Low Serum Folate Levels as a Risk Factor for Non-Hodgkin’s Lymphoma.

Folate plays an essential role in cell division by participating in DNA synthesis and regenerating S-adenosylmethionine, a universal methyl donor in methylation. Folate deficiency may be involved in carcinogenesis of several type cancers through impaired synthesis and repair of DNA, or by causing global hypomethylation of DNA. So far, there is no prior report on epidemiologic data concerning the relationship between folate intake or serum folate levels and non-Hodgkin’s lymphoma (NHL) risk. We performed a case-control study (432 cases and 1,700 controls) to examine the association between serum folate levels and risk of NHL. This is, to the best of our knowledge, the first study to show that serum folate levels and risk of NHL. We also investigate whether genetic polymorphisms in folate-metabolizing enzymes interact with serum folate levels in modifying NHL risk. Serum folate was measured by ion capture assay on an AxSYM Analyzer (Abbott Diagnostics, AbbottPark, IL). The geometric mean in cases was lower than in controls (e.g., 18.9 vs 22.1 nmol/L, P < 0.001). We found a statistically significant association between serum folate level and risk of NHL, with 3.35 of odds ratios (OR) (95% confidence interval (CI), 2.27–4.95) for individuals in the lowest serum folate level category (<11.3 nmol/L [5 ng/mL]) compared with the highest category (>22.7 nmol/L [10 ng/mL]) There was a significant thymidylate synthase (TS)-folate interaction in T-cell lymphoma subtype, but we did not observe any significant gene-folate interactions in NHL and DLBCL subtype. Among subjects with low serum folate concentration (<7.5 ng/ml), the OR of T-cell lymphoma for the 3R/3R or 2R/3R genotype were 2.80 (95% CI = 1.36–5.77) and 0.78(95% CI = 0.29–2.12) for 2R/2R genotype (P = 0.045, test for homogeneity). These results provide support for the important role of folate deficiency in the risk of NHL and folate-gene interaction in the etiology of T-cell lymphoma.