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Strong Association of C677T Polymorphism of Methylenetetrahydrofolate Reductase Gene With Nosyndromic Cleft Lip/Palate (nsCL/P)

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Abstract

Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigentic process of DNA methylation. It has been reported that abnormal DNA methylation contributes to the pathogenesis of congenital anomalies. There were many published case control studies assessing the associations of MTHFR C677T polymorphism with risks of nosyndromic cleft lip with and without palate (nsCL/P), but with inconsistent results. To derive a more precise estimation of the relationship, a meta-analysis was performed. Eligible articles were identified by search of databases including PubMed, Science Direct, Google Scholar and Springer Link up to December, 2015. Finally, a total of 22 studies with 3724 nsCL/P cases and 5275 controls were included in the present meta-analysis. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were pooled to assess the association. Subgroup analysis based on ethnicity was also performed. All statistical analyses were done by MIX program. Meta-analysis results suggested that MTHFR C677T polymorphism contributed to the increased nsCL/P risk in overall population using four genetic models except homozygote model (for T vs. C: OR = 1.24, 95% CI = 1.1–1.4; for TT + CT vs. CC: OR = 1.29, 95% CI = 1.04–1.59; for CT vs. CC: OR = 1.26, 95% CI = 0.98–1.63; for TT vs. CC: OR = 1.02, 95% CI = 0.74–1.4; for TT vs. CT + CC: OR = 1.36, 95% CI = 1.05–1.74). In conclusion, results of present meta-analysis suggested that MTHFR C677T polymorphism is significantly associated with nonsyndromic orofacial cleft.

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Abbreviations

nsCL/P:

Nonsyndromic cleft lip with or without cleft palate

MTHFR:

Methylenetetrahydrofolate reductase

References

  1. Croen LA, Shaw GM, Wasserman CR, Tolarova MM. Racial and ethnic variations in the prevalence of orofacial clefts in California 1983–1992. Am J Med Genet. 1998;79(1):42–7.

    Article  CAS  PubMed  Google Scholar 

  2. Vanderas AP. Incidence of cleft lip, cleft palate, and cleft lip and palate among races: a review. Cleft Palate J. 1987;24:216–25.

    CAS  PubMed  Google Scholar 

  3. Clark JD, Mossey PA, Sharp L, Little J. Socioeconomic status and orofacial clefts in Scotland, 1989 to 1998. Cleft Palate Craniofac J. 2003;40:481–5.

    Article  CAS  PubMed  Google Scholar 

  4. Wyszynski DF, Beaty TH. Review of the role of potential teratogens in the origin of human nonsyndromic oral clefts. Teratology. 1996;53:309–17.

    Article  CAS  PubMed  Google Scholar 

  5. Lie RT, Wilcox AJ, Skjaerven R. A population-based study of the risk of recurrence of birth defects. N Engl J Med. 1994;331:1–4.

    Article  CAS  PubMed  Google Scholar 

  6. Lie RT, Wilcox AJ, Skjaerven R. Survival and reproduction among males with birth defects and risk of recurrence in their children. JAMA. 2001;285:755–60.

    Article  CAS  PubMed  Google Scholar 

  7. Skjaerven R, Wilcox AJ, Lie RT. A population-based study of survival and childbearing among female subjects with birth defects and the risk of recurrence in their children. N Engl J Med. 1999;340:1057–62.

    Article  CAS  PubMed  Google Scholar 

  8. Bhaskar LVKS, Murthy J, Venkatesh Babu G. Polymorphisms in genes involved in folate metabolism and orofacial clefts. Arch Oral Biol. 2011;56:723–37.

    Article  CAS  PubMed  Google Scholar 

  9. Tolarova M. Orofacial clefts in Czechoslovakia. Incidence, genetics, and prevention of cleft lip and palate over a 19-year period. Scand J Plast Reconst Surg Hand Surg. 1987;21:19–25.

    CAS  Google Scholar 

  10. Tolarova M, Harris J. Reduced recurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology. 1995;51:71–8.

    Article  CAS  PubMed  Google Scholar 

  11. Shaw GM, O’Malley CD, Wasserman CR, Tolarova MM, Lammer EJ. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet. 1995;59:536–45.

    Article  CAS  PubMed  Google Scholar 

  12. Loffredo LC, Souza JM, Feitas JA, Mossey PA. Oral clefts and vitamin supplementation. Cleft Palate Craniofac J. 2001;38:76–83.

    Article  CAS  PubMed  Google Scholar 

  13. Mitchell LE, Murray JC, O’Brien S, Christensen K. Retinoic acid receptor alpha gene variants, multivitamin use, and liver intake as risk factors for oral clefts: a population based case-control study in Denmark. Am J Epidemiol. 2003;158(1):1991–4.

    Article  Google Scholar 

  14. van Rooij IA, Ocké MC, Straatman H, Zielhuis GA, Merkus HM, Steegers-Theunissen RP. Periconceptual folate intake by supplement and food reduces the risk of nonsyndromic cleft lip with or without cleft palate. Prev Med. 2004;39:689–94.

    Article  PubMed  Google Scholar 

  15. Krapels IP, Vermeij-Keers C, Muller M, de Klein A, Steegers- Theunissen RP. Nutrition and genes in the development of orofacial clefting. Nutr Rev. 2006;64:280–8.

    Article  PubMed  Google Scholar 

  16. Badovinac RL, Werler WM, Williams PL, Kelsey KT, Hayes C. Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth Def Res (Part A). 2007;79:8–15.

    Article  CAS  Google Scholar 

  17. Chevrier C, Perret C, Bahuan M, Zhu H, Nelva A, Herman C, et al. Fetal and maternal MTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts. Am J Med Genet A. 2007;143:248–57.

    Article  Google Scholar 

  18. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131–7.

    Article  Google Scholar 

  19. Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327:1832–5.

    Article  CAS  PubMed  Google Scholar 

  20. Rosenquist TH, Finell RH. Genes, folate and homocysteine in embryonic development. Proc Nutr Soc. 2001;60:1–9.

    Google Scholar 

  21. Czeizel AE. Periconceptional folic acid containing multivitamin supplementation. Eur J Obstet Gynecol Reprod Biol. 1998;78:151–61.

    Article  CAS  PubMed  Google Scholar 

  22. Itikala PR, Watkins ML, Mulinare J, Moore CA, Liu Y. Maternal multivitamin use and orofacial clefts in offspring. Teratology. 2001;63:79–86.

    Article  CAS  PubMed  Google Scholar 

  23. Boyles AL, Wilcox A, Taylor JA, Meyer K, Fredriksen A, Ueland PM, et al. Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts. Am J Med Genet A. 2008;146A:440–9.

    Article  CAS  PubMed  Google Scholar 

  24. Yazdy MM, Honein MA, Xing J. Reduction in orofacial clefts following folic acid fortification of the U.S. grain supply. Birth Defects Res A Clin Mol Teratol. 2007;79:16–23.

    Article  CAS  PubMed  Google Scholar 

  25. Ray JG, Meier C, Vermeulen MJ, Wyatt PR, Cole DE. Association between folic acid food fortification and congenital orofacial clefts. J Pediatr. 2003;143:805–7.

    Article  CAS  PubMed  Google Scholar 

  26. Shaw GM, Rozen R, Finnell RH, Todoroff K, Lammer EJ. Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip. Am J Med Genet. 1998;80:196–8.

    Article  CAS  PubMed  Google Scholar 

  27. Gaspar DA, Pavanello RC, Zatz M, Passos-Bueno MR, Andre M, Steman S, et al. Role of the C677T polymorphism at the MTHFR gene on risk to nonsyndromic cleft lip with/without cleft palate: results from a case-control study in Brazil. Am J Med Genet. 1999;87:197–9.

    Article  CAS  PubMed  Google Scholar 

  28. Mills JL, Kirke PN, Molloy AM, Burke H, Conley MR, Lee YJ, et al. Methylenetetrahydrofolate reductase thermolabile variant and oral clefts. Am J Med Genet. 1999;86:71–4.

    Article  CAS  PubMed  Google Scholar 

  29. Martinelli M, Scapoli L, Pezzetti F, Carinci F, Carinci P, Stabellini G, et al. C677T variant form at theMTHFR gene and CL/P: a risk factor for mothers? AmJ Med Genet. 2001;98:357–60.

    Article  CAS  PubMed  Google Scholar 

  30. Blanton SH, Patel S, Hecht JT, Mulliken JB. MTHFR is not a risk factor in the development of isolated nonsyndromic cleft lip and palate. Am J Med Genet. 2002;110(4):404–5.

    Article  PubMed  Google Scholar 

  31. Prescott NJ, Winter RM, Malcolm S. Maternal MTHFR genotype contributes to the risk of non-syndromic cleft lip and palate. J Med Genet. 2002;39:368–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jugessur A, Wilcox AJ, Lie RT, Murray JC, Taylor JA, Ulvik A, et al. Exploring the effects of methylenetetrahydrofolate reductase gene variants C677T and A1298C on the risk of orofacial clefts in 261 Norwegian case-parent triads. Am J Epidemiol. 2003;157:1083.

    Article  PubMed  Google Scholar 

  33. Shotelersuk V, Ittiwut C, Siriwan P, Angspatt A. Maternal 677CT/1298AC genotype of the MTHFR gene as a risk factor for cleft lip. J Med Genet. 2003;40:e64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Van Rooij LA, Swinkels DW, Blom HJ, Markus HM, Stegers-Theunissen RP. Vitamin and homocysteine status of mothers and infants and the risk of nonsyndromic orofacial clefts. Am J Obstet Gynecol. 2003;189:1155–60.

    Article  PubMed  Google Scholar 

  35. Vieira AR, Murray JC, Trembath D, Orioli IM, Castilla EE, Cooper ME, et al. Studies of reduced folate carrier 1 (RFC1) A80G and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms with neural tube and orofacial cleft defects. Am J Med Genet. 2000;135A:220–3.

    Article  Google Scholar 

  36. Frosst P, Bloom HJ, Milos R, Goyette P, Sheppard CA, Mattews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111–3.

    Article  CAS  PubMed  Google Scholar 

  37. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62:1044–51.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hobbs CA, Sherman SL, Hopkins SE, Torfs CP, Hine RJ, Pogribna M, et al. Polymorphisms in genes involved in folate metabolism as maternal risk factors for down syndrome. Hum Genet. 2000;67:623–30.

    Article  CAS  Google Scholar 

  39. Hobbs CA, Cleves MA, Karim MA, Zhao W, MacLeod SL. Maternal folate-related gene environment interactions and congenital heart defects. Obstet Gynecol. 2010;116:316–22.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hegele RA, Tully C, Young TK, Connelly PW. V677 mutation of methylenetetrahydrofolate reductases and cardiovascular disease in Canadian Inuit. Lancet. 1997;349:1221–2.

    Article  CAS  PubMed  Google Scholar 

  41. Wilcken B, Bamforth F, Li Z, Zhu H, Ritvanen A, Renlund M, et al. Geographical and ethnic variation of the 677C > T allele of 5,10-methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas worldwide. J Med Genet. 2003;40:619–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rai V, Yadav U, Kumar P, Yadav SK. Methyleletetrahydrofolate reductase polymorphism (C677T) in Muslim population of Eastern Uttar Pradesh, India. Ind J Med Sci. 2010;64(5):219–23.

    Article  Google Scholar 

  43. Rai V, Yadav U, Kumar P. Genotype prevalence and allele frequencies of 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T mutation in two caste groups of India. Cell Mol Biol. 2012;58:OL1695–701.

    PubMed  Google Scholar 

  44. Yadav U, Kumar P, Gupta S, Rai V. Distribution of MTHFR C677T gene polymorphism in healthy North Indian population and an updated meta-analysis. Ind J Clinical Biochem. 2016;. doi:10.1007/s12291-016-0619-0.

    Google Scholar 

  45. Tolarova MM, van Rooij IALM, Pastor M, van der Put NMJ, Goldberg AC, Hol F, et al. A common mutation in the MTHFR gene is a risk factor for non-syndromic cleft lip and palate anomalies. Am J Hum Genet. 1998;63:A27.

    Google Scholar 

  46. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–48.

    CAS  PubMed  Google Scholar 

  47. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  48. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol. 2004;24:1–15.

    Google Scholar 

  49. Zintzaras E, Hadjigeorgiou GM. The role of G196A polymorphism in the brain-derived neurotrophic factor gene in the cause of Parkinson’s disease: a meta-analysis. J Hum Genet. 2005;50:560–6.

    Article  CAS  PubMed  Google Scholar 

  50. Higgins JP, Thompson SE. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

    Article  PubMed  Google Scholar 

  51. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta analyses. Br Med J. 2003;327:557–60.

    Article  Google Scholar 

  52. Zintzaras E, Koufakis T, Ziakas PD, Rodopoulou P, Giannouli S, Voulgarelis M. A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia. Euro J Epidemiol. 2006;21:501–10.

    Article  CAS  Google Scholar 

  53. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.

    Article  CAS  PubMed  Google Scholar 

  54. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bax L, Yu LM, Ikeda N, Tsuruta H, Moons KG. Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Med Res Methodol. 2006;6:50.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Gaspar DA, Matioli SR, de Ca´ssia Pavanello R, Araujo BC, Alonso N, Wyszynski D, et al. Maternal MTHFR interacts with the offspring’s BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate. Eur J Hum Genet. 2004;12:521–6.

    Article  CAS  PubMed  Google Scholar 

  57. Wyszynski DF, Diehl SR. Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and risk of nonsyndromic cleft lip. Am J Med Genet. 2000;92:79–80.

    Article  CAS  PubMed  Google Scholar 

  58. Grunert RR, Braune A, Schnackenberg E, Schloot W, Krause HR. Genetic differences in enzymes of folic acid metabolism in patients with lip-jaw-palate clefts and their relatives. Mund Kiefer Gesichtschir. 2002;6:131–3.

    Article  CAS  PubMed  Google Scholar 

  59. Pezzetti F, Martinelli M, Scapoli L, Carinci F, Palmieri A, Marchesini J, et al. Maternal MTHFR variant forms increase the risk in offspring of isolated nonsyndromic cleft lip with or without cleft palate. Hum Mutat. 2004;24:104–5.

    Article  CAS  PubMed  Google Scholar 

  60. Brandalize AP, Bandinelli E, Borba JB, Felix TM, Roisenberg I, Schuler-Faccini L. Polymorphisms in genes MTHFR, MTR and MTRR are not risk factors for cleft lip/palate in South Brazil. Braz J Med Biol Res. 2007;40:787–91.

    Article  CAS  PubMed  Google Scholar 

  61. Mills JL, Molloy AM, Parle-McDermott A, Troendle JF, Brody LC, Conley MR, et al. Folate-related gene polymorphisms as risk factors for cleft lip and cleft palate. Birth Defects Res A. 2008;82:636–43.

    Article  CAS  Google Scholar 

  62. Ali A, Singh SK, Raman R. MTHFR 677TT alone and IRF6 820GG together with MTHFR 677CT, but not MTHFR A1298C, are risks for non-syndromic cleft lip with or without cleft palate in an Indian population. Genet Test Mol Biomark. 2009;13:355–60.

    Article  CAS  Google Scholar 

  63. Sözen MA, Tolarova MM, Spritz RA. The common MTHFR C677T and A1298C variants are not associated with the risk of non-syndromic cleft lip/palate in northern Venezuela. J Genet Genomics. 2009;36:283–8.

    Article  PubMed  Google Scholar 

  64. Guo JZ, Song XM, Wang Y, Zhu WL, Li SQ, Li Y. Relationship between genetic polymorphisms of MTHFR C677T and nonsyndromic cleft lip with or without palate. Beijing Da Xue Xue Bao. 2009;41:432–6.

    CAS  PubMed  Google Scholar 

  65. Chorna LB, Akopyan HR, Makukh HV, Fedoryk IM. Allelic polymorphisms in the MTHFR, MTR and MTRR genes in patients with cleft lip and/or palate and their mothers. Cytolo Genet. 2011;45:177–81.

    Article  Google Scholar 

  66. Semiç-Jusufagiç A, Bircan R, Çelebiler O, Erdim M, Akarsu N. Elçioğlu1 NH. Association between C677T and A1298C MTHFR gene polymorphism and nonsyndromic orofacial clefts in the Turkish population: a case-parent study. Turkish J Pediatr. 2012;54:617–25.

    Google Scholar 

  67. Aslar D, Ozdiler E, Tastan H, Altug AB. Determination of Methylenetetrahydrofolate Reductase (MTHFR) gene polymorphism in Turkish patients with nonsyndromic cleft lip and palate. Int J Pediatr Otorhinolaryngol. 2013;77:1143–6.

    Article  PubMed  Google Scholar 

  68. Kumari P, Ali A, Shukla KK, Singh SK, Raman R. Lower incidence of nonsyndromic cleft lip with or without cleft palate in females: Is homocysteine a factor? J Biosci. 2013;38:21–6.

    Article  CAS  PubMed  Google Scholar 

  69. Estandia-Ortega B, Velazquez-Aragon JA, Alcantara-Ortigoza MA, Reyna-Fabian ME, Villagomez-Martınez S, Gonzalez-del Angel A. 5,10-Methylenetetrahydrofolate reductase single nucleotide polymorphisms and gene–environment interaction analysis in analysis in non-syndromic cleft lip/palate. Eur J Oral Sci. 2014;122:109–13.

    Article  CAS  PubMed  Google Scholar 

  70. Rouget F, Monfort C, Bahuau M, Nelva A, Herman C, Francannet C, et al. Periconceptual folates and the prevention of orofacial clefts: role of dietary intakes in France. Rev Epidemiol Sante Publique. 2005;53:351–60.

    Article  CAS  PubMed  Google Scholar 

  71. Wilcox AJ, Lie RT, Solvoll K, Taylor J, Mcconnaughey DR, Abyholm F, et al. Folic acid supplements and risk of facial clefts: national population based case-control study. Br Med J. 2007;334:464.

    Article  Google Scholar 

  72. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. 2000;343:1608–14.

    Article  CAS  PubMed  Google Scholar 

  73. Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, et al. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001;74:233–41.

    CAS  PubMed  Google Scholar 

  74. Xiao WL, Wu M, Shi B. Folic acid rivals methylenetetrahydrofolate reductase (MTHFR) gene silencing effect on MEPM cell proliferation and apoptosis. Mol Cell Biochem. 2006;292:145–54.

    Article  CAS  PubMed  Google Scholar 

  75. Munger R. Maternal nutrition and oral clefts. In: Wyszynski D, editor. Cleft lip and palate: from origin to treatment. New York: Oxford University Press; 2002. p. 170–92.

    Google Scholar 

  76. Rai V. Polymorphism in folate metabolic pathway gene as maternal risk factor for down syndrome. Int J Biol Med Res. 2011;2(4):1055–60.

    Google Scholar 

  77. Rai V. Methylenetetrahydrofolate reductase C677T polymorphism and recurrent pregnancy loss risk in Asian population: a meta-analysis. Ind J Clin Biochem. 2016;32(4):402–13.

    Article  Google Scholar 

  78. Yadav S, Hasan N, Marjot T, Khan MS, Prasad K, Bentley P, et al. Detailed analysis of gene polymorphisms associated with ischemic stroke in South Asians. PLoS One. 2013;8(3):e57305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Rai V. Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility. Metab Brain Dis. 2016;1:727–35.

    Article  Google Scholar 

  80. Yadav U, Kumar P, Gupta S, Rai V. Role of MTHFR C677T gene polymorphism in the susceptibility of schizophrenia: an updated meta-analysis. Asian J Psychiatr. 2016;20:41–51.

    Article  PubMed  Google Scholar 

  81. Rai V. Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene and susceptibility to depression in Asian population: a systematic meta-analysis. Cell Mol Biol. 2014;60(3):29–36.

    CAS  PubMed  Google Scholar 

  82. Rai V. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and alzheimer disease risk: a meta-analysis. Mol Neurobiol. 2016;54:1173–86.

    Article  PubMed  Google Scholar 

  83. Rai V. Methylenetetrahydrofolate reductase A1298C polymorphism and breast cancer risk: a meta-analysis of 33 studies. Ann Med Health Sci Res. 2014;4(6):841–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kumar P, Yadav U, Rai V. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: evidence for genetic susceptibility. Meta Gene. 2015;6:72–84.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Yadav U, Kumar P, Rai V. Role of MTHFR A1298C gene polymorphism in the etiology of prostate cancer: a systematic review and updated meta-analysis. Egypt J Med Hum Genet. 2016;17(2):141–8.

    Article  Google Scholar 

  86. Rai V. Evaluation of the MTHFR C677T polymorphism as a risk factor for colorectal cancer in Asian populations. Asian Pac J Cancer Prev. 2016;16(18):8093–100.

    Article  Google Scholar 

  87. Verkleij-Hagoort A, Bliek J, Sayed-Tabatabaei F, Ursem N, Steegers E, Steegers-Theunissen R. Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: a meta-analysis. Am J Med Gene Part A. 2007;143A:952–60.

    Article  CAS  Google Scholar 

  88. Rai V. Maternal methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism and risk of nonsyndromic Cleft lip and/or Palate (NSCL/P) in offspring: a meta-analysis. Asian J Med Sci. 2014;6(1):16–21.

    Article  Google Scholar 

  89. Rai V. Meta-analysis of methylenetetrahydrofolate reductase (MTHFR) A1298C polymorphism and risk of orofacial cleft. J Med Genet Genomics. 2014;6:19–26.

    Article  Google Scholar 

  90. Zhao M, Ren Y, Shen L, Zhang Y, Zhou B. Association between MTHFR C677T and A1298C polymorphisms and NSCL/P risk in Asians: a meta- analysis. PLoS One. 2014;9:e88242.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The author is highly grateful to Leon Bax (Chief Scientific Officer at BiostatXL, UMC Utrecht) for his valuable suggestions which help her in statistical analysis.

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    Vandana Rai

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Rai, V. Strong Association of C677T Polymorphism of Methylenetetrahydrofolate Reductase Gene With Nosyndromic Cleft Lip/Palate (nsCL/P). Ind J Clin Biochem 33, 5–15 (2018). https://doi.org/10.1007/s12291-017-0673-2

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