Genetic Variants in the Methylenetetrahydrofolate Reductase Gene in Egyptian Children with Conotruncal Heart Defects and their Mothers

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Genetic Variants in the Methylenetetrahydrofolate Reductase Gene in Egyptian Children with Conotruncal Heart Defects and their Mothers

Aim: This study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in MTHFR gene as maternal risk factors in conotruncal heart defects (CTDs).

Material and Methods: Thirty cases with CTDs and their mothers and thirty control children and their mothers were studied. Medical and nutritional histories for all mothers were taken with emphasis on folate intake. The mutations in MTHFR gene are a C to T substitution at base pair 677 and a A to C at base pair1298 were investigated by polymerase-chain reaction, followed by restriction enzyme digestion and detection by electrophoresis.

Results: Folic acid intake was below the recommended daily allowance in case mothers compared to control mothers. No significant difference between patients and control group or their mothers regarding MTHFR gene polymorphisms at exon 4. Significant difference between case and control groups and between their mothers regarding MTHFR gene polymorphisms at exon 7. Homozygous genotype frequencies of MTHFR at position 1298 was significantly higher in cases and their mothers with an odds ratio 56 (95% confidence interval 10.3-303.7).

Conclusion: Egyptian population may have high incidence of MTHFR polymorphism at exon 7 rather than at exon 4. Preconception folate intake might decrease MTHFR polymorphism at exon 7 and decrease risk of CTD.

Botto LD and Correa A. Decreasing the burden of congenital heart anomalies: An epidemiologic evaluation of risk factors and survival. Prog Pediatr Cardiol. 2003;18:111-121.

Botto LD, Correa A, Erickson JD. Racial and temporal variations in the prevalence of heart defects. Pediatrics. 2001;107.3 e 32.

Storti S, Vittorini S, Lascone MR, Sacchelli M, Collavoli A. Association between 5, 10-methylenetetra-hydrofolate reductase C677T and A1298C polymorphisms and conotruncal heart defect. Clin Chem Lab Med. 2003;41(3):276-80

Shaw GM, Iovannisci DM, Yang W, Finnell RH, Carmichael SL, Cheng S, Lammer EG. Risks of Human Conotruncal Heart Defects Associated With 32 Single Nucleotide Polymorphisms of Selected Cardiovascular Disease-Related Genes. American Journal of Medical Genetics. 2005; 138A:21-26.

Janet S. Sinsheimer, Robert C. Elston, Wenjiang J. Fu Gene-Gene Interaction in Maternal and Perinatal Research J Biomed Biotechnol. 2010; 2010 pii: 853612.

Doolin MT, Barbaux S, McDonnell M, Hoess K, Whitehead AS, Mitchell LE. Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. Am J Hum Genet. 2002;71:1222-1226.

Goyette P, Pai A, Milos R, Frosst P, Tran P. Gene structure of human and mouse methylene-tetrahydrofolate reductase (MTHFR). Mamm Genome. 1998;9:652-656.

Botto LD. and Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies. Am J Epidemiol. 2000;151:862-877.

Hall J, Solehdin F. Folic acid for the prevention of congenital anomalies. Eur J Pediatr. 1998;157:445-450.

Zhu J, Ren A, Hao L, Pei L, Liu J, Zhu H, Li S, Finnell RH, Li Z. Variable contribution of the MTHFR C677T polymorphism to non-syndromic cleft lip and palate risk in China. Am J Med Genet. 2006;140A:551-557.

FAO/WHO/UNU Energy and protein requirements. Report of a joined FAO/WHO/UNU Expert Consultation. World health Organization. Geneva, 1985.

Food Composition Tables of National Nutrition Institute of Egypt, based on local food analysis and food composition tables in the Middle East, 1993.

Snider RA, Serwer GA, Ritter SA. Echocardiography in Pediatric Heart Disease. 2nd ed. St. Louis, MO: Mosby-Year Book, 1997:277-289.

Kowa H, Yasui K, Takeshima T, Urakami K, Sakai F, Nakashima K. The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine. Am J Med Genet. 2000;96(6):762-764.

Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111-113.

Loffredo CA, Sibergel ELR, Frenzy C, Zhangs J. Association of transposition of the great arteries in infants with maternal exposures to insecticides and radiations. Am Journal of Epidemiology. 2001;153(6):529-536.

Botto LD, Feldkamp M, Carey JC. Actual causes of congenital heart defects: A population based study, Utah 1999-2003. Paper presented at the American Society of Human Genetics, Salt Lake City, UT. 2005.

Van Driel LJ, Verkleij-Hagoort AC, Jonge R, Uitterlinden AG, Steegers EP, vanDuijn CM, et al. Two MTHFR Polymorphisms, Maternal Vitamin-B Intake, And CHDs. Birth Defects Research. 2008;82:474481.

Mooij M, Steegers T, Thomas C, Doesburg W, Eskes T. Periconceptional vitamin profiles are not suitable for identifying women at risk for neural tube defects. J Nutri. 1993;123:197-203.

Van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet. 1995;21;346(8982):1070-1071.

Shaw GM, Nelson V, Carmichael SL, Lammer E, Waston M. Maternal periconceptional vitamins: Interactions with selected factors and congenital anomalies. Epidemiology 2002; 13:625-630.

Van Beynum IM, HeijerM, Vermeulen SHHM, Kapusta L, Daniels O, Maternal M. Is a risk factor for congenital heart defects: effect medication by periconceptional folate supplementation. European Heart Journal. 2006;27:981-987.

Goldmuntz E, Lin A. Genetics of congenital heart defects. In: Hugh D, David DJ, Robert SE. Moss and Adams' Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adults. Feltes, Timothy F. 17th edition. Lippincott Williams & Wilkins. 2008;547-551.

Junker R, Kotthoff S, Vielhaber H. Infant methylenetetrahydrofolate reductase 677TT genotype is a risk factor for congenital heart disease. Cardiovas Res. 2001; 51:251-254.

Yelbuz TM, Waldo KL, Kumiski DH, Stadt HA, Wolfe RR, Leatherbury L, Kirby ML. Shortened outflow tract leads to altered cardiac looping after Neural crest ablation. Circulation. 2002;106:504-510.

Tierney BJ, Ho T, Reedy MV, Brauer PR. Homocysteine inhibits cardiac neural crest cell formation and morphogenesis in vivo. Dev Dyn. 2004;229:63-73.

Tang LS, Wlodarczyk BJ, Santillano DR, Miranda RC, Finnell RH. Development consequences of abnormal folate transport during murine heart morphogenesis. Birth Defects Res (Part A). 2004;70:449-458.

Castro R, Rivera P, Ravasco CME, Jakobs C, Blom HJ. 5,10-Methylenetetrahydrofolate reductase (MTHFR) 677C-T and 1298A-C mutations are associated with DNA hypomethylation. J Med Genet. 2004;41:454-458.

Weisberg I, Tran P, Christensen B, Sibanis S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;169-172.

Wilcken B, Bamforth F, Li Z. Geographical and ethnic variation of the 677C-T allele of 5, 10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003;40:619-625.

Meguid NA, Dardir AA, Khass M, Hossieny LE, Ezzat A, El-Awady MK. MTHFR genetic polymorphism as a risk factor in Egyptian mothers with Down syndrome children. Dis Markers. 2008;24(1):19-26.

Lupo P, Goldmuntz E, Mitchell L. Gene-Gene Interactions in the Folate Metabolic Pathway and the Risk of Conotruncal Heart Defects. Journal of Biomedicine and Biotechnology. 2009;2010:2012.

Macedonian Journal of Medical Sciences

The Journal of ID Design 2012/DOOEL Skopje, Republic of Macedonia on behalf of the Macedonian Donor Registry (MKDR), Skopje, Republic of Macedonia

Journal Information

CiteScore 2016: 0.16

SCImago Journal Rank (SJR) 2016: 0.136
Source Normalized Impact per Paper (SNIP) 2016: 0.141


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