Correlation of a well-known genetic variation in one carbon metabolism pathway with breast cancer susceptibility in Iranian population

Document Type : Systematic Review


1 Member of Research Committee, Medical School, Hamedan University of Medical Sciences, Hamedan, Iran

2 Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran

3 Department of Research and Technology of Kermanshah University of Medical Sciences, Kermanshah, Iran


The one carbon metabolism pathway is an important cycle in the cellular reactions. One of a key gene in the mentioned pathway is methylenetetrahydrofolate reductase. This gene contains numerous variations that the rs1801133 is considered as the most common polymorphism of this gene. This study aimed to examine the correlation of above-mentioned genetic variation with breast tumor risk in Iran by meta-analysis. In a systematic search, valid electronic databases such as PubMed and Goggle scholar were used to gain eligible studies. After search and screening procedure five suitable papers were included in our meta-analysis. To evaluate the strength of association values, the odds ratio (OR) and 95% confidence interval (CI) were examined by online software. The data from meta-analysis illustrated that the rs1801133 genetic variation is correlated with breast cancer in TT vs. CC and TT vs. CC+CT hereditary models within Iranian women. Also, the pooled OR revealed that the studies with sample size> 250 are associated with breast cancer. According to these finding the studied single nucleotide polymorphism could be considered as molecular genetic variation for breast cancer in Iranian women.

Graphical Abstract

Correlation of a well-known genetic variation in one carbon metabolism pathway with breast cancer susceptibility in Iranian population


  • The MTHFR is an important gene for cell procedures and tumor pathways.
  • The rs1801133 is associated with breast cancer in Iran population.
  • The rs1801133 is associated with breast cancer in studies with sample size more than 250 subjects.


Main Subjects

1. Naghibi A, Shojaeezade D, Montazeri A. Early detection of breast cancer among women in Mazandaran, Iran. Iran J Health Sci 2013; 1(1): 44-49.
2. Fang L, Barekati Z, Zhang B, Liu Z, Zhong XY. Targeted therapy in breast cancer: what's new? Swiss Med Wkly 2011; 141(2526).
3. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 1994; 7(2): 195-200.
4. Kakkoura MG, Demetriou CA, Loizidou MA, Loucaides G, Neophytou I, Marcou Y, Hadjisavvas A, Kyriacou K. Single-nucleotide polymorphisms in one-carbon metabolism genes, Mediterranean diet and breast cancer risk: a case–control study in the Greek-Cypriot female population. Genes Nutr 2015; 10(2): 5.
6. Smulders YM, Smith DE, Kok RM, Teerlink T, Gellekink H, Vaes WH, Stehouwer CD, Jakobs C. Red blood cell folate vitamer distribution in healthy subjects is determined by the methylenetetrahydrofolate reductase C677T polymorphism and by the total folate status. J Nutr Biochem 2007; 18(10): 693-699.
7. Koury MJ, Horne DW, Brown ZA, Pietenpol JA, Blount BC, Ames BN, Hard R, Koury ST. Apoptosis of late-stage erythroblasts in megaloblastic anemia: association with DNA damage and macrocyte production. Blood, J Am Soc Hematol 1997; 89(12): 4617-4623.
9. Friso S, Choi SW. Gene-nutrient interactions in one-carbon metabolism. Curr Drug Metab 2005; 6(1): 37-46.
10. Guéant-Rodriguez RM, Juillière Y, Candito M, Adjalla CE, Gibelin P, Herbeth B, Obberghen E, Guéant JL. Association of MTRRA66G polymorphism (but not of MTHFR C677T andA1298C, MTRA2756G, TCN C776G) with homocysteine and coronary artery disease in the French population. Thromb Haemost 2005; 94(3): 510-515.
13. Yang M, Mercy AO, Efehi N, Venera M, Liu X, Ebadi AG, Toughani M. Evaluation of Physicochemical and DPPH· Cleaning Activity of Ultrasonic Assisted Extraction of Polysaccharide from Leonurus japonicas. Rev Chim 2020; 71(4): 601-614.
15. Liu W, Li Y, Li R, Han X, Ma Y, Liu B, Kong X. Association of MTHFR A1298C polymorphism with breast cancer and/or ovarian cancer risk: an updated meta-analysis. Afr J Tradit Complement Altern Med 2016; 13(5): 72-86.
16. Meneses-Sanchez P, Garcia-Hernandez SC, Porchia LM, Pérez-Fuentes R, Torres-Rasgado E, Soto AD, Gonzalez-Mejia ME. C677T and A1298C methylenetetrahydrofolate reductase polymorphisms and breast cancer susceptibility among Latinos: a meta-analysis. Breast Cancer 2019; 26(5): 602-611.
17. Liang H, Khan ZI, Ahmad K, Nisar A, Mahmood Q, Ebadi AG, Toughani M. Assessment of Zinc and Nickel Profile of Vegetables Grown in Soil Irrigated with Sewage Water. Rev Chim 2020; 71(4): 500-511.
18. Mohammadzadeh G, Karimi M, Bazyar M, Hosseini SM. Lack of association between MTHFR C677T polymorphism and breast cancer risk in Ahvaz, west south-Iran. Adv Biomed Res 2016; 5.
19. Hesari A, Maleksabet A, Tirkani AN, Ghazizadeh H, Iranifar E, Mohagheg F, Anoshrvani AA, Ghasemi F. Evaluation of the two polymorphisms rs1801133 in MTHFR and rs10811661 in CDKN2A/B in breast cancer. J Cell Biochem 2019; 120(2): 2090-2097.
20. Hedayatizadeh-Omran A, Alizadeh-Navaei R, Toghani-Hulari F, Amjadi O. Association between MTHFR (C677T) gene polymorphism with breast cancer in Northern Iran. WCRJ 2017; 4(2): e876.
21. Yang M, Efehi N, Jin Y, Zhang Q, Ebadi AG, Toughani M. Hot Water Extraction of Crude Polysaccharide from Codonopsis pilosula and Determination of the Rheological Properties. Rev Chim 2020; 71(5): 441-449.
22. Rahimi Z, Bozorgi M, Rahimi Z, Shakiba E, Yari K, Jalilian N, Vaisi-Raygani A. MTHFR C677T polymorphism is associated with the risk of breast cancer among Kurdish population from Western Iran. Int J Cancer Manag 2019; 12(3).
24. Weiwei Z, Liping C, Dequan L. Association between dietary intake of folate, vitamin B6, B12 & MTHFR, MTR Genotype and breast cancer risk. Pakistan J Med Sci 2014; 30(1): 106.
25. Wang Y, Dou S, Zhang Q, Ebadi AG, Chen J, Toughani M. Bacterial Separation and Community Diversity Analysis of Petroleum Contaminated Soil in Yumen Oilfield. Rev Chim 2020; 71(3): 595-607.
27. Barbosa RdCC, Da Costa DM, Cordeiro DEF, Vieira APF, Rabenhorst SHB. Interaction of MTHFR C677T and A1298C, and MTR A2756G gene polymorphisms in breast cancer risk in a population in Northeast Brazil. Anticancer Res 2012; 32(11): 4805-4811.
28. Suzuki T, Matsuo K, Hirose K, Hiraki A, Kawase T, Watanabe M, Yamashita T, Iwata H, Tajima K. One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis 2008; 29(2): 356-362.
30. Bao S, Ebadi A, Toughani M, Dalle J, Maseleno A, Yıldızbası A. A new method for optimal parameters identification of a PEMFC using an improved version of Monarch Butterfly Optimization Algorithm. Int J Hydrogen Energy 2020; 45(35): 17882-17892.
31. Gershoni-Baruch R, Dagan E, Israeli D, Kasinetz L, Kadouri E, Friedman E. Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women. Eur J Cancer 2000; 36(18): 2313-2316.
32. Grieu F, Powell B, Beilby J, Iacopetta B. Methylenetetrahydrofolate reductase and thymidylate synthase polymorphisms are not associated with breast cancer risk or phenotype. Anticancer Res 2004; 24(5B): 3215-3220. ISSN: 02507005
33. Vaĭner AS, Boiarskikh UA, Voronina EN, Selezneva IA, Sinkina TV, Lazarev AF, Petrova VD, Filipenko ML. Polymorphic variants of folate metabolizing genes (C677T and A1298C MTHFR, C1420T SHMT1 and G1958A MTHFD) are not associated with the risk of breast cancer in West Siberian Region of Russia. Mol Biol 2010; 44(5): 816-823. ISSN: 00268984
34. Yang M, Abdalrahman H, Sonia U, Mohammed A, Vestine U, Wang M, Ebadi AG, Toughani M. The application of DNA molecular markers in the study of Codonopsis species genetic variation, a review. Cell Mol Biol 2020; 2: 23-30.
35. Ericson UC, Ivarsson MI, Sonestedt E, Gullberg B, Carlson J, Olsson H, Wirfält E. Increased breast cancer risk at high plasma folate concentrations among women with the MT HFR 677T allele. Am J Clin Nutr 2009; 90(5): 1380-1389.
36. Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hébert JR, Jin F, Zheng W. MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev 2004; 13(2): 190-196.
37. Campbell IG, Baxter SW, Eccles DM, Choong DY. Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer. Breast Cancer Res 2002; 4(6): 1-4.
38. Wen L, Zhang Y, Yang B, Han F, Ebadi AG, Toughani M. Knockdown of Angiopoietin-like protein 4 suppresses the development of colorectal cancer. Cell Mol Biol 2020; 66(5): 117-124.