Folate intake, MTHFR C677T polymorphism, alcohol consumption,
and risk for sporadic colorectal adenoma

The Health Outcome

In the U.S, colorectal cancer is the second leading cause of cancer death after lung cancer, and the fourth most common incident cancer after breast, lung and prostate cancers (1-3). Throughout the world, incidence rates vary markedly from about 25-35 per 100,000 in North America , Western Europe , and Australia to just 1 to 3 per 100,000 in India . Incidence rates are similar in men and women but vary by ethnicity; for example, the incidence among Northern European Caucasians is higher when compared to their counterparts from Southern Europe
(1-3).

The genetic component for colorectal cancer runs the spectrum from rare autosomal dominant syndromes with high penatrance (Familial Adenomatous Polyposis and Hereditary Nonpolyposis Colorectal Cancer) to genes with much lower penatrances that increase the risk of colorectal cancer through gene-gene and gene-environment in tera ctions (3) . Of particular interest in this paper was the association between folate intake, MTHFR genotype, and the risk of colorectal adenoma.

The Finding

Deficiencies along the folate metabolism pathway result in abnormal expression of oncogenes and tumor suppressor genes while compromising DNA integrity by decreasing the number of available base pairs (4-5) . As these mechanisms could cause cancer, this study attempted to explore the relationship between several elements of the folate metabolism pathway and colorectal cancer. Specifically, the authors tried to establish associations of folate intake, other micronutrients involved in folate metabolism, polymorphisms in the methylentetetrahydrofolate reductase (MTHFR) gene, and alcohol consumption with sporadic colorectal
adenoma. (1)

These relationships were examined in a case-control study conducted between 1995 and 1997. Individuals between the ages of 30 and 74 were recruited before voluntary colonoscopies at four gastroenterology practices located in the Piedmont region of North Carolina . Prior to the procedure, those who agreed to participate answered questions about their family history of cancer and anthropometrics; women were asked to provide information about their reproductive history. Participants also completed an adapted Willett semi-quantitative food frequency questionnaire and a modified Paffenbarger questionnaire to ascertain dietary and medical history, smoking and drinking habits, and physical activity. Following the colonoscopy, all individuals with adenomas were considered cases, while those who were adenoma free were used as controls. (1)

The genetic analysis was conducted using blood samples from the participants. DNA was extracted from nuclear pellets processed from these samples and amplified by PCR. Subsequently, restriction enzymes were used to identify the different variants. Quality control was assured by retyping ambiguous results and retyping 10% of all samples. (1)

The results of the study were as follows. First, a statistically significant association between total folate intake and risk of colorectal adenoma could not be established. Second, a higher consumption of alcohol was associated with an increased risk of colorectal adenoma regardless of folate intake. Finally, the data were consistent, though not statistically significant, for a possible protective effect in individuals with high folate intake and either high vitamin B consumption or homozygous TT.(1)

Public Health Implications

The major limitation of this case control study was a lack of statistical power due to small sample size. Furthermore, some bias may have been introduced as a result of recruiting controls that were having voluntary colonoscopies. As these individuals may have been considered at a higher risk of colorectal adenoma, their physicians may have recommended earlier screenings as evidenced by the younger age and greater likelihood of controls to report a history of colorectal cancer in their family. The overall effect of this bias would have been to diminish true associations toward the null value.(1)

In addition to the limitations, the authors presented a list of strengths for their analysis. First, the disease status of the controls was well established by a colonoscopy. Second, the design of the study may have reduced recall bias as the diagnoses of adenomas were subsequent to the completion of the questionnaires. Finally, information was gathered on vitamin and mineral supplement and NSAID use to examine potential confounding or modification of the observed associations.(1)

In reference to public health, lower alcohol consumption or higher vitamin B complex consumption for the population could help decrease the incidence of colorectal adenoma and possibly colorectal cancer. As with the folate fortification of grain products, this may be accomplished by fortifying more food items with additional multinutrients.(1)

Further research could be directed toward analyzing the inconclusive associations related to vitamins B6 and B12 and the MTHFR genotype with greater statistical power. This could involve new studies with greater sample sizes and research designs that avoid creating biases toward the null or meta-analysis of similar studies. (1)

References

1. Boyapati, Sonia M., et al. Folate intake MTHFR C677T polymorphism, alcohol consumption, and risk for sporadic colorectal adenoma. Cancer Causes and Control. 2004;15:493-501.
2. Potter, John D. et al. Colon Cancer: A Review of the Epidemiology. Epidemiological Reviews. 1993; 15: 499-545.
3. Potter, John D. Colorectal Cancer: Molecules and Populations. Journal of the National Cancer Institute. 1999; 91: 916-932.  
4. Bendich, A. and R.J. Deckelbaum (ed). Preventive Nutrition: The Comprehensive Guide for Health Care Professionals, 2 ed. 1997. 41-94.
5. Choi S-W, and JB Mason. Folate Status: Effects on Pathways of Colorectal Carcinogenesis. Journal of Nutrition. 2002. 132: 2413S-2418S.