Magnesium Intake in Relation to Risk of Colorectal Cancer in Women

Context Animal studies have suggested that dietary magnesium may play a role in the prevention of colorectal cancer, but data in humans are lacking.

Objective To evaluate the hypothesis that a high magnesium intake reduces the risk of colorectal cancer in women.

Design, Setting, and Participants The Swedish Mammography Cohort, a population-based prospective cohort of 61 433 women aged 40 to 75 years without previous diagnosis of cancer at baseline from 1987 to 1990.

Main Outcome Measure Incident invasive colorectal cancer.

Results During a mean of 14.8 years (911 042 person-years) of follow-up, 805 incident colorectal cancer cases were diagnosed. After adjustment for potential confounders, we observed an inverse association of magnesium intake with the risk of colorectal cancer (P for trend = .006). Compared with women in the lowest quintile of magnesium intake, the multivariate rate ratio (RR) was 0.59 (95% confidence interval [CI], 0.40-0.87) for those in the highest quintile. The inverse association was observed for both colon (RR, 0.66; 95% CI, 0.41-1.07) and rectal cancer (RR, 0.45; 95% CI, 0.22-0.89).

Conclusion This population-based prospective study suggests that a high magnesium intake may reduce the occurrence of colorectal cancer in women.

Magnesium is required for a wide range of biological functions. Apart from being essential for the maintenance of genomic stability and for DNA repair, magnesium has a crucial role in modulating cell proliferation, cell cycle progression, and cell differentiation.¹ Magnesium supplementation has been demonstrated to reduce the incidence of experimentally induced colon cancer in animals,^2,3 which might be related to a decrease in colonic epithelial cell proliferation.^3-6 Magnesium has an important role in maintaining the antioxidative status of the cell¹; animals deficient in magnesium display an increased susceptibility to oxidative stress.^1,7,8

High circulating concentrations of C-peptide, a marker for insulin secretion, have been associated with increased risk of colorectal cancer in humans^9,10; conceivably, dietary factors that improve insulin sensitivity and lower insulin concentrations may have an impact on colorectal cancer risk. Magnesium supplementation increased insulin sensitivity among healthy subjects¹¹ and among patients with type 2 diabetes.^12,13 Furthermore, recent epidemiologic studies reported an inverse association of magnesium intake with insulin concentrations.^14,15 Despite evidence that magnesium may be implicated in colorectal carcinogenesis, there is no epidemiologic study pertaining to the association between magnesium intake and risk of colorectal cancer. Therefore, we conducted a prospective analysis of magnesium intake in relation to incidence of colorectal cancer using data from the Swedish Mammography Cohort, a population-based prospective cohort of 61 433 women.

Details of the Swedish Mammography Cohort have been described previously.¹⁶ In brief, this population-based cohort was established between 1987 and 1990, when all women aged 40 to 75 years living in Uppsala and Västmanland counties, central Sweden, received a mailed questionnaire that elicited information about diet (along with data on weight, height, and educational level). In total, 66 651 women, representing 74% of the source population, returned a completed questionnaire. A new questionnaire, sent to all surviving participants in 1997, was expanded to include data on a family history of colorectal cancer, cigarette smoking, physical activity, and use of multivitamin supplements and aspirin. The study was approved by the ethics committee at the Karolinska Institutet in Stockholm and the Uppsala University Hospital.

Nutrient intakes were computed by multiplying the consumption frequency of each food by the nutrient content of age-specific (<53, 53-65, ≥66 years) servings, using composition values from the Swedish National Food Administration Database.¹⁷ In a validation study in a subsample of 129 women randomly selected from the cohort (A. Wolk, unpublished data 1992), Pearson correlation coefficient between intake of magnesium reported in the baseline questionnaire and in four 1-week dietary records was 0.44, indicating reasonable validity of our questionnaire-based assessment of magnesium intake.

For this analysis, we excluded women with an erroneous national registration number, women with extreme energy intake estimates (ie, 3 SDs from the mean value for log-transformed energy), and women with previously diagnosed cancer (other than nonmelanoma skin cancer) at baseline. After exclusions, the study population comprised 61 433 eligible women who were followed up until a diagnosis of colorectal cancer, death, or June 30, 2004.

The women were categorized into quintiles according to magnesium intake. After determining that the data conformed to the proportional hazards assumptions, we used Cox proportional hazards modeling¹⁸ with age in months as the underlying time variable to estimate rate ratios (RRs) with 95% confidence intervals (CIs). All multivariate models were also simultaneously adjusted for body mass index (BMI), educational level, and intakes of total energy, saturated fat, dietary fiber, calcium, zinc, beta carotene, folate, and vitamin B₆. Intakes of nutrients were adjusted for total energy intake with the residual method.¹⁹ To calculate the P value for trend, participants were assigned the median value of their quintile of magnesium intake, and this variable was used as a continuous variable.²⁰ We used restricted cubic spline regression with 5 knots to flexibly model the association between magnesium intake and colorectal cancer risk.²¹ Analyses were conducted using SAS software (version 8.2, SAS Institute Inc, Cary, NC). All P values were 2-tailed; P <.05 was considered statistically significant.

The age-standardized baseline characteristics of the study population by quintiles of magnesium intake are shown in Table 1. Compared with women with a low intake of magnesium, those with higher intakes generally had lower intakes of energy and saturated fat and higher intakes of dietary fiber, calcium, zinc, beta carotene, folate, and vitamin B₆. Women with greater magnesium intake also were more likely to have a postsecondary education.

Over an average follow-up of 14.8 years (911 042 person-years), 805 women were diagnosed with colorectal cancer (547 colon cancer, 252 rectal cancer, and 6 cases with both colon and rectal cancer). We observed a statistically significant inverse association between magnesium intake and risk of colorectal cancer in both the age- and multivariate-adjusted models (Table 2). Compared with women in the lowest quintile of magnesium intake, the multivariate RR of colorectal cancer for those in the highest quintile was 0.59 (95% CI, 0.40-0.87; P for trend = .006). Further control for consumption of red meat, fruits, vegetables, and whole grain foods yielded virtually the same results (RR, 0.61; 95% CI, 0.41-0.91). In addition, the inverse association with magnesium intake persisted when we added 1 at a time to a multivariate model intake of vitamins A, C, D, and E, and (in place of total dietary fiber) cereal fiber, vegetable fiber, and fruit fiber (data not shown). The RR was only slightly attenuated when all these nutrients were included simultaneously in a multivariate model (RR, 0.67; 95% CI, 0.45-1.00). Using data from the 1997 questionnaire, the results remained essentially unchanged after adjustment for a family history of colorectal cancer, cigarette smoking, physical activity, and use of multivitamin supplements and aspirin (RR, 0.60; 95% CI, 0.40-0.88). Excluding cases of colorectal cancer that occurred within the first 3 years of follow-up did not appreciably alter the results (multivariate RR comparing extreme quintiles, 0.62; 95% CI, 0.41-0.93). Intake of magnesium was inversely associated with both colon and rectal cancer (Table 2); the inverse association was similar for proximal colon (RR comparing extreme quintiles, 0.56; 95% CI, 0.27-1.16) and distal colon cancer (RR, 0.63; 95% CI, 0.27-1.47).

Because the inverse association of magnesium intake with colorectal cancer risk appeared to be linear (Figure), we analyzed magnesium intake as a continuous variable. The multivariate RR of colorectal cancer for a 50-mg/d increment of magnesium—approximately equivalent to the magnesium content in 1 small serving of spinach per day, 1 large banana per day, 1 serving of cooked oatmeal per day, 2 slices of whole grain bread per day, or a half serving of beans per day—was 0.78 (95% CI, 0.62-0.99).

This large population-based prospective cohort study is, to the best of our knowledge, the first to examine and observe a significant inverse dose-response relationship between magnesium intake and risk of colorectal cancer.

Major strengths of our study include its large size, population-based and prospective design, the large number of colorectal cancer cases, and the completeness of case ascertainment through the Swedish Cancer Registry System.²² These features of the study increase the generalizability of our results and eliminate potential recall and selection biases. Our study also has several potential limitations. Because magnesium intake was assessed through a self-administered food-frequency questionnaire, and our analysis was based on a single baseline measurement of dietary intake, some misclassification of magnesium intake is inevitable, which would potentially attenuate any true relationship. Although we adjusted our estimates for a wide range of potential confounders, we cannot rule out the possibility that our findings may be biased by unmeasured confounders or by residual confounding. However, multivariate analyses yielded results similar to those from age-adjusted analyses, suggesting that residual confounding is unlikely to have affected our results materially.

In conclusion, this population-based cohort study of women suggests that a high magnesium intake may reduce the risk of colorectal cancer. While our findings require confirmation by other large well-designed studies, they support potential benefits of increasing consumption of major foods contributing to magnesium intake, including fruits and vegetables, whole grain foods, and beans, in reducing colorectal cancer incidence. However, the efficiency and safety of magnesium supplementation for the prevention of colorectal cancer needs to be specifically addressed in a randomized trial.

Corresponding Author: Susanna C. Larsson, MSc, Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, PO Box 210, SE-171 77 Stockholm, Sweden (susanna.larsson@imm.ki.se).

Author Contributions: Ms Larsson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Larsson, Bergkvist, Wolk.

Acquisition of data: Wolk.

Analysis and interpretation of data: Larsson, Wolk.

Drafting of the manuscript: Larsson.

Critical revision of the manuscript for important intellectual content: Larsson, Bergkvist, Wolk.

Statistical analysis: Larsson.

Obtained funding: Bergkvist, Wolk.

Administrative, technical, or material support: Wolk.

Study supervision: Bergkvist, Wolk.

Funding/Support: This work was supported by research grants from the Swedish Cancer Foundation and the Swedish Research Council/Longitudinal Studies.

Role of the Sponsors: Funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.