Nutrients Contributing to One-Carbon Metabolism and Risk of Non-Hodgkin
Stella Koutros1,2, Yawei Zhang1, Yong Zhu1, Susan T. Mayne1, Sheila Hoar Zahm2, Theodore R.
Holford1, Brian P. Leaderer1, Peter Boyle3, and Tongzhang Zheng1
1Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT.
2Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
3International Agency for Research on Cancer, Lyon, France.
Received for publication May 22, 2007; accepted for publication September 21, 2007.
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 re-
gression, 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) ¼ 0.54, 95% confidence interval (CI): 0.30, 0.98; p-trend ¼ 0.02) and marginal
zone lymphoma (highest quartile vs. lowest: OR ¼ 0.08, 95% CI: 0.02, 0.26; p-trend < 0.0001) associated with
folate. Vitamin B6intake was also associated with lower risk of NHL overall and of marginal zone lymphoma
(highest quartile vs. lowest: OR ¼ 0.23, 95% CI: 0.08, 0.65; p-trend ¼ 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.
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 com-
pounded by the reality that NHL comprises many histolog-
ically 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 in-
tracellular one-carbon metabolism. This refers to the pro-
cess of interrelated biochemical reactions that involve the
transfer of methyl groups (5). One-carbon metabolism
involves nutrients as enzymatic cofactors (folate and vita-
mins 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
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: email@example.com).
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