Dietary B vitamin and methionine intakes and plasma folate are not associated with colorectal cancer risk in Chinese women

INTRODUCTION

Dietary factors involved in one-carbon metabolism may play a role in colorectal carcinogenesis (1). We evaluated whether dietary intakes of folate, methionine, and associated B vitamins were related to colorectal cancer risk using data from a large prospective cohort study of women in Shanghai, China. We further evaluated the relationship between baseline plasma folate levels and subsequent colorectal cancer risk in a nested case-control study from the same study population.

MATERIALS AND METHODS

The Shanghai Women’s Health Study (SWHS) is a population-based prospective study of 74,942 Chinese women aged 40 to 70 years at cohort entry(2). Relevant committees for the use of human participants in research approved the study protocol and informed consent was obtained from all participants. All participants were interviewed using a validated food frequency questionnaire(3). The Chinese Food Composition Table was used to estimate daily intake levels of most nutrients. Methionine, vitamin B6, and vitamin B12 were derived using the United States Department of Agriculture food composition tables as previously described(4). The cohort was followed for cancer incidence and mortality by a combination of follow-up surveys and annual record linkage to cancer case data collected by the Shanghai Cancer Registry and death certificates collected by the Shanghai Municipal Center for Disease Control and Prevention (2). In order to allow for the delay in records processing, the date of the last follow-up was set as December 31, 2005 for study participants whose last in-person interview occurred before the censoring date, 6 months after the most recent record linkage (June 30, 2006). For the nested case-control study, cases were matched to controls (up to 4 per case) on age at baseline (± 2 years), date (≤ 30 days) and time (morning or afternoon) of blood collection, interval since last meal (≤ 2 hours), menopausal status (pre- or post-), and antibiotic use (yes/no) in the past week. Baseline plasma folate levels were analyzed using the microbiological assay (5, 6).

Statistical Analysis

Nutrients were residual energy-adjusted (7). Cutpoints were based on the control distribution (nested case-control) or whole cohort (cohort analysis). The cohort analysis included 72,861 participants including 394 cases after excluding those with previous history of cancer (n=1,490), unreasonably high or low energy intake (n=132), or emigration from Shanghai shortly after baseline recruitment (n=10). We estimated associations using hazard ratios (HR) and 95% confidence intervals (95% CI) derived from Cox proportional hazard regression models (8) stratifying on birth cohort (9). Stratified analyses were performed to evaluate potential effect modifiers. In the case-control analysis, conditional logistic regression analysis was used to estimate odd ratios and 95% CI. Tests for trend were performed by entering the categorical variables as continuous parameters in the models. P values of < 0.05 (2-sided probability) were interpreted as being statistically significant. Statistical analyses were conducted by using SAS statistical software (version 9.1; SAS Institute, Cary, NC).

RESULTS

Baseline characteristics of cohort members are previously published (2). Few women in this population ever smoked cigarettes, consumed alcoholic beverages, or used non-steroidal anti-inflammatory medicines (data not shown). No statistically significant associations between dietary intakes of folate, methionine, and other B vitamins and colorectal cancer risk were observed (Table 1). Neither was any apparent association observed when limited to women who did not drink alcohol, women diagnosed with colorectal cancer more than two years after recruitment, women who did not use B vitamin supplements, pre-menopausal women, or postmenopausal women (data not shown in table).

Table 1.

Associations between dietary intakes of methionine and B vitamins in the Shanghai Women’s Health Study.

	Quintiles of Dietary Intake					p for trend
	Q1 (low)	Q2	Q3	Q4	Q5 (high)
Folate
Events, n	76	89	64	82	83
Mean Intake, µg/day	213	235	269	318	419
HR (95% CI)a	1.0 (ref)	1.3 (1.0–1.8)	1.0 (0.7–1.4)	1.2 (0.8–1.7)	1.1 (0.8–1.7)	0.78
Methionine
Events, n	104	69	77	70	74
Mean Intake, g/day	1.26	1.28	1.39	1.58	2.07
HR (95% CI) a	1.0 (ref)	0.8 (0.6–1.1)	1.0 (0.7–1.4)	1.0 (0.7–1.5)	1.2 (0.8–1.8)	0.27
Vitamin B12
Events, n	117	79	85	76	74
Mean Intake, µg/day	1.28	1.69	2.22	2.93	4.86
HR (95% CI) a	1.0 (ref)	0.9 (0.6–1.2)	1.0 (0.7–1.4)	1.1 (0.8–1.6)	1.3 (0.9–1.9)	0.10
Vitamin B6
Events, n	97	72	76	85	64
Mean Intake, mg/day	1.36	1.44	1.59	1.80	2.33
HR (95% CI) a	1.0 (ref)	0.8 (0.6–1.1)	0.9 (0.6–1.3)	1.0 (0.7–1.5)	0.7 (0.4–1.2)	0.74
Niacin (B3)
Events, n	97	74	72	75	76
Mean Intake, mg/day	12.9	12.5	13.1	14.4	18.3
HR (95% CI) a	1.0 (ref)	0.8 (0.6–1.2)	0.9 (0.6–1.3)	1.0 (0.7–1.4)	1.0 (0.7–1.6)	0.68
Riboflavin (B2)
Events, n	107	77	73	64	73
Mean Intake, mg/day	0.62	0.68	0.79	0.94	1.22
HR (95% CI) a	1.0 (ref)	0.9 (0.6–1.2)	0.9 (0.6–1.3)	0.9 (0.6–1.3)	1.1 (0.7–1.9)	0.69

^aAdjusted for age, educational attainment, baseline household income, smoking status, drinking status, physical activity, hormone replacement therapy, menopausal status, family history of colorectal cancer, body mass index (BMI), NSAID use, use of a B vitamin supplement, history of colorectal polyps, diabetes history, and daily intakes of energy, vegetables, fruits, red meats, and calcium.

The associations between dietary B vitamin and methionine intakes and colorectal cancer risk were similar in the nested case-control and cohort analyses. Plasma folate was not correlated with dietary methionine and B vitamin intakes among controls. The associations between plasma folate tertiles and colorectal cancer risk in the nested case-control study are presented in Table 2. Plasma folate was not associated with colorectal cancer risk overall nor when evaluated jointly with dietary intakes of methionine and B vitamins.

Table 2.

Associations between colorectal cancer risk and plasma folate and joint plasma folate and dietary intake in a nested case-control study from the Shanghai Women’s Health Study.

	Plasma Folate Tertiles
	T1 (Low)	T2	T3
	2.04–7.54 µg/ml	7.55–11.09 µg/ml	11.10–304.00 µg/ml
	OR 95% CI	OR 95% CI	OR 95% CI	p for trend
Cases	96	95	112
Controls	396	396	396
OR 95% CI	1.0 (ref)	1.0 (0.7–1.3)	1.2(0.8–1.7)	0.30
Diet				p for interaction
Methionine
Low	1.0 (ref)	0.9 (0.6–1.4)	1.2 (0.8–1.9)
High	1.0 (0.6–1.6)	1.0 (0.6–1.6)	1.1 (0.7–1.9)	0.52
Vitamin B12
Low	1.0 (ref)	0.9 (0.6–1.5)	1.1 (0.7–1.7)
High	0.9 (0.6–1.5)	0.9 (0.6–1.5)	1.2 (0.8–2.0)	0.69
Vitamin B6
Low	1.0 (ref)	0.6 (0.4–1.0)	1.3 (0.8–2.0)
High	0.8 (0.5–1.3)	1.1 (0.7–1.8)	1.0 (0.6–1.6)	0.40
Niacin (B3)
Low	1.0 (ref)	0.7 (0.4–1.1)	1.2 (0.7–1.8)
High	0.6 (0.4–1.0)	0.8 (0.5–1.3)	0.8 (0.5–1.3)	0.50
Riboflavin (B2)
Low	1.0 (ref)	0.8 (0.5–1.3)	1.0 (0.7–1.6)
High	0.9 (0.5–1.5)	1.0 (0.6–1.6)	1.2 (0.7–2.0)	0.75

^aAdjusted for age, educational attainment, baseline household income, smoking status, drinking status, physical activity, hormone replacement therapy, menopausal status, family history of colorectal cancer, body mass index (BMI), NSAID use, use of a B vitamin supplement, history of colorectal polyps, diabetes history, and daily intakes of energy, vegetables, fruits, red meats, and calcium.

DISCUSSION

One carbon metabolism is important in several biological processes including methylation, DNA synthesis, and DNA repair. Folate and methionine are the major sources of dietary methyl groups and vitamin B6, vitamin B12, and riboflavin are important cofactors in one carbon metabolism. However, in our comprehensive evaluation of these factors, we found no evidence to support their associations with colorectal cancer risk.

The role of one carbon metabolism in colorectal cancer risk has been evaluated in previous studies with equivocal results. A recent meta-analysis of folate intake found that higher dietary but not total (including supplemental) folate intake was related to a modest decreased risk of colorectal cancer in both cohort and case-control studies (10). However, similar to our study, other studies published since the meta-analysis have largely reported null associations (11–15), although one study observed an inverse relationship (16). Only a handful of nested case-control studies, none in a Chinese population, have evaluated biological measures of folate, including plasma folate (17–22), and most have reported a null association (19–22). These studies were mostly smaller and had lower folate levels than our study (17–20). Few studies have evaluated other dietary factors in one-carbon metabolism and colorectal cancer risk, and findings are also inconsistent (11, 13–15, 23–27).

In our study, we were able to evaluate a variety of factors related to one carbon metabolism in a population with no vitamin fortification of the food supply and low prevalence of alcohol use and vitamin supplement use. The prospective design, high participation rate, and high follow-up rates minimized the possibility of recall or selection bias. Since many foods which are rich in folate, such as green leafy vegetables, are also rich in other nutrients it is possible that nutrients other than folate and B vitamins or the interactions between these nutrients were responsible for previous observed associations or obscured associations in this study. It is also possible that the timing of our exposure assessment did not capture the relevant exposure window.

In summary, our study does not support a role for one carbon related dietary factors and plasma folate in the development of colorectal cancer in Chinese women.