Abstract
An imbalance in folate metabolism can adversely affect DNA synthesis and methylation systems which can lead to susceptibility to non-Hodgkin lymphoma (NHL). Whether single nucleotide polymorphisms (SNPs) and their haplotypes in the methylenetetrahydrofolate reductase (MTHFR) are associated with NHL, remain inconclusive. We investigated the association between MTHFR C677T and A1298C SNPs and NHL risk in a population which is made up of Malay, Chinese and Indian ethnic subgroups. A total of 372 NHL patients and 722 controls were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects failed to demonstrate significant association between the MTHFR C677T and A1298C SNPs with NHL and its subtypes. The results were in agreement with the previous meta-analyses. In the Indian ethnic subgroup however, single locus analysis of MTHFR A1298C appears to confer risk to NHL (Odds ratio (OR) 1.91, 95% confidence interval (95% CI) 1.22–3.00, P=0.006). The risk is almost doubled in homozygous carrier of MTHFR 1298CC (OR 4.03, 95% CI 1.56–10.43, P=0.004). Haplotype analysis revealed higher frequency of CC in the Indian NHL patients compared with controls (OR 1.86, 95% CI 1.18–2.93, P=0.007). There is lack of evidence to suggest an association between MTHFR C677T and A1298C with the risk of NHL in the Malays and Chinese. In the Indians however, the MTHFR A1298C confers risk to NHL. This study suggests ethnicity modifies the relationship between polymorphisms in the folate-metabolizing gene and NHL.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Huh, J Epidemiologic overview of malignant lymphoma. Korean J. Hematol. 47, 92–104 (2012).
Ferlay, J, Shin, HR, Bray, F, Forman, D, Mathers, C & Parkin, DM Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127, 2893–2917 (2010).
Jemal, A, Bray, F, Center, MM, Ferlay, J, Ward, E & Forman, D Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011).
Lee, KM, Lan, Q, Kricker, A, Purdue, MP, Grulich, AE, Vajdic, CM et al. One-carbon metabolism gene polymorphisms and risk of non-Hodgkin lymphoma in Australia. Hum. Genet. 122, 525–533 (2007).
Turner, JJ, Morton, LM, Linet, MS, Clarke, CA, Kadin, ME, Vajdic, CM et al. InterLymph hierarchical classification of lymphoid neoplasms for epidemiologic research based on the WHO classification (2008): update and future directions. Blood 116, e90–e98 (2010).
Lanzkowsky, P Manual of Pediatric Hematology and Oncology Fourth Edition 371–414 (Academic Press: Burlington, 2005).
Alexander, DD, Mink, PJ, Adami, HO, Chang, ET, Cole, P, Mandel, JS et al. The non-Hodgkin lymphomas: a review of the epidemiologic literature. Int. J. Cancer. 120 (suppl 12), 1–39 (2007).
Boccolini, PdMM, Boccolini, CS, Chrisman, JdR, Markowitz, SB, Koifman, S, Koifman, RJ et al. Pesticide use and non-Hodgkin's lymphoma mortality in Brazil. Int. J. Hyg. and Envir. Heal. 216, 461–466 (2013).
Filipovich, AH, Mathur, A & Kamat, D Primary Immunodeficiencies: Genetic Risk Factors for Lymphoma. Cancer Res. 52, 5465–5467 (1992).
Siegel, R, Naishadham, D & Jemal, A Cancer statistics, 2013. CA. Cancer J. Clin. 63, 11–30 (2013).
Jorde, LB & Wooding, SP Genetic variation, classification and 'race'. Nat. Genet. 36, S28–S33 (2004).
Koutros, S, Zhang, Y, Zhu, Y, Mayne, ST, Zahm, SH, Holford, TR et al. Nutrients contributing to one-carbon metabolism and risk of non-Hodgkin lymphoma subtypes. Am. J. Epidemiol. 167, 287–294 (2008).
Gemmati, D, Ongaro, A, Scapoli, GL, Della Porta, M, Tognazzo, S, Serino, ML et al. 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 (2004).
Lightfoot, TJ, Skibola, CF, Willett, EV, Skibola, DR, Allan, JM, Coppede, F et al. Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes. Cancer Epidemiol. Biomarkers Prev. 14, 2999–3003 (2005).
Skibola, CF, Forrest, MS, Coppede, F, Agana, L, Hubbard, A, Smith, MT et al. Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood 104, 2155–2162 (2004).
Frosst, P, Blom, HJ, Milos, R, Goyette, P, Sheppard, CA, Matthews, RG et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 10, 111–113 (1995).
Habib, EE, Aziz, M & Kotb, M Genetic polymorphism of folate and methionine metabolizing enzymes and their susceptibility to malignant lymphoma. J. Egyp. Natl Canc. Inst. 17, 184–192 (2005).
Liu, J & Ward, RL Advances in Genetics Vol. 71, 79–121 (Academic Press, 2010).
Skibola, CF, Curry, JD & Nieters, A Genetic susceptibility to lymphoma. Haematologica 92, 960–969 (2007).
Kim, HN, Lee, IK, Kim, YK, Tran, HT, Yang, DH, Lee, JJ et al. Association between folate-metabolizing pathway polymorphism and non-Hodgkin lymphoma. Br. J. Haematol. 140, 287–294 (2008).
Weiner, AS, Beresina, OV, Voronina, EN, Voropaeva, EN, Boyarskih, UA, Pospelova, TI et al. Polymorphisms in folate-metabolizing genes and risk of non-Hodgkin's lymphoma. Leuk. Res. 35, 508–515 (2011).
Ismail, SI, Ababneh, NA, Khader, Y, Abu-Khader, AA & Awidi, A Methylenetetrahydrofolate reductase genotype association with the risk of follicular lymphoma. Cancer. Genet. Cytogenet. 195, 120–124 (2009).
Berglund, M, Enblad, G, Turesson, I, Edman, V & Thunberg, U Folate-metabolizing genes in lymphoma patients from Sweden. Scand. J. Immunol. 70, 408–410 (2009).
Gra, OA, Glotov, AS, Nikitin, EA, Glotov, OS, Kuznetsova, VE, Chudinov, AV et al. Polymorphisms in xenobiotic-metabolizing genes and the risk of chronic lymphocytic leukemia and non-Hodgkin's lymphoma in adult Russian patients. Am. J. Hematol. 83, 279–287 (2008).
Siraj, AK, Ibrahim, M, Al-Rasheed, M, Bu, R, Bavi, P, Jehan, Z et al. Genetic polymorphisms of methylenetetrahydrofolate reductase and promoter methylation of MGMT and FHIT genes in diffuse large B cell lymphoma risk in Middle East. Ann. Hematol. 86, 887–895 (2007).
Timuragaoglu, A, Dizlek, S, Uysalgil, N, Tosun, O & Yamac, K Methylenetetrahydrofolate reductase C677T polymorphism in adult patients with lymphoproliferative disorders and its effect on chemotherapy. Ann. Hematol. 85, 863–868 (2006).
Deligezer, U, Akisik, EE, Yaman, F, Erten, N & Dalay, N MTHFR C677 T gene polymorphism in lymphoproliferative diseases. J. Clin. Lab. Anal. 20, 37–41 (2006).
Niclot, S, Pruvot, Q, Besson, C, Savoy, D, Macintyre, E, Salles, G et al. Implication of the folate-methionine metabolism pathways in susceptibility to follicular lymphomas. Blood 108, 278–285 (2006).
Seidemann, K, Book, M, Zimmermann, M, Meyer, U, Welte, K, Stanulla, M et al. MTHFR 677 (C—>T) polymorphism is not relevant for prognosis or therapy-associated toxicity in pediatric NHL: results from 484 patients of multicenter trial NHL-BFM 95. Ann. Hematol. 85, 291–300 (2006).
Stanulla, M, Seidemann, K, Schnakenberg, E, Book, M, Mehles, A, Welte, K et al. Methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and risk of pediatric non-Hodgkin lymphoma in a German study population. Blood 105, 906–907 (2005).
Toffoli, G, Rossi, D, Gaidano, G, Cecchin, E, Boiocchi, M & Carbone, A Methylenetetrahydrofolate reductase genotype in diffuse large B-cell lymphomas with and without hypermethylation of the DNA repair gene O6-methylguanine DNA methyltransferase. Int. J. Biol. Markers 18, 218–221 (2003).
Gonzalez Ordonez, AJ, Fernandez Carreira, JM, Fernandez Alvarez, CR, Martin, L, Sanchez Garcia, J, Medina Rodriguez, JM et al. Normal frequencies of the C677T genotypes on the methylenetetrahydrofolate reductase (MTHFR) gene among lymphoproliferative disorders but not in multiple myeloma. Leuk. Lymphoma 39, 607–612 (2000).
Linnebank, M, Schmidt, S, Kolsch, H, Linnebank, A, Heun, R, Schmidt-Wolf, IG et al. The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma. Br. J. Cancer 90, 1969–1971 (2004).
Periasamy, M in Biblioasia Vol. 3, (National Library Board Singapore: Singapore, 2007).
Bamshad, M, Kivisild, T, Watkins, WS, Dixon, ME, Ricker, CE, Rao, BB et al. Genetic evidence on the origins of Indian caste populations. Genome Res. 11, 994–1004 (2001).
Ekstrom-Smedby, K Epidemiology and etiology of non-Hodgkin lymphoma—a review. Acta. Oncol. 45, 258–271 (2006).
Dayakar, S, Goud, KI, Reddy, TP, Rao, SP, Sesikeran, SB & Sadhnani, M Sequence variation of the methylene tetrahydrofolate reductase gene (677C>T and 1298 A>C) and traditional risk factors in a South Indian population. Genet. Test Mol. Biomarkers 15, 765–769 (2011).
Lincz, LF, Scorgie, FE, Kerridge, I, Potts, R, Spencer, A & Enno, A 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 (2003).
van der Put, NMJ, Trijbels, FJM, Gabreels, F, Eskes, TKAB, Stevens, EMB, Smeitink, JAM et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am. J. Hum. Genet. 62, 1044–1051 (1998).
Lightfoot, TJ, Johnston, WT, Painter, D, Simpson, J, Roman, E, Skibola, CF et al. Genetic variation in the folate metabolic pathway and risk of childhood leukemia. Blood 115, 3923–3929 (2010).
Ulrich, CM, Reed, MC & Nijhout, HF Modeling folate, one-carbon metabolism, and DNA methylation. Nutr. Rev. 66 (suppl 1), S27–S30 (2008).
Crossette, B State of the World Population 2011: People and Possibilities in a World of 7 billion, (United Nations Population Fund: New York, 2011).
Acknowledgements
We gratefully acknowledge the subjects for their participation in this study and to the staffs of UMMC and Ampang Hospital for their assistance in subject recruitment. This study was supported by the University Malaya Research Grant (UMRG) (RG300/11HTM), University Malaya IPPP grant (PV072/2011B) and University Malaya IPPP grant (PS190/2010B).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Suthandiram, S., Gan, G., Zain, S. et al. Polymorphisms in methylenetetrahydrofolate reductase gene and risk of non-Hodgkin lymphoma in a multi-ethnic population. J Hum Genet 59, 280–287 (2014). https://doi.org/10.1038/jhg.2014.19
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2014.19
