Associations between Genes in the One-Carbon Metabolism Pathway and Advanced Colorectal Adenoma Risk in Individuals with Low Folate Intake

DOI: 10.1158/1055-9965.EPI-11-0782 Published March 2012

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Figure 1.
A, association tests between SNPs and advanced colorectal adenoma risk stratified by dietary folate. Each quartile is a different color. For example, the dots in red represent nominal P values for each individual one-carbon metabolism SNP for subjects in the lowest quartile of folate intake (Q1), and the dots in blue represent nominal P values for each individual SNP for subjects in the highest quartile of folate intake (Q4). B, gene-level P values using the ARTP method in lowest folate quartile. C, gene-level P values using the ARTP method in quartile 2. D, gene-level P values using the ARTP method in quartile 3. E, gene-level P values using the ARTP method in quartile 4. Each dot represents a P value (y-axis) for each gene, as listed along the x-axis.

Table 1.

Characteristics of advanced colorectal adenoma cases and controls in PLCO genotyped for this study

Characteristic	Cases	%	Controls	%	p-value
No. of individuals	1,331		1,501
Gender					0.75
Female	481	36.1	551	36.7
Male	850	63.9	950	63.3
Age at randomization (y)					0.11
55–59	395	29.7	509	33.9
60–64	423	31.8	458	30.5
65–69	330	24.8	340	22.7
70–74	183	13.8	194	12.9
Race					0.13
White non-Hispanic	1,234	92.7	1,368	91.1
Other	97	7.3	133	8.9
Family history of colorectal cancer					0.01
Yes	169	13.2	147	10.2
No	1,331	86.8	1,298	89.8
Alcohol consumption (g/d)					0.06
<1	486	40.1	580	41.5
1–15	392	32.3	479	34.3
15–30	131	10.8	158	11.3
≥30	203	16.8	181	13.0
Prefortification dietary folate (mcg/d)					0.0002
<400	822	67.8	850	60.8
≥400	390	32.2	548	39.2
Postfortification dietary folate (mcg/d)					<0.0001
<400	604	49.8	587	42.0
≥400	608	50.2	811	58.0
Multivitamin use
Ever	141	16.5	156	15.1	0.42
Never	714	83.5	875	84.9
Body mass index (kg/m²)					0.08
<18.5	8	0.6	8	0.5
18.5–25	348	26.3	440	29.5
25–30	597	45.2	683	45.8
≥30	369	27.9	359	24.1
Strenuous physical activity (h/wk)
0	225	18.6	182	13.1	0.0002
<1	217	18.0	231	16.6
1	155	12.8	179	12.9
2	184	15.2	218	15.7
3	184	15.2	215	15.4
≥4	243	20.1	368	26.4
Smoking status					<0.0001
Never	510	38.4	718	47.8
Former	196	14.7	105	7.0
Current	624	46.9	678	45.2

NOTE: May not sum to total number of participants due to missing covariate values.

Table 2.

Top findings from association tests in the entire population

Gene	SNP	Location	Risk allele	Nominal P	OR (95% CI)
MTHFD1	rs11627387	IVS26-955G>A	G	0.0027	0.84 (0.75–0.94)
GLS	rs12185688	IVS14-3683T>C	T	0.0033	0.79 (0.67–0.92)
MTHFD1	rs2230491	Ex1-1015C>T	C	0.0045	0.80 (0.69–0.93)
UNG2	rs231625	-4520T>C	C	0.0088	1.26 (1.06–1.50)
TYMS	rs2298582	IVS13+122A>C	A	0.0090	0.80 (0.67–0.95)
MTHFS	rs622506	IVS2-1411T>G	G	0.0121	1.15 (1.03–1.28)
MTHFD1	rs2281603	IVS27-380T>C	T	0.0138	0.85 (0.75–0.97)
GART	rs9984077	Ex11+195G>A	A	0.0138	1.17 (1.03–1.34)
UNG2	rs231622	IVS1+5C>T	T	0.0141	1.16 (1.03–1.30)
MTHFD2	rs7587117	IVS29-27A>G	G	0.0146	1.15 (1.03–1.29)

Table 3.

Top findings from association tests in each quartile of prefortification dietary folate

Gene	SNP	Location	Risk allele	Dietary folate quartile	Nominal P^a	OR per allele	95% CI
ADA	rs244072	IVS2-1496T>C	C	1	2.37E-05^b	2.33	1.60–3.50
				2	0.7194	1.07	0.75–1.50
				3	0.4952	1.15	0.77–1.70
				4	0.9398	0.99	0.68–1.40
FOLR1	rs10501409	7502T>G	T	1	0.0010	1.77	1.25–2.50
				2	0.8014	1.05	0.74–1.48
				3	0.8105	0.96	0.72–1.52
				4	0.3134	1.22	0.83–1.81
TYMS	rs11664283	−6774A>G	A	1	0.0016	1.45	1.15–1.85
				2	0.0598	0.79	0.63–1.01
				3	0.3690	1.12	0.91–1.45
				4	0.9589	1.01	0.77–1.30
CDO1	rs34869	−599C>G	C	1	0.0018	1.41	1.14–1.75
				2	0.0177	1.31	1.05–1.64
				3	0.1311	1.20	0.66–1.06
				4	0.4069	0.90	0.71–1.15
MAT2B	rs4869087	IVS2-1783C>A	C	1	0.7900	1.03	0.81–1.30
				2	0.1579	1.18	0.94–1.50
				3	0.0020	0.65	0.49–0.86
				4	0.2827	1.16	0.89–1.50

NOTE: P value that is the most significant in each SNP is marked bold.

↵^aNominal P before adjustment for multiple comparisons.
↵^bP value that is statistically significant (P < 0.05) after adjustment for multiple testing.

Table 4.

Associations between rs244072 (ADA) and advanced colorectal adenoma risk in subjects in the lowest folate quartile, using different folate measures

		Per-allele OR (Nominal P)
Food composition database	Folate measure	Quartile 1^a 356/350^b	Quartile 2 301/349	Quartile 3 281/349	Quartile 4 274/350
USDA	Prefortification dietary folate	2.33 (2.37E-05)	1.07 (0.72)	1.15 (0.50)	0.99 (0.94)
	Postfortification dietary folate	2.12 (9.28E-05)	1.07 (0.71)	1.01 (0.92)	1.06 (0.74)
	Total folate from diet (post-fortification) and supplements	1.61 (8.90E-03)	1.17 (0.41)	0.93 (0.73)	1.28 (0.21)
University of Minnesota Nutrition Data Systems for Research	Postfortification dietary folate^c	1.88 (6.80E-04)	1.1 (0.61)	1.02 (0.90)	1.11 (0.58)
	Postfortification dietary folate^d	1.89 (5.70E-04)	1.09 (0.65)	0.88 (0.57)	1.18 (0.36)
	Natural folate^e	2.16 (6.45E-05)	0.85 (0.40)	1.26 (0.20)	1.04 (0.81)
	Synthetic folate^f	1.55 (1.53E-02)	1.2 (0.33)	0.93 (0.74)	1.23 (0.25)
N/A	Plasma folate	1.68 (0.14)	1.87 (0.13)	1.41 (0.29)	0.93 (0.84)

↵^aQuartiles were calculated based on the distribution of the folate variable among the controls.
↵^bThe number of cases and controls.
^cNatural + synthetic, based on microbiologic folate assays.
^dNatural + synthetic, based on estimated bioavailability.
^eFood folate from diet.
^fFolic acid from diet (postfortification).