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Pediatric Cardiology

, Volume 34, Issue 1, pp 46–51 | Cite as

Polymorphism 677C→T MTHFR Gene in Mexican Mothers of Children With Complex Congenital Heart Disease

  • Norma A. Balderrábano-Saucedo
  • Rocio Sánchez-Urbina
  • José A. Sierra-Ramírez
  • Normand García-Hernández
  • Adriana Sánchez-Boiso
  • Miguel Klunder-Klunder
  • Diego Arenas-Aranda
  • Gabriela Bravo-Hernández
  • Penelope Noriega-Zapata
  • Alfredo Vizcaíno-Alarcón
Original Article

Abstract

Congenital heart defects (CHD) are the third leading cause of death in children <1 year of age in Mexico where there is a high prevalence of the 677C→T polymorphism of the MTHFR gene. This is important because the homozygous 677T/T MTHFR gene and deficiency of folic acid (FA) intake have been associated with CHD. Our objective was to analyze the possible association between the genotype 677T/T of the MTHFR gene and supplementation of FA in Mexican women with the presence of complex CHD in their children. We analyzed genotypes of 31 mothers of children with complex CHD (group I) and 62 mothers of healthy children (group II) and investigated FA supplementation during pregnancy in both study groups. Allele frequencies in group I were 41.9 % for C and 58.1 % for T and 22.6 % for genotype frequencies CC, 38.7 % for CT, and 38.7 % for TT. Allele frequencies in group II were 63.7 % for C and 36.3 % for T and 38.7 % for genotype frequencies CC, 50 % for CT and 11.3 % for TT. Both populations are in Hardy–Weinberg equilibrium. Odds ratio for having a child with a complex CHD was 5.9, p = 0.008 (95 % CI 1.67; 20.63) for the TT genotype. FA supplementation at any time during pregnancy was 90.3 and 87.9 % in groups II and I respectively (p > 0.05). Association was found between the maternal genotype (677/TT MTHFR) with the presence of complex CHD in their offspring. No differences in FA supplementation during any stage were found between groups.

Keywords

MTHFR gene 677→T polymorphism Congenital heart disease Folic acid 

Notes

Acknowledgements

We are grateful to the authorities of the Research Directive of Hospital Infantil de México Federico Gómez for help in carrying out this study. This project was performed under the auspices of the Federal Fund program (2009) from the Ministry of Health, México.

References

  1. 1.
    Bentley TGK, Weinstein MC, Willett WC, Kuntz KM (2008) A cost-effectiveness analysis of folic acid fortification policy in the United States. Public Health Nutr 12:455–467PubMedCrossRefGoogle Scholar
  2. 2.
    Blom HJ (2000) Genetic determinants of hyperhomocysteinaemia: the roles of cystathionine beta-synthase and 5,10-methylenetetrahydrofolate reductase. Eur J Pediatr 159:S208–S212PubMedCrossRefGoogle Scholar
  3. 3.
    Botto LD, Yang Q (2000) 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies. A HuGE review. Am J Epidemiol 151:862–877PubMedCrossRefGoogle Scholar
  4. 4.
    Botto LD, Khoury MJ, Mulinare J, Erickson JD (1996) Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based, case-control study. Pediatrics 98:911–917PubMedGoogle Scholar
  5. 5.
    Busby A, Armstrong B, Dolk H, Armstrong N, Haeusler M, Berghold A et al (2005) Preventing neural tube defects in Europe: a missed opportunity. Reprod Toxicol 20:393–402PubMedCrossRefGoogle Scholar
  6. 6.
    Dalziel K, Segal L, Katz R (2010) Cost-effectiveness of mandatory folate fortification v. other options for the prevention of neural tube defects: Results from Australia and New Zealand. Public Health Nutr 13:566–578PubMedCrossRefGoogle Scholar
  7. 7.
    Davalos RIP, Olivares P, Castillo MT, Cantú JM, Ibarra B, Moran MC (2000) The C677T polymorphism of the methylenetetrahydrofolate reductase gene in Mexican mestizo neural-tube defect parents, control mestizo and native populations. Ann Genet 43:89–92PubMedCrossRefGoogle Scholar
  8. 8.
    De Wals P, Tairou F, Van Allen MI, Uh SH, Lowry RB, Sibbald B et al (2007) Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 2:135–142CrossRefGoogle Scholar
  9. 9.
    Dirección General de Información en Salud, Secretaria de Salud (2005) Mortalidad preescolar. Bol Med Hosp Infant Mex 62:69–82Google Scholar
  10. 10.
    Ferencz C, Neill CA, Boughman JA, Rubin JD, Brenner JI, Perry LW (1989) Congenital cardiovascular malformations associated with chromosome abnormalities: an epidemiologic study. J Pediatr 114:79–86PubMedCrossRefGoogle Scholar
  11. 11.
    Frosst P, Blom H, Milos R (1995) Identification of a candidate genetic risk factor for vascular disease: a common mutation in methylentetrahydrofolate reductase. Nat Genet 10:111–113PubMedCrossRefGoogle Scholar
  12. 12.
    García-Fragoso L, García-García I, Leavitt G, Renta J, Ayala MA, Cadilla CL (2010) MTHFR polymorphisms in Puerto Rican children with isolated congenital heart disease and their mothers. Int J Genet Mol Biol 2(3):43–47PubMedGoogle Scholar
  13. 13.
    González-Herrera L, García-Escalante G, Castillo-Zapata I, Canto-Herrera J, Pinto-Escalante D, Díaz-Rubio F et al (2002) Frequency of thermolabile variant defects in the State of Yucatan, México. Clin Genet 62:394–398PubMedCrossRefGoogle Scholar
  14. 14.
    Goyette P, Sumner JS, Milos R, Duncan AMV, Rosenblatt DS, Matthews RG et al (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7:195–200PubMedCrossRefGoogle Scholar
  15. 15.
    Guéant-Rodriguez RM, Guéant JL, Debard R, Thirion S, Hong LX, Bronowicki JP et al (2006) Prevalence of methylenetetrahydrofolate reductase 6777T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations. Am J Clin Nutr 83:701–707PubMedGoogle Scholar
  16. 16.
    Hoffman JIE, Chistianson R (1978) Congenital heart disease in a cohort of 19,502 births with long-term follow-up. Am J Cardiol 42:641–647PubMedCrossRefGoogle Scholar
  17. 17.
    Ionescu-Ittu R, Marelli AJ, Mackie AS, Pilote L (2009) Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec. Canada. Br Med J 338:b1673CrossRefGoogle Scholar
  18. 18.
    Junker R, Kotthoff S, Heintich V, Halimeh S, Kosch A, Koch HG et al (2001) Infant methylenetetrahydrofolate reductase 677TT genotype is a risk factor for congenital heart disease. Cardiovasc Res 51:251–254PubMedCrossRefGoogle Scholar
  19. 19.
    Kapusta L, Haagmans MLM, Steegers EAP, Cuypers MHM, Blom HJ, Eskes TKAB (1999) Congenital heart defects and maternal derangement of metabolism. J Pediatr 135:773–774PubMedCrossRefGoogle Scholar
  20. 20.
    Kueh K, Loffredo C, Lammer EJ, Iovannisci DM, Shaw GM (2010) Association of congenital cardiovascular malformations with 33 single nucleotide. Birth Defects Res A Clin Mol Teratol 88:101–110Google Scholar
  21. 21.
    Li D, Pickell L, Liu Y, Wu Q, Cohn JS, Rozen R (2005) Maternal methylenetetrahydrofolate reductase deficiency and low dietary folate lead to adverse reproductive outcomes and congenital heart defects in mice. Am J Clin Nutr 82:188–195PubMedGoogle Scholar
  22. 22.
    Loffredo CA (2000) Epidemiology of cardiovascular malformations: relevance and risk factors. Am J Med Genet 97:319–325PubMedCrossRefGoogle Scholar
  23. 23.
    Marín-García J (2004) Pediatric cardiology in the genomic era. Rev Esp Cardiol 57:331–346PubMedCrossRefGoogle Scholar
  24. 24.
    Marinho C, Alho I, Guerra A, Rego C, Areias J, Bicho M (2009) The methylenetetrahydrofolate reductase gene variant (C677T) as a susceptibility gene for tetralogy of Fallot. Rev Port Cardiol 28:809–812PubMedGoogle Scholar
  25. 25.
    McBride KL, Fernbach S, Menesses A, Molinari L, Quay E, Pignatelli R et al (2004) A family-based association study of congenital left-sided heart malformations and 5,10 methylenetetrahydrofolate reductase. Birth Defects Res A Clin Mol Teratol 70:825–830PubMedCrossRefGoogle Scholar
  26. 26.
    Mutchinick OM, López MA, Luna L, Waxman J, Babinsky VE (1999) RYVEMCE Collaborative Group. High prevalence of the thermolabile metylenetetrahydrofolate reductase variant in México: a country with a very high prevalence of neural tube defects. Mol Genet Metab 68:461–467PubMedCrossRefGoogle Scholar
  27. 27.
    Palacios-Macedo A (2008) Birth of a new program in Mexico City: The Kardias experience. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 11:7–10CrossRefGoogle Scholar
  28. 28.
    Pereira AC, Xavier-Neto J, Mesquita SM, Mota GFA, Lopes AA, Krieger JE (2005) Lack of evidence of association between MTHFR C677T polymorphism and congenital heart disease in a TDT study design. Int J Cardiol 105:15–18PubMedCrossRefGoogle Scholar
  29. 29.
    Richards AA, Garg V (2010) Genetics of congenital heart disease. Curr Cardiol Rev 6:91–97PubMedCrossRefGoogle Scholar
  30. 30.
    Rosenquist TH, Tatashak SA, Selhub J (1996) Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci USA 93:1527–15232CrossRefGoogle Scholar
  31. 31.
    Storti S, Vittorini S, Iascone MR, Sacchelli M, Collavoli A, Ripoli A et al (2003) Association between 5,10-methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and conotruncal heart defects. Clin Chem Lab Med 41:276–280PubMedCrossRefGoogle Scholar
  32. 32.
    van Beynum IM, Kapusta L, den Heijer M, Vermeulen SHHM, Kouwenberg M, Daniëls O et al (2006) Maternal MTHFR 677C > T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation. Eur Heart J 27:981–987PubMedCrossRefGoogle Scholar
  33. 33.
    van Beynum IM, den Heijer M, Blom HJ, Kapusta L (2007) The MTHFR 677C-T polymorphism and the risk of congenital heart defects: a literature review and meta-analysis. Qual J Med 100:743–753CrossRefGoogle Scholar
  34. 34.
    Verkleij-Hagoort AC, Verlinde M, Ursem N, Lindemans J, Helbing WA, Ottenkamp J et al (2006) Maternal hyperhomocysteinemia is a risk factor for congenital heart disease. BJOG 113:1412–1418PubMedCrossRefGoogle Scholar
  35. 35.
    Verkleij-Hagoort A, Bliek J, Sayed-Tabataebaei F, Ursem N, Steegers E, Steegers-Theunissen R (2007) Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: a meta-analysis. Am J Med Genet Part A 143A:952–960PubMedCrossRefGoogle Scholar
  36. 36.
    Wenstrom KD, Johanning GL, Johnston KE, Dubard M (2001) Association of the C677T methylenetetrahydrofolate reductase mutation and elevated homocysteine levels with congenital cardiac malformations. Am J Obstet Gynecol 184:806–817PubMedCrossRefGoogle Scholar
  37. 37.
    Wilcken B, Bamforth F, Li Z, Zhu H, Ritvanen A, Renlund M et al (2003) Geographical and ethnic variation of the 677C > T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): Findings from over 7,000 newborns from 16 areas worldwide. J Med Genet 40:619–625PubMedCrossRefGoogle Scholar
  38. 38.
    Zhu WL, Li Y, Yan L, Dao J, Li S (2006) Maternal and offspring MTHFR gene C677T polymorphism as predictors of congenital atrial septal defect and patent ductus arteriosus. Mol Hum Reprod 12:51–54PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Norma A. Balderrábano-Saucedo
    • 1
  • Rocio Sánchez-Urbina
    • 2
  • José A. Sierra-Ramírez
    • 3
    • 4
  • Normand García-Hernández
    • 5
  • Adriana Sánchez-Boiso
    • 6
  • Miguel Klunder-Klunder
    • 7
  • Diego Arenas-Aranda
    • 5
  • Gabriela Bravo-Hernández
    • 5
  • Penelope Noriega-Zapata
    • 3
    • 8
  • Alfredo Vizcaíno-Alarcón
    • 1
  1. 1.Departamento de CardiologíaHospital Infantil de México Federico Gómez (HIMFG)MexicoMexico
  2. 2.Laboratorio de Investigación en Biología del Desarrollo y Teratogénesis ExperimentalHIMFGMexicoMexico
  3. 3.Escuela Superior de MedicinaInstituto Politécnico NacionalMexicoMexico
  4. 4.Instituto Nacional de PerinatologíaMexicoMexico
  5. 5.Laboratorio de Genómica Funcional y Proteómica, Unidad de Investigación Médica en Genética HumanaHospital de Pediatría del Centro Médico Nacional Siglo XXI, IMSSMexicoMexico
  6. 6.Departamento de GenéticaHIMFGMexicoMexico
  7. 7.Departamento de Investigación en Salud ComunitariaHIMFGMexicoMexico
  8. 8.Clínica de Especialidades de la MujerSecretaria de la Defensa NacionalMexicoMexico

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