Author(s): Ariana Younes, Mazen Khaddour, Mazen Salloum, Suzan Samra, Samer Akel

Email(s): ,

DOI: 10.52711/0974-360X.2023.00714   

Address: Ariana Younes1*, Mazen Khaddour1, Mazen Salloum2, Suzan Samra1,3, Samer Akel4
1Department of Biochemistry and Microbiology, Tishreen University, Latakia – Syria.
2AlHawash Private University, Homs, Syria.
3Al-Andalus University for Medical Sciences, Tartous, Syria.
4Assistant Professor, Department of Oncology and Hematology, Tishreen University Hospital Latakia – Syria.
*Corresponding Author

Published In:   Volume - 16,      Issue - 9,     Year - 2023

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene mutations can reduce the activity of the enzyme, which has been shown to be a significant factor in the risk of developing certain types of cancer and numerous other diseases, including cardiovascular conditions, diabetes, ischemia, venous thrombosis, hypotonia, and many others. This study aims to determine the frequency of the two most prevalent MTHFR gene polymorphisms, C677T and A1298C, in the Syrian coastal population. Real-time PCR is used to detect MTHFR gene variants in samples from seventy healthy males from Syrian Coastal Area. The frequency of the C/C, C/T, and T/T genotypes for the C677T polymorphism was 47.14 percent, 38.57 percent, and 14.29 percent, respectively. The overall carrier rate was 52.86%, and the allelic frequency was 0.336. The genotypic prevalence of A/A, A/C, and C/C for the A1298C polymorphism was 44.29%, 35.71%, and 20%, respectively, with an allelic frequency of 0.378, while the overall carrier rate was 55.71%. In conclusion, the high prevalence of the MTHFR A1298C polymorphism is a significant finding that must be investigated in terms of clinical implications and reveals an additional genetic trait unique to the Syrian coast population.

Cite this article:
Ariana Younes, Mazen Khaddour, Mazen Salloum, Suzan Samra, Samer Akel, Prevalence of MTHFR Gene (C677T and A1298C) Polymorphism in the Syrian Coastal Area, Research Journal of Pharmacy and Technology 2023; 16(9):4365-9. doi: 10.52711/0974-360X.2023.00714

Ariana Younes, Mazen Khaddour, Mazen Salloum, Suzan Samra, Samer Akel, Prevalence of MTHFR Gene (C677T and A1298C) Polymorphism in the Syrian Coastal Area, Research Journal of Pharmacy and Technology 2023; 16(9):4365-9. doi: 10.52711/0974-360X.2023.00714   Available on:

1.    Arruda VR, Siqueira LH, Gonçalves MS, Von Zuben PM, Soares MCP, Menezes R, Annichino-Bizzacchi JM, Costa FF. Prevalence of the mutation C677 → T in the methylene tetrahydrofolate reductase gene among distinct ethnic groups in Brazil. Am J Med Genet. 1998;  78:332–335; doi: 10.1002/(sici)1096-8628(19980724)78:4<332::aid-ajmg5>;2-n
2.    Graydon JS, Claudio K, Baker S, Kocherla M, Ferreira M, Roche-Lima A, Rodríguez-Maldonado J, Duconge J, Ruaño G. Ethnogeographic prevalence and implications of the 677C>T and 1298A>C MTHFR polymorphisms in US primary care populations. Biomark Med. 2019;  13:649–661; doi: 10.2217/bmm-2018-0392
3.    Dean L.  Methylenetetrahydrofolate Reductase Deficiency. Med. Genet. Summ. 2016; Bookshelf ID: NBK66131
4.    Sandeep Goyal, V.K. Bansal, Dhruba Sankar Goswami, Suresh Kumar. sVascular Endothelial Dysfunction: Complication of Diabete Mellitus and Hyperhomocysteinemia. Research J. Pharm. and Tech. 2010; 3 (3): 657-664.
5.    Izmirli M.  A literature review of MTHFR (C677T and A1298C polymorphisms) and cancer risk. Mol Biol Reports. 2012; 40:625–637; doi: 10.1007/s11033-012-2101-2
6.    Liew SC, Gupta E Das. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: Epidemiology, metabolism and the associated diseases. Eur J Med Genet. 2015; 58:1–10; doi: 10.1016/j.ejmg.2014.10.004
7.    Weisberg I, Tran P, Christensen B, Sibani S, Rozen R.  A Second Genetic Polymorphism in Methylenetetrahydrofolate Reductase (MTHFR) Associated with Decreased Enzyme Activity. Mol Genet Metab. 1998; 64:169–172; doi: 10.1006/mgme.1998.2714
8.    You W, Li Z, Jing C, Qian-Wei X, Yu-Ping Z, Weng-Guang L, Hua-Lei L. MTHFR C677T and A1298C Polymorphisms were associated with bladder cancer risk and disease progression: A meta-analysis. DNA Cell Biol. 2012; 32:260–267; doi: 10.1089/dna.2012.1931
9.    Ferlazzo N, Currò M, Zinellu A, Caccamo D, Isola G, Ventura V, Carru C, Matarese G, Ientile R. Influence of MTHFR Genetic Background on p16 and MGMT Methylation in Oral Squamous Cell Cancer. Int J Mol Sci. 2017; doi: 10.3390/ijms18040724
10.    Pande M, Chen J, Amos CI, Lynch PM, Broaddus R, Frazier ML. Influence of Methylenetetrahydrofolate Reductase Gene Polymorphisms C677T and A1298C on Age-Associated Risk for Colorectal Cancer in a Caucasian Lynch Syndrome Population. Cancer Epidemiol Biomarkers. 2017; 16:1753–1759; doi: 10.1158/1055-9965.EPI-07-0384
11.    Eldeeb MK, Shoaib MMAE, Abd-Elmonem EA, Saeed HMS, Embaby AM, Farouk AM, Rashad RM. Genetic polymorphisms and gene expression of one-carbon metabolizing enzymes and their relation to breast cancer. Egypt J Med Hum Genet. 2022; 23:1–17; doi:
12.    Petrone I, Bernardo PS, Santos EC Dos, Abdelhay E. MTHFR C677T and A1298C Polymorphisms in Breast Cancer, Gliomas and Gastric Cancer: A Review. Genes. 2021; 12: 587doi: 10.3390/genes12040587
13.    V. Jayashree, Malarkodi Velraj. Breast Cancer and various Prognostic Biomarkers for the diagnosis of the disease: A Review. Research J. Pharm. and Tech. 2017; 10(9): 3211-3216. doi: 10.5958/0974-360X.2017.00570.4
14.    Waill A. Elkhateeb, Mohamed A. Mohamed, Walid Fayad, Mahmoud Emam, Ibrahim M. Nafady, Ghoson M. Daba. Molecular Identification, Metabolites profiling, Anti-breast cancer, Anti-colorectal cancer, and antioxidant potentials of Streptomyces zaomyceticus AA1 isolated from a remote bat cave in Egypt. Research J. Pharm. and Tech. 2020; 13(7): 3072-3080. doi: 10.5958/0974-360X.2020.00545.4
15.    Shiv Kumar Patel, Moumita Sinha, Mitashree Mitra. Glutathione-S-transferase M1 and T1 gene Polymorphism as Risk Factors of Oral Squamous Cell Carcinoma: A Preliminary Investigation. Research J. Pharm. and Tech. 2012; 5(7): 918-920.
16.    F. Mariyam Niyas, Savitha G. Metabolic Antioxidant Status in Oral Squamous Cell Carcinoma. Research J. Pharm. and Tech. 2018; 11(10): 4362-4364. doi: 10.5958/0974-360X.2018.00798.9
17.    Roushan Mubarak, Shaden Haddad, Outhman Hamdan. Frequency of CYP1A1*2A Polymorphism in Syrian Children with Acute Lymphoblastic Leukemia. Research J. Pharm. and Tech. 2016; 9(2):  135-138. doi: 10.5958/0974-360X.2016.00022.6
18.    Zainab Mir1, Rosliza2, Behroz Naeem1, Ilyas Muhammad Nadeem2, Prof. Nordin Bin Simbak, Prof. Zubaidi ALA, Prof. Tengku Mohammad Ariff, Khalili MR, Mohammad Amjad Kamal, Atif Amin Baig. Synergistic Molecular Effect of BDNF, ApoE and MTHFR in inducing Depression in Alzheimer’s Disease. Research J. Pharm. and Tech. 2018; 11(10): 4317-4323. doi: 10.5958/0974-360X.2018.00790.4
19.    Sriram S., Arul Amutha Elizabeth, Akila L. Cost Analysis of SGLT2 Inhibitors in patients with type 2 Diabetes in India. Research J. Pharm. and Tech. 2020; 13(12):5861-5865. doi: 10.5958/0974-360X.2020.01021.5
20.    S. Preethikaa, M. P. Brundha. Awareness of Diabetes Mellitus among General Population. Research J. Pharm. and Tech. 2018; 11(5):1825-1829 doi: 10.5958/0974-360X.2018.00339.6
21.    Vinod K Mathew, Kishore Gnana Sam, Beulah Samuel, Amit Kumar Das. Epidemiology of Schizophrenia in an Indian Hospital. Research J. Pharm. and Tech. 2020; 13(1):219-223. doi: 10.5958/0974-360X.2020.00044.X
22.    Nursal AF, Kaya S, Sezer O, Karakus N, Yigit S. MTHFR gene C677T and A1298C variants are associated with FMF risk in a Turkish cohort. J Clin Lab Anal. 2018; doi: 10.1002/jcla.22259
23.    Safarinejad MR, Shafiei N, Safarinejad S. Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men. Med Oncol. 2010; 281 28:398–412; doi: 10.1007/s12032-010-9723-9
24.    Mutchinick OM, López MA, Luna L, et al. High Prevalence of the Thermolabile Methylenetetrahydrofolate Reductase Variant in Mexico: A Country with a Very High Prevalence of Neural Tube Defects. Mol Genet Metab. 1999; 68:461–467; doi: 10.1006/mgme.1999.2939
25.    Lu Y, Zhao Y, Liu G, Wang X, Liu Z, Chen B, Hui R. Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population. Thromb Res. 2002; 106:7–12; doi: 10.1016/s0049-3848(02)00064-6
26.    Gemmati D, Ongaro A, Scapoli GL, 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. 2004; 13:787–794; PMID: 15159311
27.    De Franchis R, Mancini FP, D’Angelo A, Sebastio G, Fermo I, De Stefano V, Margaglione M, Mazzola G, Di Minno G, Andria G. Elevated total plasma homocysteine and 677C-->T mutation of the 5,10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease. Am J Hum Genet. 1996; 59:262; PMID: 8659535
28.    Franco RF, Araújo AG, Guerreiro JF, Elion J, Zago MA. Analysis of the 677 C→T mutation of the methylenetetrahydrofolate reductase gene in different ethnic groups. Thromb Haemost. 1998; 79:119–121; PMID: 9459335
29.    Nishio H, Lee MJ, Fujil M, Kario K, Kayaba K, Shimada K, Matsuo M, Sumino K. A common mutation in methylenetetrahydrofolate reductase gene among the Japanese population. Jpn J Hum Genet. 1996; 41:247–251; doi: 10.1007/BF01875985
30.    Antoniadi T, Hatzis T, Kroupis C, Economou-Petersen E, Petersen MB. Prevalence of Factor V Leiden, Prothrombin G20210A, and MTHFR C677T Mutations in a Greek Population of Blood Donors. J Hematol. 1999; 61:265–267; doi: 10.1002/(sici)1096-8652(199908)61:4<265::aid-ajh8>;2-#
31.    Sazci A, Ergul E, Kaya G, Kara I. Genotype and allele frequencies of the polymorphic methylenetetrahydrofolate reductase gene in Turkey. Cell Biochem Funct. 2005; 23:51–54; doi: 10.1002/cbf.1132
32.    Koch MC, Stegmann K, Ziegler A, Schröter B, Ermert A. Evaluation of the MTHFR C677T allele and the MTHFR gene locus in a German spina bifida population. Eur J Pediatr. 1998; 1576 157:487–492; doi: 10.1007/s004310050860
33.    Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci U S A. 1999; 96:12810; doi: 10.1073/pnas.96.22.12810
34.    Van Der Put NMJ, Gabreëls F, Stevens EMB, Smeitink JAM, Trijbels FJM, Eskes TKAB, Van Den Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998; 62:1044; doi: 10.1086/301825
35.    Al-Habboubi H, Tamim H, Ameen G, Almawi WY. A common mutation in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene in two Arab communities. J Thromb Haemost. 2003; 1:2246–2248; doi: 10.1046/j.1538-7836.2003.00390.x
36.    Thomas F, Motsinger-Reif AA, Hoskins JM, Dvorak A, Roy S, Alyasiri A, Myerson RJ, Fleshman JW, Tan BR, McLeod HL. Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer. Br J Cancer. 2011; 10511 105:1654–1662; doi: 10.1038/bjc.2011.442
37.    Sabbagh AS, Mahfoud Z, Taher A, Zaatari G, Daher R, Mahfouz RAR. High prevalence of MTHFR gene A1298C polymorphism in Lebanon. Genet Test. 2008; 12:75–80; doi: 10.1089/gte.2007.0064
38.    Eid SS, Rihani G. Prevalence of Factor V Leiden, Prothrombin G20210A, and MTHFR C677T Mutations in 200 Healthy Jordanians. Am Soc Clin Lab Sci. 2004; 17:200–202; PMID: 15559724
39.    Stevenson RE, Schwartz CE, Du YZ, Adams J. Differences in methylenetetrahydrofolate reductase genotype frequencies, between Whites and Blacks. Am J Hum Genet. 1997 60:229; PMID: 8981967
40.    Angeline T, Jeyaraj N, Granito S, Tsongalis GJ (2004) Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians. Exp Mol Pathol. 2004; 77:85–88; doi: 10.1016/j.yexmp.2004.04.006
41.    Gibson CS, MacLennan AH, Rudzki Z, et al. (2005) The prevalence of inherited thrombophilias in a Caucasian Australian population. Pathology. 2005; 37:160–163; doi: 10.1080/00313020500058250
42.    Almawi WY, Finan RR, Tamim H, Daccache JL, Irani-Hakime N. (2004) Differences in the Frequency of the C677T Mutation in the Methylenetetrahydrofolate Reductase (MTHFR) Gene Among the Lebanese Population. Am J Hematol. 2004; 76:85–87; doi: 10.1002/ajh.20047
43.    Kahleová R, Palyzová D, Zvára K, Zvárová J, Hrach K, Nováková I, Hyánek J, Bendlová I, Ko ich V. (2002) Essential hypertension in adolescents: Association with insulin resistance and with metabolism of homocysteine and vitamins. Am J Hypertens. 2002; 15:857–864; doi: 10.1016/s0895-7061(02)02984-9
44.    Falchi A, Giovannoni L, Piras IS, Calo CM, Moral P, Vona G, Varesi L. (2005) Prevalence of genetic risk factors for coronary artery disease in Corsica island (France). Exp Mol Pathol. 2005; 79:210–213; doi: 10.1016/j.yexmp.2005.09.005
45.    Zetterberg H, Coppola A, D’Angelo A, Palmér M, Rymo L, Blennow K. No association between the MTHFR A1298C and transcobalamin C776G genetic polymorphisms and hyperhomocysteinemia in thrombotic disease. Thromb Res. 2002; 108:127–131; doi: 10.1016/s0049-3848(03)00004-5
46.    Esfahani ST, Cogger EA, Caudill MA. (2003) Heterogeneity in the prevalence of methylenetetrahydrofolate reductase gene polymorphisms in women of different ethnic groups. J Am Diet Assoc. 2003; 103:200–207; doi: 10.1053/jada.2003.50030
47.    Pereira TV, Rudnicki M, Pereira AC, Pombo-De-Oliveira MS, Franco RF. 5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Acute Lymphoblastic Leukemia Risk: A Meta-analysis. Cancer Epidemiol Biomarkers Prev. 2006; 15:1956–63; doi: 10.1158/1055-9965.EPI-06-0334
48.    Kiffmeyer WR, Langer E, Davies SM, Envall J, Robison LL, Ross JA. Genetic polymorphisms in the Hmong population. Cancer. 2004; 100:411–417; doi: 10.1002/cncr.11913
49.    De Marco P, Calevo MG, Moroni A, Arata L, Merello E, Finnell RH, Zhu H, Andreussi L, Cama A, Capra V. Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. J Hum Genet. 2002; 47:319–324; doi: 10.1007/s100380200043
50.    Peng F, Labelle LA, Rainey BJ, Tsongalis GJ. Single nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene are common in US Caucasian and Hispanic American populations. Int J Mol Med. 2001; 8:509–511; doi: 10.3892/ijmm.8.5.509
51.    Perez ABA, D’Almeida V, Vergani N, Oliveira AC de, Lima FT de, Brunoni D. Methylenetetrahydrofolate reductase (MTHFR): incidence of mutations C677T and A1298C in Brazilian population and its correlation with plasma homocysteine levels in spina bifida. Am J Med Genet Part A. 2003; 119A:20–25; doi: 10.1002/ajmg.a.10059
52.    Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hébert JR, Jin F, Zheng W. MTHFR Polymorphisms, Dietary Folate Intake, and Breast Cancer RiskResults from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev. 2004; 13:190–196; doi: 10.1158/1055-9965.epi-03-0273
53.    Hiraoka M, Kato K, Saito Y, Yasuda K, Kagawa Y. Gene–nutrient and gene–gene interactions of controlled folate intake by Japanese women. Biochem Biophys Res Commun. 2004; 316:1210–1216; doi: 10.1016/j.bbrc.2004.02.174
54.    Markan S, Sachdeva M, Sehrawat BS, Kumari S, Jain S, Khullar M. MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians. Mol Cell Biochem. 2007; 3021 302:125–131; doi: 10.1007/s11010-007-9434-5
55.    Lievers KJ, Boers GH, Verhoef P, Heijer M, Kluijtmans LA, Put NM, Trijbels FJ, Blom HJ. A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. J Mol Med. 2001; 799 79:522–528; doi: 10.1007/s001090100253
56.    Isotalo PA, Wells GA, Donnelly JG. Neonatal and Fetal Methylenetetrahydrofolate Reductase Genetic Polymorphisms: An Examination of C677T and A1298C Mutations. Am J Hum Genet. 2000; 67:986; doi: 10.1086/303082

Recomonded Articles:

Research Journal of Pharmacy and Technology (RJPT) is an international, peer-reviewed, multidisciplinary journal.... Read more >>>

RNI: CHHENG00387/33/1/2008-TC                     
DOI: 10.5958/0974-360X 

56th percentile
Powered by  Scopus

SCImago Journal & Country Rank

Recent Articles


Not Available