Among 39 246 US women in the Nurse's Health Study who were initially free of cancer or polyps and who underwent endoscopy from 1984 through 2002, 2408 were documented as having adenoma (1841 distal colon adenomas and 675 rectal adenomas).
We calculated the distribution of potential risk factors for adenomas by quintiles of choline and betaine intake in 1984 (). Women with higher choline intake were more likely to be past smokers, to exercise regularly, and to use aspirin on a regular basis, and they consumed more fiber, calcium, folate, methionine, vitamin B6, and vitamin B12. Similar trends were observed for those with higher betaine intake, except that aspirin use was not associated with betaine intake.
Characteristics of participants in the Nurses' Health Study according to energy-adjusted choline and betaine intake in 1984*
presents energy-adjusted mean intakes and correlations with energy-adjusted choline and betaine in 1984. The energy-adjusted mean choline intake was 331 mg/day (standard deviation [SD] = 80). More than half of choline intake came from phosphatidylcholine. The energy-adjusted mean betaine intake was 189 mg/day (SD = 97). The correlation between choline and betaine intake was low, and food sources for these nutrients were different. Major food sources for choline were red meat (18% of intake), eggs (13%), poultry (9%), and milk (9%). Major food sources for betaine were spinach (34% of intake), white bread (8%), cold breakfast cereal (8%), pasta (7%), and dark bread (7%). Choline, betaine, and B vitamins that are related to one-carbon metabolism (folate and vitamins B6 and B12) share some food sources. However, the correlations between intakes of betaine and these vitamins were low (0.30 for folate, 0.18 for vitamin B6, and 0.15 for vitamin B12). The correlations between choline and these vitamins were modest (0.32 for folate, 0.34 for vitamin B6, and 0.47 for vitamin B12).
Mean intake (mg/day) and Spearman correlation coefficients of energy-adjusted choline compounds and betaine in women in the Nurses' Health Study in 1984
Higher intake of dietary choline was not, contrary to our hypothesis, inversely related to risk of distal colorectal adenoma (). On the contrary, choline intake was associated with an elevated risk of colorectal adenoma; the multivariable relative risks (95% CI) for increasing quintiles of intake were 1.00 (referent), 1.03 (0.90 to 1.18), 1.01 (0.88 to 1.16), 1.23 (1.07 to 1.41), and 1.45 (1.27 to 1.67; Ptrend<.001). Betaine intake was inversely associated with colorectal adenoma risk in age-adjusted analyses, but the association was much attenuated in multivariable analyses, mainly due to adjustment for folate intake. Betaine intake had a nonlinear inverse association with colorectal adenomas; the multivariable relative risks for increasing quintiles of intake (95% CIs) were 1.00 (referent), 0.94 (0.83 to 1.07), 0.85 (0.75 to 0.97), 0.86 (0.75 to 0.98), and 0.90 (95% CI = 0.78 to 1.04; Ptrend = .09). Additional adjustment for intakes of other nutrients related to methyl-group metabolism, including methionine and vitamins B6 and B12, did not substantially affect the associations (data not shown). Among individual sources of choline, choline from phosphatidylcholine and sphingomyelin was positively related to risk of colorectal adenoma (). The results were essentially the same when women with adenomas proximal to the descending colon but without synchronous distal adenoma were excluded from the non-case participants (data not shown). The positive association between choline intake and colorectal adenoma risk was consistent for larger and smaller adenomas (<1 versus ≥1 cm) and for distal versus rectal adenomas (data not shown).
Relative risks (with 95% confidence intervals) of colorectal adenoma according to quintile of energy-adjusted choline and betaine intake in women in the Nurses' Health Study*
Because choline is involved in methyl-group metabolism, we investigated whether the availability of other dietary factors related to methyl-group metabolism would modify the association between choline and adenoma risk. We examined choline intake and adenoma risk by levels of folate intake (<250, 250 to <400, and ≥400 μg/day) and alcohol intake (none, >0 to <10 g/day, and ≥10 g/day) (). The association between choline intake and adenoma risk was strongest among those with low folate intake and higher alcohol intake. However, none of the P values for interaction were statistically significant. We also examined beta-ine intake and adenoma risk by levels of folate and alcohol intakes. Betaine intake was not associated with adenoma risk at any levels of folate/alcohol intake (data not shown).
Multivariable relative risk and 95% confidence intervals of colorectal adenoma according to quintile of energy-adjusted choline intake by intakes of folate and alcohol in women in the Nurses' Health Study*
To address the possibility that the positive association between choline and colorectal adenoma is due to some particular foods that contribute to choline intake (e.g., red meat), we examined the association of major food sources of dietary choline with colorectal adenoma risk. Intakes of eggs and red meat were each positively related to colorectal adenoma risk. The relative risks for top versus bottom quintiles of intake were 1.25 (95% CI = 1.09 to 1.42) for eggs and 1.36 (95% CI = 1.15 to 1.60) for red meat. Next, we adjusted for intakes of these foods in a multivariable model with choline. The positive associations between choline intake and colorectal adenomas remained similar and statistically significant even after adjusting for the food sources (data not shown). Finally, we examined choline intake and adenoma risk by levels of red meat intake (<0.5, 0.5 to <1, and ≥1 servings/day) (). In this analysis, choline intake was positively associated with adenoma risk regardless of the level of red meat intake.