Abstract
Purpose
Genetic polymorphisms in one-carbon metabolizing pathway genes have been associated with risk of malignant lymphoma. However, the results have been inconsistent. The objectives of this study were to examine the potential relationship between gene–nutrient interactions and the risk of non-Hodgkin lymphoma (NHL).
Methods
We examined 25 polymorphisms in 16 one-carbon metabolism genes for their main effect and gene–nutrient interactions in relation to NHL risk among 518 incident cases and 597 population-based controls of Connecticut women enrolled between 1996 and 2000.
Results
A significantly reduced risk of NHL was associated with the homozygous TT genotype in CBS (rs234706, Ex9+33C>T) (OR = 0.51, 95 % CI 0.31–0.84), the homozygous CC genotype in MBD2 (rs603097, −2176C>T) (OR = 0.37, 95 % CI 0.17–0.79), the heterozygote AG genotype in FTHFD (rs1127717, Ex21+31A>G) (OR = 0.73, 95 % CI 0.55–0.98), and a borderline significantly reduced risk of NHL was observed for the homozygous CC genotype in MTRR (rs161870, Ex5+136T>C) (OR = 0.23, 95 % CI 0.05–1.04). The reduced risk of NHL associated with these genotypes was predominately in those with higher dietary vitamin B6 and methionine intakes, as well as with higher dietary folate intake although results were less stable. A borderline significantly increased risk of NHL was also observed for CBS (rs1801181, Ex13+41C>T), FTHFD (rs2305230, Ex10−40G>T), SHMT1 (rs1979277, Ex12+138C>T), and SHMT1 (rs1979276, Ex12+236T>C), and these associations appeared to be contingent on dietary nutrient intakes.
Conclusion
Our results suggest that variation in several one-carbon metabolizing pathway genes may influence the risk of NHL through gene–nutrient interactions involving dietary nutrient intakes.
Similar content being viewed by others
References
Nauss KM, Newberne PM (1981) Effects of dietary folate, vitamin B12 and methionine/choline deficiency on immune function. Adv Exp Med Biol 135:63–91
Zheng T, Mayne ST, Boyle P, Holford TR, Liu WL, Flannery J (1992) Epidemiology of non-Hodgkin lymphoma in Connecticut. 1935–1988. Cancer 70:840–849
Bassig BA, Lan Q, Rothman N, Zhang Y, Zheng T (2012) Current understanding of lifestyle and environmental factors and risk of non-Hodgkin lymphoma: an epidemiological update. J Cancer Epidemiol 2012:978930
Kuppers R (2005) Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5:251–262
Rossi D, Capello D, Gloghini A et al (2004) Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia. Haematologica 89:154–164
Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC (1993) bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 82:1820–1828
Matsuo K, Suzuki R, Hamajima N et al (2001) Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma. Blood 97:3205–3209
Robien K, Ulrich CM (2003) 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemiol 157:571–582
Skibola CF, Curry JD, Nieters A (2007) Genetic susceptibility to lymphoma. Haematologica 92:960–969
Lim U, Wang SS, Hartge P et al (2007) Gene–nutrient interactions among determinants of folate and one-carbon metabolism on the risk of non-Hodgkin lymphoma: NCI-SEER case–control study. Blood 109:3050–3059
Linnebank M, Schmidt S, Kolsch H et al (2004) The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma. Br J Cancer 90:1969–1971
Lincz LF, Scorgie FE, Kerridge I, Potts R, Spencer A, Enno A (2003) Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B-cell non-Hodgkin’s lymphoma or multiple myeloma. Br J Haematol 120:1051–1054
Niclot S, Pruvot Q, Besson C et al (2006) Implication of the folate-methionine metabolism pathways in susceptibility to follicular lymphomas. Blood 108:278–285
Hishida A, Matsuo K, Hamajima N et al (2003) Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Haematologica 88:159–166
Skibola CF, Smith MT, Hubbard A et al (2002) Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood 99:3786–3791
Lightfoot TJ, Skibola CF, Willett EV et al (2005) Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes. Cancer Epidemiol Biomarkers Prev 14:2999–3003
Lee KM, Lan Q, Kricker A et al (2007) One-carbon metabolism gene polymorphisms and risk of non-Hodgkin lymphoma in Australia. Hum Genet 122:525–533
Skibola CF, Forrest MS, Coppede F et al (2004) Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood 104:2155–2162
Skibola CF, Smith MT, Kane E et al (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 96:12810–12815
Matsuo K, Hamajima N, Suzuki R et al (2004) Methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms and reduced risk of malignant lymphoma. Am J Hematol 77:351–357
Gemmati D, Ongaro A, Scapoli GL et al (2004) Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin’s lymphoma in adults. Cancer Epidemiol Biomarkers Prev 13:787–794
Chang ET, Balter KM, Torrang A et al (2006) Nutrient intake and risk of non-Hodgkin’s lymphoma. Am J Epidemiol 164:1222–1232
Koutros S, Zhang Y, Zhu Y et al (2008) Nutrients contributing to one-carbon metabolism and risk of non-Hodgkin lymphoma subtypes. Am J Epidemiol 167:287–294
Lim U, Schenk M, Kelemen LE et al (2005) Dietary determinants of one-carbon metabolism and the risk of non-Hodgkin’s lymphoma: NCI-SEER case–control study, 1998–2000. Am J Epidemiol 162:953–964
Polesel J, Talamini R, Montella M et al (2006) Linoleic acid, vitamin D and other nutrient intakes in the risk of non-Hodgkin lymphoma: an Italian case–control study. Ann Oncol 17:713–718
Zheng T, Holford TR, Leaderer B et al (2004) Diet and nutrient intakes and risk of non-Hodgkin’s lymphoma in Connecticut women. Am J Epidemiol 159:454–466
Lan Q, Zheng T, Chanock S et al (2007) Genetic variants in caspase genes and susceptibility to non-Hodgkin lymphoma. Carcinogenesis 28:823–827
Zhang Y, Lan Q, Rothman N et al (2005) A putative exonic splicing polymorphism in the BCL6 gene and the risk of non-Hodgkin lymphoma. J Natl Cancer Inst 97:1616–1618
Willett WC (1998) Nutritional epidemiology, 2nd edn. Oxford University Press, New York
(2007) University of Minnesota Nutrition Coordinating Center. NDSR, University of Minnesota Nutrition Coordinating Center, Minneapolis, MN
Frosst P, Blom HJ, Milos R et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113
van der Put NM, Gabreels F, Stevens EM et al (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62:1044–1051
Kawakami K, Salonga D, Park JM et al (2001) Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 7:4096–4101
Lim U, Peng K, Shane B et al (2005) Polymorphisms in cytoplasmic serine hydroxymethyltransferase and methylenetetrahydrofolate reductase affect the risk of cardiovascular disease in men. J Nutr 135:1989–1994
Choi SW, Mason JB (2000) Folate and carcinogenesis: an integrated scheme. J Nutr 130:129–132
Metayer C, Scelo G, Chokkalingam AP et al (2011) Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia. Cancer Causes Control CCC 22:1243–1258
Hendrich B, Abbott C, McQueen H, Chambers D, Cross S, Bird A (1999) Genomic structure and chromosomal mapping of the murine and human Mbd1, Mbd2, Mbd3, and Mbd4 genes. Mamm Genome 10:906–912
Ng HH, Zhang Y, Hendrich B et al (1999) MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet 23:58–61
Reuland SN, Vlasov AP, Krupenko SA (2006) Modular organization of FDH: exploring the basis of hydrolase catalysis. Protein Sci 15:1076–1084
Krupenko SA, Oleinik NV (2002) 10-formyltetrahydrofolate dehydrogenase, one of the major folate enzymes, is down-regulated in tumor tissues and possesses suppressor effects on cancer cells. Cell Growth Differ 13:227–236
Krajinovic M, Lamothe S, Labuda D et al (2004) Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood 103:252–257
Corella D, Ordovas JM (2005) Single nucleotide polymorphisms that influence lipid metabolism: interaction with dietary factors. Annu Rev Nutr 25:341–390
Garcia-Closas M, Thompson WD, Robins JM (1998) Differential misclassification and the assessment of gene-environment interactions in case–control studies. Am J Epidemiol 147:426–433
Garcia-Closas M, Rothman N, Lubin J (1999) Misclassification in case–control studies of gene-environment interactions: assessment of bias and sample size. Cancer Epidemiol Biomark Prev 8:1043–1050
Morton LM, Wang SS, Cozen W et al (2008) Etiologic heterogeneity among non-Hodgkin lymphoma subtypes. Blood 112:5150–5160
Acknowledgments
This work was supported by the National Institutes of Health (Grant CA62006), the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the National Institutes of Health Fogarty (training Grants D43TW008323-01 and D43TW007864-01).
Conflict of interest
None declared.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Li, Q., Lan, Q., Zhang, Y. et al. Role of one-carbon metabolizing pathway genes and gene–nutrient interaction in the risk of non-Hodgkin lymphoma. Cancer Causes Control 24, 1875–1884 (2013). https://doi.org/10.1007/s10552-013-0264-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10552-013-0264-3