DOI QR코드

DOI QR Code

Allele and Genotype Frequencies of the Polymorphic Methylenetetrahydrofolate Reductase and Lung Cancer in ther Jordanian Population: a Case Control Study

  • Al-Motassem, Yousef (Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan) ;
  • Shomaf, Maha (Department of Pathology, Faculty of Medicine, The University of Jordan) ;
  • Said, Ismail (Department of Biochemistry, Molecular Biology Research Lab, Faculty of Medicine, The University of Jordan) ;
  • Berger, Sondra (Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina) ;
  • Ababneh, Nidaa (Department of Biochemistry, Molecular Biology Research Lab, Faculty of Medicine, The University of Jordan) ;
  • Diab, Ola (Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan) ;
  • Obeidat, Nathir (Department of Internal Medicine, Faculty of Medicine, The University of Jordan) ;
  • Awidi, Abdallah (Thrombosis and Molecular Hematology Laboratory, Department of Medicine and Hematology, Faculty of Medicine, The University of Jordan)
  • Published : 2015.04.29

Abstract

Background: Methylenetetrahydrofolate reductase (MTHFR) is involved in amino acid synthesis and DNA function. Two common polymorphisms are reported, C677T and A1298C, that are implicated in a number of human diseases, including cancer. Objective: The association between MTHFR C677T and A1298C genotype and haplotype frequencies in risk for lung cancer (LC) was investigated in the Jordanian population. Materials and Methods: A total of 98 LC cases were studied for MTHFR C677T and A1298C polymorphisms, compared to 89 controls taken from the general population, employing the PCR-RFLP technique. Results: The frequency of the genotypes of MTHFR C677T among Jordanians was: CC, 59.6%, CT, 33%; and TT, 7.4% among LC cases and 49.4%, 40.2% and 10.3% among controls. No significant association was detected between genetic polymorphism at this site and LC. At MTHFR A12987C, the genotype distribution was AA, 29.5%; AC, 45.3%, and CC 25.3% among LC cases and 36.8%, 50.6% and 12.6% among controls. Carriers of the CC genotype were more likely to have LC (OR=2.5; 95%CI: 1.04-6; p=0.039) as compared to AA carriers. Smokers and males with the CC genotype were 9.9 and 6.7 times more likely to have LC, respectively ($OR_{smokers}=9.9$; 95%CI: 1.2-84.5, p=0.018; $OR_{men}=6.6$; 95%CI: 1.7-26.2, p=0.005). Haplotype analysis of MTHFR polymorphism at the two loci showed differential distribution of the CC haplotype (677C-1298C) between cases and controls. The CC haplotype was associated with an increased risk for lung cancer (OR=1.6; 95% CI: 1.03-2.4, p=0.037). Conclusions: The genetic polymorphism of MTHFR at 1298 and the CC haplotype (risk is apparently lower with the C allele at position 677) may modulate the risk for LC development among the Jordanian population. Risk associated with the 1298C allele is increased in smokers and in males. The results indicate that a critical gene involved in folate metabolism plays a modifying role in lung cancer risk, at least in the Jordanian population.

Keywords

Lung cancer;methylene tetrahydrofolate reductase;polymorphism;Jordanian population

References

  1. Arslan S, Karadayi S, Yildirim ME, et al (2011). The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk. Mol Biol Rep, 38, 991-6. https://doi.org/10.1007/s11033-010-0194-z
  2. Bagley PJ, Selhub J (1998). A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci USA, 95, 13217-20. https://doi.org/10.1073/pnas.95.22.13217
  3. Boccia S, Boffetta P, Brennan P, et al (2009). Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer. Cancer Lett, 273, 55-61. https://doi.org/10.1016/j.canlet.2008.07.026
  4. Brockton NT (2006). Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate? Cancer Causes Control, 17, 1005-16. https://doi.org/10.1007/s10552-006-0051-5
  5. Brooker R (ed.) (2005). Genetics, Analysis and Principles, McGraw-Hill, USA.
  6. Central Intelligence Agency (2012). The world factbook [Online]. Available: https://www.cia.gov/library/publications/theworld-factbook/fields/2075.html [Accessed Feb 18th 2012].
  7. Chandy S, Sadananda Adiga MN, Ramachandra N, et al (2010). Association of methylenetetrahydrofolate reductase gene polymorphisms & colorectal cancer in India. Indian J Med Res, 131, 659-64.
  8. Chango A, Boisson F, Barbe F, et al (2000). The effect of 677C-->T and 1298A-->C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. Br J Nutr, 83, 593-6. https://doi.org/10.1017/S0007114500000751
  9. Chen J, Giovannucci E, Kelsey K, et al (1996). A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res, 56, 4862-4.
  10. Chen J, Ma J, Stampfer MJ, et al (2002). Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer. Pharmacogenetics, 12, 339-42. https://doi.org/10.1097/00008571-200206000-00011
  11. Cheng Z, Wang W, Dai LL, et al (2012). MTHFR C667T polymorphism association with lung cancer risk in Henan province: a case-control study. Asian Pac J Cancer Prev, 13, 2491-4. https://doi.org/10.7314/APJCP.2012.13.6.2491
  12. Cicek MS, Nock NL, Li L, et al (2004). Relationship between methylenetetrahydrofolate reductase C677T and A1298C genotypes and haplotypes and prostate cancer risk and aggressiveness. Cancer Epidemiol Biomarkers Prev, 13, 1331-6.
  13. Cui LH, Shin MH, Kim HN, et al (2011). Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population. BMC Med Genet, 12, 28.
  14. Curtin K, Bigler J, Slattery ML, et al (2004). MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev, 13, 285-92. https://doi.org/10.1158/1055-9965.EPI-03-0083
  15. Dastur DK, Quadros EV, Wadia NH, et al (1972). Effect of vegetarianism and smoking on vitamin B12, thiocyanate, and folate levels in the blood of normal subjects. Br Med J, 3, 260-3. https://doi.org/10.1136/bmj.3.5821.260
  16. Ergul E, Sazci A, Utkan Z, et al (2003). Polymorphisms in the MTHFR gene are associated with breast cancer. Tumour Biol, 24, 286-90. https://doi.org/10.1159/000076460
  17. Ferlay J, Shin HR, Bray F, et al (2012). GLOBOCAN 2012:Estimated Cancer Incidence, Mortality and Prevalence Worldwide 2012 [Online]. Lyon, France: International Agency for Research on Cancer; 2012. Available: http://globocan.iarc.fr [Accessed Jan 2014 2014].
  18. Friedman G, Goldschmidt N, Friedlander Y, et al (1999). A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr, 129, 1656-61.
  19. 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, 111-3. https://doi.org/10.1038/ng0595-111
  20. Goyette P, Pai A, Milos R, et al (1998). Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome, 9, 652-6. https://doi.org/10.1007/s003359900838
  21. Graph Pad Software Inc. Available: http://www.graphpad.com/quickcalcs/chisquared1.cfm [Accessed 20th February 2011].
  22. Heijmans BT, Boer JM, Suchiman HE, et al (2003). A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer. Cancer Res, 63, 1249-53.
  23. Hong W, Wang K, Zhang YP, et al (2013). Methylenetetrahydrofolate reductase C677T polymorphism predicts response and time to progression to gemcitabine-based chemotherapy for advanced non-small cell lung cancer in a Chinese Han population. J Zhejiang Univ Sci B, 14, 207-15. https://doi.org/10.1631/jzus.B1200101
  24. Hou XH, Huang YM, Mi YY (2012). Methylenetetrahydrofolate reductase gene C677T polymorphism and lung cancer: an updated meta-analysis. Asian Pac J Cancer Prev, 13, 2025-9. https://doi.org/10.7314/APJCP.2012.13.5.2025
  25. Hung RJ, Hashibe M, McKay J, et al (2007). Folate-related genes and the risk of tobacco-related cancers in Central Europe. Carcinogenesis, 28, 1334-40. https://doi.org/10.1093/carcin/bgm067
  26. Jeng YL, Wu MH, Huang HB, et al (2003). The methylenetetrahydrofolate reductase 677C-->T polymorphism and lung cancer risk in a Chinese population. Anticancer Res, 23, 5149-52.
  27. Jordan Cancer Registry (2010). Cancer incidence in Jordan [Internet]. [Online]. Amman, Jordan: Jordan National Cancer Registry; 2008. Available: http://www.moh.gov.jo/AR/Documents/Annual%20Incidence%20of%20cancer%20in%20Jordan%202010.pdf [Accessed January 2014].
  28. Keku T, Millikan R, Worley K, et al (2002). 5, 10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites. Cancer Epidemiol Biomarkers Prev, 11, 1611-21.
  29. Kiyohara C, Horiuchi T, Takayama K, et al (2011). Methylenetetrahydrofolate reductase polymorphisms and interaction with smoking and alcohol consumption in lung cancer risk: a case-control study in a Japanese population. BMC Cancer, 11, 459. https://doi.org/10.1186/1471-2407-11-459
  30. Kiyohara C, Horiuchi T, Takayama K, et al (2013). Methylenetetrahydrofolate reductase polymorphisms and interaction with smoking and alcohol consumption in lung cancer risk: a case-control study in a Japanese population. BMC Cancer, 11, 459.
  31. Kono S, Chen K (2005). Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma. Cancer Sci, 96, 535-42. https://doi.org/10.1111/j.1349-7006.2005.00090.x
  32. Li H, Xu WL, Shen HL, et al (2011). Methylenetetrahydrofolate reductase genotypes and haplotypes associated with susceptibility to colorectal cancer in an eastern Chinese Han population. Genet Mol Res, 10, 3738-46. https://doi.org/10.4238/2011.December.14.8
  33. Lievers KJ, Boers GH, Verhoef P, et al (2001). 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 (Berl), 79, 522-8. https://doi.org/10.1007/s001090100253
  34. Liu CS, Tsai CW, Hsia TC, et al (2009). Interaction of methylenetetrahydrofolate reductase genotype and smoking habit in Taiwanese lung cancer patients. Cancer Genomics Proteomics, 6, 325-9.
  35. Liu H, Jin G, Wang H, et al (2008). Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population. Lung Cancer, 61, 21-9. https://doi.org/10.1016/j.lungcan.2007.12.001
  36. Liu ZB, Wang LP, Shu J, et al (2013). Methylenetetrahydrofolate reductase 677TT genotype might be associated with an increased lung cancer risk in Asians. Gene, 515, 214-9. https://doi.org/10.1016/j.gene.2012.11.036
  37. Lowi MR 1995. Water and power: the politics of a scarce resource in the Jordan River basin, Cambridge, Cambridge University Press.
  38. Lucock M (2004). Is folic acid the ultimate functional food component for disease prevention? BMJ, 328, 211-4. https://doi.org/10.1136/bmj.328.7433.211
  39. Ma J, Stampfer MJ, Giovannucci E, et al (1997). Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res, 57, 1098-102.
  40. Mao R, Fan Y, Jin Y, et al (2008). Methylenetetrahydrofolate reductase gene polymorphisms and lung cancer: a metaanalysis. J Hum Genet, 53, 340-8. https://doi.org/10.1007/s10038-008-0262-6
  41. Meisel C, Cascorbi I, Gerloff T, et al (2001). Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease. Atherosclerosis, 154, 651-8. https://doi.org/10.1016/S0021-9150(00)00679-1
  42. Ogino S, Wilson RB (2003). Genotype and haplotype distributions of MTHFR677C>T and 1298A>C single nucleotide polymorphisms: a meta-analysis. J Hum Genet, 48, 1-7. https://doi.org/10.1007/s100380300000
  43. Pardini B, Kumar R, Naccarati A, et al (2011). MTHFR and MTRR genotype and haplotype analysis and colorectal cancer susceptibility in a case-control study from the Czech Republic. Mutat Res, 721, 74-80. https://doi.org/10.1016/j.mrgentox.2010.12.008
  44. Paul RT, McDonnell AP, Kelly CB (2004). Folic acid: neurochemistry, metabolism and relationship to depression. Hum Psychopharmacol, 19, 477-88. https://doi.org/10.1002/hup.614
  45. Perera FP (1998). Molecular epidemiology of environmental carcinogenesis. Recent Results Cancer Res, 154, 39-46. https://doi.org/10.1007/978-3-642-46870-4_3
  46. Rai V (2014). Folate Pathway Gene MTHFR C677T polymorphism and risk of lung cancer in Asian populations. Asian Pac J Cancer Prev, 15, 9259-64. https://doi.org/10.7314/APJCP.2014.15.21.9259
  47. Sharp L, Little J (2004). Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol, 159, 423-43. https://doi.org/10.1093/aje/kwh066
  48. Shen H, Spitz MR, Wang LE, et al (2001). Polymorphisms of methylene-tetrahydrofolate reductase and risk of lung cancer: a case-control study. Cancer Epidemiol Biomarkers Prev, 10, 397-401.
  49. Shen M, Rothman N, Berndt SI, et al (2005). Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China. Lung Cancer, 49, 299-309. https://doi.org/10.1016/j.lungcan.2005.04.002
  50. Shi M, Caprau D, Romitti P, et al (2003). Genotype frequencies and linkage disequilibrium in the CEPH human diversity panel for variants in folate pathway genes MTHFR, MTHFD, MTRR, RFC1, and GCP2. Birth Defects Res A Clin Mol Teratol, 67, 545-9. https://doi.org/10.1002/bdra.10076
  51. Shi Q, Zhang Z, Li G, et al (2005). Sex differences in risk of lung cancer associated with methylene-tetrahydrofolate reductase polymorphisms. Cancer Epidemiol Biomarkers Prev, 14, 1477-84. https://doi.org/10.1158/1055-9965.EPI-04-0905
  52. Shields PG (2002). Molecular epidemiology of smoking and lung cancer. Oncogene, 21, 6870-6. https://doi.org/10.1038/sj.onc.1205832
  53. Siemianowicz K, Gminski J, Garczorz W, et al (2003). Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms in patients with small cell and nonsmall cell lung cancer. Oncol Rep, 10, 1341-4.
  54. Stern LL, Mason JB, Selhub J, et al (2000). Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev, 9, 849-53.
  55. Stolzenberg-Solomon RZ, Qiao YL, Abnet CC, et al (2003). Esophageal and gastric cardia cancer risk and folate- and vitamin B(12)-related polymorphisms in Linxian, China. Cancer Epidemiol Biomarkers Prev, 12, 1222-6.
  56. Suzuki T, Matsuo K, Hiraki A, et al (2007). Impact of onecarbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study. Carcinogenesis, 28, 1718-25. https://doi.org/10.1093/carcin/bgm104
  57. Swartz MD, Peterson CB, Lupo PJ, et al (2013). Investigating multiple candidate genes and nutrients in the folate metabolism pathway to detect genetic and nutritional risk factors for lung cancer. PLoS One, 8, 53475. https://doi.org/10.1371/journal.pone.0053475
  58. Terrazzino S, Agostini M, Pucciarelli S, et al (2006). A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation. Pharmacogenet Genomics, 16, 817-24. https://doi.org/10.1097/01.fpc.0000230412.89973.c0
  59. The Royal Hashemite Court. 2012. Keys to the Kingdom-The People of Jordan. [Online]. Available: http://www.kinghussein.gov.jo/people.html [Accessed Feb 18th 2012].
  60. Truong T, Sauter W, McKay JD, et al (2010). International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants. Carcinogenesis, 31, 625-33. https://doi.org/10.1093/carcin/bgq001
  61. 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, 1044-51. https://doi.org/10.1086/301825
  62. Vineis P, Veglia F, Garte S, et al (2007). Genetic susceptibility according to three metabolic pathways in cancers of the lung and bladder and in myeloid leukemias in nonsmokers. Ann Oncol, 18, 1230-42. https://doi.org/10.1093/annonc/mdm109
  63. Weisberg I, Tran P, Christensen B, et al (1998). A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab, 64, 169-72. https://doi.org/10.1006/mgme.1998.2714
  64. Witter FR, Blake DA, Baumgardner R, et al (1982). Folate, carotene, and smoking. Am J Obstet Gynecol, 144, 857.
  65. Yi P, Pogribny I, Jill James S (2002). Multiplex PCR for simultaneous detection of 677 C-->T and 1298 A-->C polymorphisms in methylenetetrahydrofolate reductase gene for population studies of cancer risk. Cancer Lett, 181, 209. https://doi.org/10.1016/S0304-3835(02)00060-5
  66. Zhang Y, Chen GQ, Ji Y, et al (2012). Quantitative assessment of the effect of MTHFR polymorphisms on the risk of lung carcinoma. Mol Biol Rep, 39, 6203-11. https://doi.org/10.1007/s11033-011-1439-1

Cited by

  1. Thymidylate Synthase Polymorphisms and Risk of Lung Cancer among the Jordanian Population: a Case Control Study vol.16, pp.18, 2016, https://doi.org/10.7314/APJCP.2015.16.18.8287
  2. MTHFR gene C677T and A1298C variants are associated with FMF risk in a Turkish cohort pp.08878013, 2017, https://doi.org/10.1002/jcla.22259
  3. Genetic association analysis of ERBB4 polymorphisms with the risk ofschizophrenia susceptibility in a Jordanian population of Arab descent vol.47, pp.13036165, 2017, https://doi.org/10.3906/sag-1603-25