MTHFR Genotype and Colorectal Adenoma Recurrence: Data from a Double-blind Placebo-controlled Clinical Trial

DOI: 10.1158/1055-9965.EPI-07-2670 Published September 2008

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Figure 1.
MTHFR, methylenetetrahydrofolate reductase; DHFR, dihydrofolate reductase; THF, tetrahydrofolate; SHMT1, cytosolic serine hydroxymethyltransferase; 5,10-MTHF, 5,10-methylentetrahydrofolate; MTHFD1, methyltetrahydrofolate hydrogenase; 5-MTHF, 5-methyltetrahydro folate; HCY, homocysteine; MTR, 5- Methyltetrahydrofolate-homocysteine s-methyltransferase; MAT, Methionine adenosyltransferase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; SAHH, S-adenosylhomocysteine hydrolase; B₂, B₆, B₁₂, B-vitamin co-factors.

Table 1.

Selected subject characteristics at baseline and year 3

Characteristic	Placebo (n = 461)	Folic acid (n = 462)	P
Mean age in y (SD)	57.5 (9.6)	57.7 (9.6)	0.726
Male sex n (%)	297 (64.4)	296 (64.1)	0.910
Race/Ethnicity n (%)
White	405 (87.9)	410 (88.7)	0.695
African American	25 (5.4)	20 (4.3)
Hispanic	17 (3.7)	22 (4.8)
Other	14 (3.0)	10 (2.2)
Current cigarette smoker n (%)	60 (13.1)	70 (15.2)	0.615
Mean dietary intake in kcal/d (SD)	1,642.3 (649.6)	1,616.2 (656.8)	0.552
Mean dietary folate intake in μg/d (SD)	329.0 (165.3)	317.2 (145.1)	0.260
Mean baseline plasma folate in nmol/L (SD)	23.7 (16.8)	23.9 (18.1)	0.873
Mean year-3 plasma folate in nmol/L (SD)	30.0 (14.1)	74.9 (35.9)	<0.0001
Mean baseline plasma T-homocysteine in μmol/L (SD)	9.8 (2.9)	9.8 (2.9)	0.806
Mean year-3 plasma T-homocysteine in μmol/L (SD)	9.2 (2.5)	8.9 (2.2)	0.074
MTHFR 677 C>T genotype
CC n (%)	207 (45.0)	213 (46.2)	0.614
CT n (%)	201 (43.7)	205 (44.5)
TT n (%)	52 (11.3)	43 (9.3)
MTHFR 1298 A>C genotype
AA n (%)	234 (50.8)	220 (47.6)		0.283
AC n (%)	193 (41.9)	195 (42.2)
CC n (%)	34 (7.4)	47 (10.2)
Joint genotypes (677/1298)
CC/AA (baseline) n (%)	72 (15.7)	71 (15.4)
CC/AC n (%)	101 (22.0)	96 (20.8)
CC/AA n (%)	34 (7.4)	46 (10.0)	0.670
CT/AA n (%)	110 (23.9)	106 (23.0)
CT/AC n (%)	91 (19.8)	99 (21.5)
CT/CC n (%)	0	0
TT/AA n (%)	52 (11.3)	43 (9.3)
TT/AC n (%)	0	0
TT/CC n (%)	0	0

NOTE: Of the 1,021 subjects randomized to folate treatment or placebo, MTHFR 677C>T and MTHFR 1298A>C genotype data were available for for 923 subjects (90%) and of these subjects 23 did not have a year-3 colonoscopy and are not included in further analyses. Missing data: Smoking status, n = 4; Dietary folate, n = 36; Dietary intake, n = 36; Plasma folate, n = 67; Baseline HCY, n = 64; Year-3 plasma folate and HCY, n = 119.

Table 2.

Association of MTHFR genotype and risk of recurrent adenomas

↵* Advanced adenoma defined as >25% tubulovillous or villous adenoma, large adenoma (≥1 cm), advanced dysplasia, carcinoma in situ, or invasive cancer.
↵† RRs were adjusted for age, sex, clinical center, treatment assignment, and follow-up time.
↵‡ Wald test used to generate P values.

Table 3.

Effect of folate treatment on the risk of adenomas, by MTHFR genotype

↵* Advanced adenoma defined as tubulovillous or villous adenoma, large adenoma (≥1 cm), carcinoma in situ, or invasive cancer.
↵† Number of subjects in folate/placebo treatment groups.
↵‡ RR, risk ratio for effect of 1 mg/day folate supplement versus placebo on adenoma recurrence risk; RRs were adjusted for age, sex, clinical center, and aspirin treatment assignment.