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American Journal of Epidemiology Advance Access published online on November 6, 2007
American Journal of Epidemiology, doi:10.1093/aje/kwm307
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Original Contribution

Nutrients Contributing to One-Carbon Metabolism and Risk of Non-Hodgkin Lymphoma Subtypes

Stella Koutros1,2, Yawei Zhang1, Yong Zhu1, Susan T. Mayne1, Sheila Hoar Zahm2, Theodore R. Holford1, Brian P. Leaderer1, Peter Boyle3 and Tongzhang Zheng1

1 Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT
2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
3 International Agency for Research on Cancer, Lyon, France

Correspondence to Stella Koutros, Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Executive Plaza South 8111, MSC 7240, Rockville, MD 20852 (e-mail: koutross{at}mail.nih.gov).

Received for publication May 22, 2007. Accepted for publication September 21, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Because little is known about the etiology of non-Hodgkin lymphoma (NHL), a heterogeneous disease, and because dietary factors are modifiable, the authors examined the associations between nutrients related to one-carbon metabolism and risk of NHL in a population-based case-control study of Connecticut women diagnosed between 1996 and 2000. A total of 594 cases and 710 controls completed a food frequency questionnaire for determination of intakes of folate, vitamins B2, B6, and B12, and methionine. Through unconditional logistic regression, the authors estimated the risk of NHL associated with intake of each nutrient. Comparing the highest quartile of intake with the lowest, the authors found lower risks of all NHL associated with increasing intakes of folate and methionine. Analysis by NHL subtype indicated lower risks of diffuse large B-cell lymphoma (highest quartile vs. lowest: odds ratio (OR) = 0.54, 95% confidence interval (CI): 0.30, 0.98; p-trend = 0.02) and marginal zone lymphoma (highest quartile vs. lowest: OR = 0.08, 95% CI: 0.02, 0.26; p-trend < 0.0001) associated with folate. Vitamin B6 intake was also associated with lower risk of NHL overall and of marginal zone lymphoma (highest quartile vs. lowest: OR = 0.23, 95% CI: 0.08, 0.65; p-trend = 0.002). These findings suggest that these nutrients may be important for susceptibility to NHL.

case-control studies; diet; folic acid; lymphoma, non-Hodgkin; metabolism; methionine; vitamins

Abbreviations: CI, confidence interval; CLL, chronic lymphocytic leukemia; NHL, non-Hodgkin lymphoma; OR, odds ratio; SLL, small lymphocytic lymphoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The incidence of non-Hodgkin lymphoma (NHL) nearly doubled from the early 1970s through the 1990s. Data from the Surveillance, Epidemiology, and End Results program show that the age-adjusted incidence rate increased from 11.1 per 100,000 population in 1975 to 19.3 per 100,000 in 2002 (1, 2). Reasons for the increased incidence remain largely unknown, and the search for explanations is compounded by the reality that NHL comprises many histologically distinct lymphoid malignancies (3). Since the only established risk factors for NHL are primary, acquired, or iatrogenic immunodeficiencies (4), many etiologic studies have been undertaken to explore potential hypotheses.

Several recent epidemiologic studies have focused on intracellular one-carbon metabolism. This refers to the process of interrelated biochemical reactions that involve the transfer of methyl groups (5). One-carbon metabolism involves nutrients as enzymatic cofactors (folate and vitamins B2, B6, and B12) as alternative suppliers of one-carbon units (methionine), with alcohol potentially disrupting these actions (6). Deficiencies in folate and other nutrients contributing to one-carbon metabolism can impair DNA methylation and cause disruption of DNA integrity and DNA repair, which can lead to carcinogenesis (7). In addition, deficiencies in folate, vitamin B12, and methionine can lead to an impaired immune response (8), the only known risk factor for NHL. These consequences suggest that higher dietary intake of these nutrients could confer a lower risk of NHL.

Nutrients involved in one-carbon metabolism are found in a variety of foods. Many of these food groups or food items have been examined for associations with NHL. Some investigators have found inverse associations for fruits (9–13) and vegetables (9, 11–16), although some reported null associations as well. Other studies have suggested that high intakes of saturated fat and animal protein (9, 13, 15, 17) may be positively associated with risk of NHL, while findings for breads, grains, and cereals have been mixed or inconsistent (9, 11, 15, 16, 18). So far, however, few studies have examined specific nutrients that contribute to one-carbon metabolism and risk of NHL. Zhang et al. (12) reported no association between dietary folate and NHL in the Nurses' Health Study cohort, while in another cohort study, Lim et al. (19) observed an inverse association for vitamin B12 only among male smokers. Three recent case-control analyses have had mixed findings. Lim et al. (20) found a significant inverse association for vitamin B6 and methionine, as well as an inverse risk associated with folate, among diffuse lymphoma subtypes; Chang et al. (21) found an inverse risk for folate among all NHL cases; and Polesel et al. (22) found no association for vitamin B2 or B6 or folate (22). The reasons for these conflicting results are probably related to differing study populations, differing methods of assessing nutrient intake, and small numbers of cases, with limited ability to examine histologic differences. Here we sought to examine the association between intakes of nutrients that contribute to one-carbon metabolism and the risk of NHL in a population-based case-control study of Connecticut women, using the largest case series available to date, with particular interest in NHL subtype differences.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
A detailed description of the study population has been given elsewhere (13). Briefly, cases included female patients with histologically confirmed (International Classification of Diseases for Oncology, Second Edition, codes M-9590–9595, 9670–9688, 9690–9698, and 9700–9723) incident non-Hodgkin lymphoma who were aged 21–84 years and had no previous diagnosis of cancer, except nonmelanoma skin cancer. All subjects were diagnosed in Connecticut between 1996 and 2000 and were alive at the time of interview. Cases were identified through the Yale Cancer Center's Rapid Case Ascertainment Shared Resource, an agent of the Connecticut Tumor Registry. Of 832 eligible cases, 594 (71 percent) completed in-person interviews and were included in this analysis. Population-based controls with Connecticut addresses were recruited using either random digit dialing for those below age 65 years or Centers for Medicare and Medicaid Services files for those aged 65 years or above. The participation rate for random digit dialing controls was 69 percent, and that for Centers for Medicare and Medicaid Services controls was 47 percent; this resulted in the identification of 710 controls. Reasons for nonparticipation included physician refusal, patient refusal, inability to contact the participant, and inability to speak English.

We frequency-matched cases and controls by age in 5-year groups, by adjusting the number of controls randomly selected in each age stratum every few months. A standardized, structured questionnaire elicited demographic data and information on other major known or suspected risk factors that might confound or modify the association between dietary intakes and risk of NHL. All participants provided informed consent, and the protocol was approved by the Human Investigations Committee at Yale School of Medicine.

For accurate and consistent histologic classification of the cases, pathology slides (or tissue blocks) were obtained for all cases from the pathology departments in which the cases were diagnosed. The specimens were reviewed by two study pathologists experienced in the diagnosis of lymphoma. The NHL cases were classified as being either a major B-cell subtype (follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, or chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)) or T-cell lymphoma.

Dietary assessment
A semiquantitative food frequency questionnaire developed at the Fred Hutchinson Cancer Research Center (Seattle, Washington) was completed by each subject. Subjects were asked to characterize their usual diets in the year prior to being interviewed. This type of assessment is highly correlated with diet in the more distant past (23). The food frequency questionnaire collected data on consumption frequency and portion size for approximately 120 foods and beverages. After completion, the food frequency questionnaire was sent to the Fred Hutchinson Cancer Research Center for analysis. Average daily nutrient intakes were calculated using the University of Minnesota Nutrition Coordinating Center's Nutrition Data System for Research database (24). Intakes of all nutrients were examined from food alone. Folate values represent preenrichment levels, as prefortification folate levels are most representative of usual adult diet. Information about supplemental vitamin intake was not assessed on the food frequency questionnaire.

Data analysis
Unconditional logistic regression was used to estimate the association between the risk of NHL and intake of nutrients related to one-carbon metabolism in simple and multivariate-adjusted models. All nutrient data were adjusted for total energy intake by means of the multivariate nutrient density method, where each nutrient density is computed (nutrient/calories) and then results are entered together with total energy into a multiple logistic regression model (23).

For each nutrient, quartiles of consumption were produced by dividing the frequency distribution of the control group at the 25th, 50th, and 75th percentiles. Simple adjusted models included the matching factor, age, along with total energy intake. For the multivariate model, confounding variables were added to the model if they significantly contributed to the model at the {alpha} = 0.05 level or if their addition changed the parameter estimates by more than 10 percent. The following confounding variables were included in the final model: age (in years, as a continuous variable), body mass index (as a continuous variable; weight (kg)/height (m)2), family history of NHL in first-degree relatives (yes/no/missing data), alcohol intake (ever drinker or never drinker), and other significant nutrients (categorical variables, by quartile of intake). Adjustments for other variables such as race (White, Black, other), educational level (some high school or less, some college or more), tobacco smoking (ever/never), animal protein intake (g/1,000 kcal), saturated fat intake (g/1,000 kcal), and calcium intake (mg/1,000 kcal) did not result in significant changes in the observed association and thus were not included in the model. Examination of potential effect modification by alcohol intake (ever/never) showed no significant differences in risk (data not shown).

We also investigated the potential for multicollinearity in models by examining the variance estimates. Variables that were highly correlated (r > 0.70) with nutrients related to one-carbon metabolism and that resulted in a tolerance level below 0.40 were judged to be negatively affecting the variance estimates and subsequently dropped from the model (25). This was only apparent with the addition of fiber intake as a covariate for models of folate and vitamin B6, where the direction of the association was not changed but variance estimates became unstable and inflated. Similar results were observed when modeling fiber as the main effect and adding folate or vitamin B6 to the model, further confirming multicollinearity.

Other variables were included for descriptive purposes and were compared among cases and controls using t tests and Wilcoxon nonparametric tests for continuous variables and chi-squared tests for categorical variables. All p values are two-sided. Testing for linear trend and calculation of odds ratios and 95 percent confidence intervals were carried out using SAS statistical software (SAS Institute, Inc., Cary, North Carolina).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Characteristics of the study sample are shown in table 1. Cases and controls were similar with respect to age (by design), race, and smoking status. More cases than controls reported a family history of NHL, while controls had a higher educational level and were more likely to drink alcohol. Cases reported higher total energy intakes and higher body mass indices than did controls. Variables that changed parameter estimates by more than 10 percent in multivariate-adjusted models were body mass index, family history of NHL, and alcohol intake. Increasing level of body mass index was associated with increased risk of NHL. Compared with never drinkers, ever drinkers had a moderately lower risk of NHL, and reported family history of NHL in first-degree relatives was also associated with an increased risk of NHL in this population.


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  		TABLE 1. Characteristics* of non-Hodgkin lymphoma cases and controls among Connecticut women, 1996–2000

 
Table 2 shows the simple and multivariate-adjusted associations between nutrients and NHL. In multivariate models, women whose estimated folate intakes were in the two highest quartiles had lower risks of NHL (odds ratio (OR) = 0.68 (95 percent confidence interval (CI): 0.48, 0.96) and OR = 0.60 (95 percent CI: 0.41, 0.88), respectively) than those in the lowest quartile. The lower risk of NHL associated with each increasing level of folate intake was dose-dependent, with a significant linear trend (p-trend = 0.006). Higher methionine intake was associated with a lower risk of NHL, with an approximately 40 percent lower risk for the highest quartile (OR = 0.61, 95 percent CI: 0.43, 0.86; p-trend = 0.008). A higher vitamin B6 intake was also associated with a lower risk of NHL (highest quartile vs. lowest: OR = 0.72, 95 percent CI: 0.50, 1.05; p-trend = 0.03). However, we found a higher risk of NHL associated with the highest level of vitamin B2 intake (OR = 1.74, 95 percent CI: 1.22, 2.49). No other nutrient intake showed a significant association with NHL risk when NHL was considered in total.


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  		TABLE 2. Multivariate association of nutrients related to one-carbon metabolism with non-Hodgkin lymphoma among Connecticut women, 1996–2000

 
Table 3 presents the multivariate associations of nutrients with major NHL subtypes. Folate intake showed a significant inverse association with risk of diffuse large B-cell lymphoma and marginal zone lymphoma (p-trend values were 0.02 and <0.0001, respectively). Odds ratios for women in the highest quartile of folate intake were 0.54 (95 percent CI: 0.30, 0.98) for diffuse large B-cell lymphoma and 0.08 (95 percent CI: 0.02, 0.26) for marginal zone lymphoma. Increased levels of vitamin B6 intake were associated with lower risk of CLL/SLL and marginal zone lymphoma; odds ratios for the highest quartiles were 0.45 (95 percent CI: 0.20, 1.02; p-trend = 0.04) and 0.23 (95 percent CI: 0.08, 0.65; p-trend = 0.002), respectively. Methionine intake seemed to be consistently associated with lower risk of major types of NHL, but the trend was most consistent for diffuse large B-cell lymphoma and T-cell lymphoma. For diffuse large B-cell lymphoma, the odds of NHL for women in the highest quartile of intake were 0.61 (95 percent CI: 0.36, 1.04; p-trend = 0.06). For T-cell lymphoma, the odds were 0.43 (95 percent CI: 0.16, 1.13) compared with women in the lowest quartile of intake (p-trend = 0.08).


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  		TABLE 3. Multivariate-adjusted* associations of selected nutrients with subtypes of non-Hodgkin lymphoma among Connecticut women, 1996–2000

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this population-based case-control study, we found that nutrients contributing to one-carbon metabolism were associated with the risk of NHL. In particular, higher dietary intakes of folate and methionine were associated with significantly lower risks of NHL, with evidence of a dose-dependent relation. For folate, the decreased risks were most evident for diffuse large B-cell lymphoma and marginal zone lymphoma. For methionine, the decreased risk was evident for all NHL subtypes, particularly T-cell lymphoma and follicular lymphoma. In addition, higher intake of dietary vitamin B6 was associated with lower risk of marginal zone lymphoma, as well as a lower risk for CLL/SLL subtypes. On the other hand, we found an increased risk of NHL associated with higher vitamin B2 intake.

A potential relation between these nutrient intakes and NHL risk is biologically plausible. There are several possible mechanisms by which these nutrients may modulate cancer risk. The biochemical function of folate is to mediate the transfer of one-carbon (methyl) units. Folate is critical for the synthesis of S-adenosylmethionine, a compound that serves as a methyl donor for methylation of DNA. It has also been shown that folate deficiency can result in excess uracil incorporation in DNA, which increases the risk of DNA damage and thus carcinogenesis (5, 26, 27). In addition, adverse effects of folate deficiency on immune function have been described. Low levels of folate are reported to decrease the number of T cells, reduce cytotoxic activity against foreign transplanted cells, and possibly reduce humoral immunity (28). These immune implications lend further evidence to support the idea that increased intake of folate might decrease NHL risk, since altered immune status is the only established risk factor for NHL.

We also found that methionine intake was significantly inversely associated with a lower risk of NHL. Methionine plays a critical role in the one-carbon metabolism pathway. It is converted to S-adenosylmethionine, which then donates the labile methyl group it previously derived from 5-methyltetrahydrofolate for more than 80 biologic methylation reactions, including an array of reactions whereby specific sites within DNA and RNA become methylated (5). Alteration or inhibition of these reactions can lead to altered DNA methylation, which can lead to lymphomagenesis. In this analysis, the decreased risk associated with increasing intake was particularly suggestive for certain NHL subtypes that have rarely been examined. We observed an inverse trend for follicular lymphoma and diffuse large B-cell lymphoma associated with increasing methionine intake. We also observed an inverse trend for the less common subtype, T-cell lymphoma.

Our results also suggested a decreased risk associated with vitamin B6 intake for all types of NHL combined, as well as for CLL/SLL subtypes. Like folate, a highly significant decreased risk was observed with increased intake of vitamin B6 among cases of marginal zone lymphoma, a subtype that has not been previously reported on in similar studies. Vitamin B6 is a structural and functional component of cystathionine ß-synthase, the enzyme that converts homocysteine to cystathionine (29). Elevations in homocysteine levels have been associated with inhibition of methylation and DNA damage due to the disruption of the one-carbon pathway. Vitamin B6 also has important immune effects; deficiency alters lymphocyte differentiation and maturation, reduces delayed-type hypersensitivity responses, and may indirectly impair antibody production (30). In controlled human studies, low vitamin B6 intakes have been found to decrease lymphocyte mitogenic responsiveness and interleukin-2 production, as well as to decrease the percentage of helper T cells and serum immunoglobulin concentration (31, 32).

In one-carbon metabolism, the formation of 5-methyltetrahydrofolate requires vitamin B2; the conversion of homocysteine to methionine and the conversion of 5-methyltetrahydrofolate to tetrahydrofolate are vitamin B12-dependent (33). Deficiency of these cofactors can impair methylation and/or nucleotide synthesis or repair pathways, which leads to lymphomagenesis. Despite this, there were no consistent associations in this analysis with vitamin B12 intake, and we observed an increased risk of all NHL for higher intake of vitamin B2. These elevated risk estimates were similarly increased in all subtype analyses. We do not know of any biologic mechanism that would cause increased riboflavin intake to be associated with increased risk of lymphoma, but other nutrients involved in one-carbon metabolism, such as choline and betaine, have similarly been associated with increased risk of carcinogenesis (34). It is possible that the lack of association for vitamins B2 and B12 may be partly due to confounding by animal and/or dairy food sources that contain other potentially detrimental constituents, although adjustment for numerous potential confounders did not affect our risk estimates. Aside from the nutrients, there are many genes that code for enzymatic actions in the one-carbon pathway. Polymorphisms in these genes have been of great interest and are the topic of increasing epidemiologic investigation (35–40). In future work, investigators should continue to examine the influence of gene-nutrient interactions in the risk of NHL.

The strengths and limitations of our study should be considered in interpreting the results. One of the advantages of this population-based case-control study is that all incident cases were histologically confirmed by two experienced and independent pathologists. The histologic confirmation reduced the potential for disease misclassification of NHL subtypes, which has been an issue in cancer registry-based data (41). Previous investigations have evaluated only diffuse or follicular lymphoma, while we were able to consider some of the other major NHL subtypes, in light of the heterogeneity of the disease. Still, some analyses were based on small numbers of cases and may have lacked statistical power; more cases or pooled analyses would help in understanding some of the suggestive subtype findings.

A possible limitation of this analysis was the lack of information on the intake of nutrients related to one-carbon metabolism from dietary supplements. However, previous studies that examined these nutrients and had information on supplement use observed significant findings from food sources alone (20, 42). Furthermore, associations with supplemental intake of these nutrients are difficult to disentangle from other components of multivitamins and may be related to certain unknown effects of health-related behaviors. These effects have been well-described in the context of colon cancer, the most studied cancer in relation to one-carbon metabolism (43). Another limitation was the low participation rate, which is common in population-based case-control studies, and the potential for recall bias.

In this analysis, we observed that intakes of fiber, folate, and vitamin B6 were highly correlated. As a result, it is difficult to disentangle the separate effects of these factors. However, our results could also offer a potential explanation for our earlier observation that fiber intake was associated with a lower risk of NHL (13). There is no established or suggested mechanism which supports the observation that fiber intake itself is associated with NHL risk. However, vegetables and fruits are major natural sources of fiber, folate, and vitamin B6, and studies have shown that intakes of vegetables and fruits are associated with a lower risk of NHL. Because of the established important role of nutrients involved in one-carbon metabolism in DNA synthesis, repair, and methylation and their potential impact on human cancer risk, we believe this to be a more plausible explanation for the observed association, although future work to help determine the predominant factor is warranted.

In summary, in this population-based case-control study of women in Connecticut, we observed significant inverse associations for nutrients related to one-carbon metabolism that varied by NHL subtype. Larger studies are needed to examine the roles of genetics and gene-nutrient interaction for a greater understanding of the role of the one-carbon pathway in NHL risk, particularly among some of the less common NHL subtypes.


   ACKNOWLEDGMENTS
 
This study was supported by grants CA62006 and TU2 CA105666 from the National Cancer Institute. Certain data used in the study were obtained from the Connecticut Tumor Registry, Connecticut Department of Public Health.

The authors thank the institutions that allowed access to diagnostic materials and pathology reports, including the following hospitals: Charlotte Hungerford Hospital, Danbury Hospital, Greenwich Hospital, Griffin Hospital, Hartford Hospital, Johnson Memorial Hospital, Middlesex Hospital, Lawrence and Memorial Hospital, New Britain General Hospital, Bradley Memorial Hospital, Norwalk Hospital, St. Francis Hospital and Medical Center, St. Mary's Hospital, Hospital of St. Raphael, St. Vincent's Medical Center, Stamford Hospital, William W. Backus Hospital, Waterbury Hospital, Yale-New Haven Hospital, Manchester Memorial Hospital, Rockville General Hospital, Bridgeport Hospital, Windham Hospital, Sharon Hospital, Milford Hospital, New Milford Hospital, Bristol Hospital, MidState Medical Center, and Day-Kimball Hospital.

The authors assume full responsibility for the analysis and interpretation of these data.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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J. L. Mills and T. C. Carter
Invited Commentary: Preventing Neural Tube Defects and More via Food Fortification?
Am. J. Epidemiol., January 1, 2009; 169(1): 18 - 21.
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