A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer.
We examined the relationship of a common polymorphism (667C-->T) of the methylenetetrahydrofolate reductase (MTHFR) gene with the risk of colorectal cancer in a case-control study conducted in the Health Professionals Follow-up Study. MTHFR genotypes were ascertained from blood samples among 144 men previously diagnosed with colorectal cancer and 627 controls. The adjusted odds ratio (OR) for the MTHFR variant homozygous (val/val) genotype was 0.57 [95% confidence interval (CI), 0.30-1.06]. High dietary intake of methionine (OR, 0.27; 95% CI, 0.06-1.20) and low consumption of alcohol (OR, 0.11; 95% CI, 0.01-0.85) were associated with reduced incidence of colorectal cancer. Alcohol intake was a stronger risk factor among men with the val/val genotype (P, trend = 0.01), and consumption of five or more alcoholic drinks per week abolished the reduced risk of colorectal cancer among val/val individuals (P, interaction = 0.02). The inverse association of methionine with colorectal cancer risk was slightly stronger among individuals with the MTHFR val/val genotype. These data suggest that dietary methyl supply is particularly critical among MTHFR val/val individuals. When dietary methyl supply is high, MTHFR val/val individuals may be at reduced risk of colorectal cancer probably because higher levels of 5,10-methylenetetrahydrofolate may prevent imbalances of nucleotide pools during DNA synthesis. In contrast, when 5-methyltetrahydrofolate is depleted by alcohol consumption, val/val individuals may be less able to compensate, leading to potentially oncogenic alterations in DNA methylation.
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
J
J
Chen
E
E
Giovannucci
K
K
Kelsey
E B
EB
Rimm
M J
MJ
Stampfer
G A
GA
Colditz
D
D
Spiegelman
W C
WC
Willett
D J
DJ
Hunter
D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D000431:Ethanol / Q000009:adverse effects; D005492:Folic Acid / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D008297:Male; D008715:Methionine / Q000008:administration & dosage; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012307:Risk Factors
D000431:Ethanol; D005492:Folic Acid; D008715:Methionine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)