 1.06)	0.97 (0.67, 1.41)	0.63 (0.42, 0.93)	0.90 (0.63, 1.29)	0.77
Multivariable-adjusted HR (95% CI)	1 (referent)	0.71 (0.47, 1.09)	1.08 (0.75, 1.58)	0.71 (0.47, 1.07)	1.04 (0.70, 1.55)	0.16
Methionine (g/d)
Person-years	551,331	821,344	639,180	515,328	679,801	—
All colorectal cancers							—
Cases, n	195	270	173	166	189	—
Age-adjusted HR (95% CI)	1 (referent)	1.01 (0.83, 1.21)	0.77 (0.63, 0.95)	0.88 (0.72, 1.09)	0.75 (0.61, 0.92)	0.001
Multivariable-adjusted HR (95% CI)	1 (referent)	1.03 (0.85, 1.24)	0.81 (0.65, 1.01)	0.95 (0.76, 1.19)	0.83 (0.66, 1.04)	0.064
IGF2 DMR0 methylation level							0.006
First quartile (≤25%)
Cases, n	47	55	42	43	60	—
Age-adjusted HR (95% CI)	1 (referent)	0.80 (0.54, 1.19)	0.77 (0.51, 1.17)	0.93 (0.61, 1.41)	0.94 (0.64, 1.37)	0.20
Multivariable-adjusted HR (95% CI)	1 (referent)	0.82 (0.55, 1.21)	0.80 (0.52, 1.22)	0.99 (0.65, 1.51)	1.05 (0.70, 1.55)	0.056
Second quartile (26–50%)
Cases, n	48	76	42	39	47	—
Age-adjusted HR (95% CI)	1 (referent)	1.10 (0.76, 1.58)	0.77 (0.51, 1.16)	0.82 (0.54, 1.26)	0.73 (0.49, 1.09)	0.69
Multivariable-adjusted HR (95% CI)	1 (referent)	1.12 (0.78, 1.62)	0.81 (0.53, 1.23)	0.88 (0.57, 1.36)	0.82 (0.54, 1.24)	0.74
Third quartile (51–75%)
Cases, n	45	79	39	39	46	—
Age-adjusted HR (95% CI)	1 (referent)	1.27 (0.88, 1.84)	0.77 (0.50, 1.18)	0.91 (0.59, 1.40)	0.80 (0.53, 1.20)	0.20
Multivariable-adjusted HR (95% CI)	1 (referent)	1.31 (0.90, 1.89)	0.81 (0.52, 1.25)	0.98 (0.63, 1.53)	0.89 (0.58, 1.36)	0.58
Fourth quartile (>75%)
Cases, n	55	60	50	45	36	—
Age-adjusted HR (95% CI)	1 (referent)	0.74 (0.52, 1.08)	0.77 (0.52, 1.13)	0.84 (0.57, 1.25)	0.48 (0.32, 0.73)	0.009
Multivariable-adjusted HR (95% CI)	1 (referent)	0.76 (0.53, 1.11)	0.81 (0.54, 1.19)	0.91 (0.61, 1.37)	0.54 (0.35, 0.84)	0.063
Folate (μg/d)	<200	200–299	300–399	≥400	—	—
Person-years	573,056	943,363	594,407	1,096,159	—	—
All colorectal cancers							—
Cases, n	156	292	200	345	—	—
Age-adjusted HR (95% CI)	1 (referent)	0.90 (0.74, 1.10)	0.80 (0.64, 1.00)	0.75 (0.61, 0.91)	—	0.004
Multivariable-adjusted HR (95% CI)	1 (referent)	0.96 (0.78, 1.19)	0.93 (0.72, 1.20)	1.00 (0.76, 1.32)	—	0.69
IGF2 DMR0 methylation level							0.68
First quartile (≤25%)
Cases, n	31	76	46	94	—	—
Age-adjusted HR (95% CI)	1 (referent)	1.21 (0.80, 1.85)	1.04 (0.65, 1.64)	1.14 (0.75, 1.72)	—	0.87
Multivariable-adjusted HR (95% CI)	1 (referent)	1.32 (0.86, 2.02)	1.26 (0.78, 2.02)	1.69 (1.08, 2.64)	—	0.026
Second quartile (26–50%)
Cases, n	33	83	54	82	—	—
Age-adjusted HR (95% CI)	1 (referent)	1.32 (0.88, 1.98)	1.21 (0.78, 1.87)	0.95 (0.63, 1.43)	—	0.17
Multivariable-adjusted HR (95% CI)	1 (referent)	1.44 (0.95, 2.17)	1.47 (0.94, 2.32)	1.41 (0.90, 2.20)	—	0.40
Third quartile (51–75%)
Cases, n	48	72	48	80	—	—
Age-adjusted HR (95% CI)	1 (referent)	0.78 (0.54, 1.12)	0.72 (0.48, 1.08)	0.65 (0.45, 0.94)	—	0.047
Multivariable-adjusted HR (95% CI)	1 (referent)	0.85 (0.59, 1.24)	0.89 (0.58, 1.36)	0.97 (0.65, 1.46)	—	0.77
Fourth quartile (>75%)
Cases, n	44	61	52	89	—	—
Age-adjusted HR (95% CI)	1 (referent)	0.72 (0.49, 1.07)	0.89 (0.59, 1.34)	0.82 (0.57, 1.19)	—	0.77
Multivariable-adjusted HR (95% CI)	1 (referent)	0.79 (0.53, 1.18)	1.09 (0.71, 1.66)	1.22 (0.81, 1.84)	—	0.08

¹Cox proportional cause-specific hazards regression for competing risk data were used to compute HRs and 95% CIs. All analyses were stratified by age (in mo), year of questionnaire return, and sex. Multivariable-adjusted HRs were further adjusted for BMI (in kg/m²; <25 compared with 25–29.9 compared with ≥30), pack-years smoked (0 compared with 1–19 compared with 20–39 compared with ≥40 pack-years), family history of colorectal cancer in any first-degree relative, endoscopy status (no endoscopy compared with history of adenomatous polyps compared with negative endoscopy), physical activity level (quintiles of mean metabolic equivalent task-hours per week), red meat intake (quintiles of servings/d), total calorie intake (quintiles of kcal/d), calcium intake (quintiles of mg/d), current multivitamin use, regular aspirin use, and intakes of vitamin B-6, vitamin B-12, folate, and methionine. DMR0, differentially methylated region-0; IGF2, insulin-like growth factor 2.

²Linear trend test by using the median value of each category.

³The test for the heterogeneity of the association between one-carbon nutrient intake and colorectal cancer risk according to IGF2 DMR0 methylation level.