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The Health Outcome
Colorectal cancer is a leading cause of cancer mortality in developed countries. The disease is believed to develop when normal colonic epithelium gives rise to an adenomatous polyp, which subsequently undergoes malignant transformation. Colorectal adenomas are common, present in about 20% of people at age 50, and increase in prevalence as people age. Epidemiologic evidence suggests that smoking and folate deficiency are associated with an increased risk of colorectal adenomas and cancer. Polymorphisms of the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) may also influence risk, but evidence of this association is inconclusive.
The Finding
Ulvik et al.(1) report that smoking, folate status, and the C667T MTHFR polymorphism are strong, interactive determinants of colorectal adenoma risk. They report that adenoma risk is particularly high in smokers who have low folate levels and either the heterozygous CT or homozygous TT genotypes. These associations were found in a cross-sectional study of 442 Norwegians. A detailed abstraction of this article is available online as part of the HuGENet™ e-journal club (2). The study included participants in the Telemark Polyp Study-I, a population-based prospective study of colorectal cancer prevention by sigmoidoscopy, who accepted an offer of colonoscopy and polypectomy in 1996. All study participants reported smoking status and provided blood samples for determination of folate levels and genotyping of the C677T polymorphism of the MTHFR gene. Presence of adenoma was ascertained by colonoscopy (hyperplastic polyps were also ascertained, but the primary outcome reported in the study is high-risk adenomatous polyps).
As expected, folate levels were lower in smokers, and both smoking (OR = 4.0) and low folate levels (OR = 3.1) were associated with a significantly increased risk of high-risk adenoma. In the sample as a whole, there was no significant association between the MTHFR genotype and high-risk adenoma. The authors report a strong three-way interaction between smoking status, folate level, and MTHFR genotype. They observed an increased risk associated with smoking (OR = 8.2) in subjects with the CT or TT genotype and low folate levels. Unexpectedly, they also observed an increase in risk among smokers with the CC genotype and high folate levels (OR = 11.9). The authors conclude that, in smokers, high folate may confer increased or decreased risk of adenoma, depending on MTHFR genotype.
Public Health Implications
Results of this study are consistent with the established literature, which suggests a protective effect of folate and a risk-enhancing effect of smoking on colorectal adenoma and cancer. Smoking (the authors= primary exposure of concern) conferred about a fourfold increase in risk, but the stratification of this risk by MTHFR genotype (OR = 3.76 for CC and 4.23 for CT or TT) yields little additional information of practical value. Analysis of the three-way interaction between folate, smoking, and genotype yielded unexpected results B high folate being protective in some instances but deleterious in others B that are difficult to reconcile with plausible biological mechanisms. More research on interactions among smoking, nutritional factors, and MTHFR may eventually lead to improved colorectal cancer prevention.
References
- Ulvik A, Evensen ET, Lien EA et al. Smoking, folate, and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of colorectum. Am J Med Genet 2001;101:246-254
- Ulvik A. et al. electronic journal club abstraction
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