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Risk of congenital heart defects is influenced by genetic variation in folate metabolism

Published online by Cambridge University Press:  05 April 2012

Karen E. Christensen ,
Yassamin Feroz Zada ,
Charles V. Rohlicek ,
Gregor U. Andelfinger ,
Jacques L. Michaud ,
Jean-Luc Bigras ,
Andrea Richter ,
Marie-Pierre Dubé  and
Rima Rozen
Karen E. Christensen
Affiliation:
Departments of Pediatrics and Human Genetics, McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
Yassamin Feroz Zada
Affiliation:
Institut de Cardiologie de Montréal/StatGen, Montreal, Quebec, Canada
Charles V. Rohlicek
Affiliation:
Division of Cardiology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Gregor U. Andelfinger
Affiliation:
Department of Pediatrics, Cardiovascular Genetics, McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada Service of Pediatric Cardiology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Jacques L. Michaud
Affiliation:
Division of Medical Genetics, Research Center of CHU Sainte Justine, University of Montréal, Montreal, Quebec, Canada
Jean-Luc Bigras
Affiliation:
Service of Pediatric Cardiology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Andrea Richter
Affiliation:
Division of Medical Genetics, Research Center of CHU Sainte Justine, University of Montréal, Montreal, Quebec, Canada
Marie-Pierre Dubé
Affiliation:
Institut de Cardiologie de Montréal/StatGen, Montreal, Quebec, Canada
Rima Rozen*
Affiliation:
Departments of Pediatrics and Human Genetics, McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
*
Correspondence to: Dr Rima Rozen, PhD, FRSC, FCAHS, FCCMG, McGill University-Montreal Children's Hospital Research Institute, 4060 Ste Catherine West, Room 200, Montreal, Quebec, Canada H3Z 2Z3. Tel: +514 412 4358; Fax: +514 412 4331; E-mail: rima.rozen@mcgill.ca
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Abstract

Genetic disturbances in folate metabolism may increase risk for congenital heart defects. We examined the association of heart defects with four polymorphisms in folate-related genes (methylenetetrahydrofolate reductase (MTHFR) c.677C > T, MTHFR c.1298A > C, methionine synthase reductase (MTRR) c.66A > G, and reduced folate carrier (SLC19A1) c.80A > G) in a case–control study of children (156 patients, 69 controls) and mothers of children with heart defects (181 patients, 65 controls), born before folic acid fortification. MTRR c.66A > G in children modified odds ratios for overall heart defects, specifically ventricular septal defect and aortic valve stenosis (p-value below 0.05). The 66GG and AG genotypes were associated with decreased odds ratios for heart defects (0.42, 95% confidence interval (0.18–0.97) and 0.39 (0.18–0.84), respectively). This overall association was driven by decreased risk for ventricular septal defect for 66GG and AG (odds ratio 0.32 (0.11–0.91) and 0.25 (0.09–0.65)) and decreased odds ratio for aortic valve stenosis for 66AG (0.27 (0.09–0.79)). The association of ventricular septal defect and 66AG remained significant after correction for multiple testing (p = 0.0044, multiple testing threshold p = 0.0125). Maternal MTHFR 1298AC genotype was associated with increased odds ratio for aortic valve stenosis (2.90 (1.22–6.86), p = 0.0157), but this association did not meet the higher multiple testing threshold. No association between MTHFR c.677C > T or SLC19A1 c.80A > G and heart defect risk was found. The influence of folate-related polymorphisms may be specific to certain types of heart defects; larger cohorts of mothers and children with distinct sub-classes are required to adequately address risk.

Keywords

Ventricular septal defectgenetic polymorphismone-carbon folate metabolismmethylenetetrahydrofolate reductasemethionine synthase reductase
Type
Original Article
Information
Cardiology in the Young , Volume 23 , Issue 1 , February 2013 , pp. 89 - 98
Copyright
Copyright © Cambridge University Press 2012

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References

1. Hoffman, JI, Kaplan, S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890–1900.CrossRefGoogle ScholarPubMed
2. Boneva, RS, Botto, LD, Moore, CA, Yang, Q, Correa, A, Erickson, JD. Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979–1997. Circulation 2001; 103: 2376–2381.CrossRefGoogle ScholarPubMed
3. Baird, CD, Nelson, MM, Monie, IW, Evans, HM. Congenital cardiovascular anomalies induced by pteroylglutamic acid deficiency during gestation in the rat. Circ Res 1954; 2: 544–554.CrossRefGoogle ScholarPubMed
4. Bailey, LB, Berry, RJ. Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. Am J Clin Nutr 2005; 81(5): 1213S–1217S.CrossRefGoogle ScholarPubMed
5. van Beynum, IM, Kapusta, L, Bakker, MK, den Heijer, M, Blom, HJ, de Walle, HE. Protective effect of periconceptional folic acid supplements on the risk of congenital heart defects: a registry-based case-control study in the northern Netherlands. Eur Heart J 2010; 31: 464–471.CrossRefGoogle ScholarPubMed
6. Ionescu-Ittu, R, Marelli, AJ, Mackie, AS, Pilote, L. Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada. BMJ 2009; 338: b1673.CrossRefGoogle ScholarPubMed
7. 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 Genet A 2007; 143A: 952–960.CrossRefGoogle ScholarPubMed
8. Christensen, KE, Rozen, R. Genetic variation: effect on folate metabolism and health. In: Bailey LB (ed.). Folate in Health and Disease, second edition. CRC Press, Boca Raton, FL, 2010, pp 75–110.Google Scholar
9. Frosst, P, Blom, HJ, Milos, R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113.CrossRefGoogle ScholarPubMed
10. 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.Google ScholarPubMed
11. Jacques, PF, Bostom, AG, Williams, RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996; 93: 7–9.CrossRefGoogle ScholarPubMed
12. van der Put, NM, Steegers-Theunissen, RP, Frosst, P, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995; 346: 1070–1071.CrossRefGoogle ScholarPubMed
13. Fredriksen, A, Meyer, K, Ueland, PM, Vollset, SE, Grotmol, T, Schneede, J. Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism. Hum Mutat 2007; 28: 856–865.CrossRefGoogle ScholarPubMed
14. Yang, QH, Botto, LD, Gallagher, M, et al. Prevalence and effects of gene–gene and gene–nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank. Am J Clin Nutr 2008; 88: 232–246.CrossRefGoogle ScholarPubMed
15. Relton, CL, Wilding, CS, Pearce, MS, et al. Gene–gene interaction in folate-related genes and risk of neural tube defects in a UK population. J Med Genet 2004; 41: 256–260.CrossRefGoogle Scholar
16. Brown, NM, Pratt, VM, Buller, A, et al. Detection of 677CT/1298AC “double variant” chromosomes: implications for interpretation of MTHFR genotyping results. Genet Med 2005; 7: 278–282.CrossRefGoogle ScholarPubMed
17. Li, D, Pickell, L, Liu, Y, Wu, Q, Cohn, JS, Rozen, R. Maternal methylenetetrahydrofolate reductase deficiency and low dietary folate lead to adverse reproductive outcomes and congenital heart defects in mice. Am J Clin Nutr 2005; 82: 188–195.CrossRefGoogle ScholarPubMed
18. Yamada, K, Gravel, RA, Toraya, T, Matthews, RG. Human methionine synthase reductase is a molecular chaperone for human methionine synthase. Proc Natl Acad Sci U S A 2006; 103: 9476–9481.CrossRefGoogle ScholarPubMed
19. Gulati, S, Chen, Z, Brody, LC, Rosenblatt, DS, Banerjee, R. Defects in auxiliary redox proteins lead to functional methionine synthase deficiency. J Biol Chem 1997; 272: 19171–19175.CrossRefGoogle ScholarPubMed
20. Olteanu, H, Munson, T, Banerjee, R. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Biochemistry 2002; 41: 13378–13385.CrossRefGoogle ScholarPubMed
21. Wilson, A, Platt, R, Wu, Q, et al. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab 1999; 67: 317–323.CrossRefGoogle ScholarPubMed
22. van der Linden, IJ, den Heijer, M, Afman, LA, et al. The methionine synthase reductase 66A > G polymorphism is a maternal risk factor for spina bifida. J Mol Med 2006; 84: 1047–1054.CrossRefGoogle ScholarPubMed
23. O'Leary, VB, Mills, JL, Pangilinan, F, et al. Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Mol Genet Metab 2005; 85: 220–227.CrossRefGoogle ScholarPubMed
24. Elmore, CL, Wu, X, Leclerc, D, et al. Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase. Mol Genet Metab 2007; 91: 85–97.CrossRefGoogle ScholarPubMed
25. Deng, L, Elmore, CL, Lawrance, AK, Matthews, RG, Rozen, R. Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice. Mol Genet Metab 2008; 94: 336–342.CrossRefGoogle ScholarPubMed
26. Whetstine, JR, Gifford, AJ, Witt, T, et al. Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His27 and Arg27 Carriers. Clin Cancer Res 2001; 7: 3416–3422.Google ScholarPubMed
27. Baslund, B, Gregers, J, Nielsen, CH. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells. Rheumatology (Oxford) 2008; 47: 451–453.CrossRefGoogle Scholar
28. Pei, L, Zhu, H, Ren, A, et al. Reduced folate carrier gene is a risk factor for neural tube defects in a Chinese population. Birth Defects Res A Clin Mol Teratol 2005; 73: 430–433.CrossRefGoogle ScholarPubMed
29. Shaw, GM, Lammer, EJ, Zhu, H, Baker, MW, Neri, E, Finnell, RH. Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. Am J Med Genet 2002; 108: 1–6.CrossRefGoogle ScholarPubMed
30. Taparia, S, Gelineau-van Waes, J, Rosenquist, TH, Finnell, RH. Importance of folate–homocysteine homeostasis during early embryonic development. Clin Chem Lab Med 2007; 45: 1717–1727.CrossRefGoogle ScholarPubMed
31. Christensen, KE, Rohlicek, CV, Andelfinger, GU, et al. The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects. Hum Mutat 2009; 30: 212–220.CrossRefGoogle ScholarPubMed
32. van Beynum, IM, Kapusta, L, den Heijer, M, et al. Maternal MTHFR 677C > T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation. Eur Heart J 2006; 27: 981–987.CrossRefGoogle ScholarPubMed
33. van Driel, LM, Verkleij-Hagoort, AC, de Jonge, R, et al. Two MTHFR polymorphisms, maternal B-vitamin intake, and CHDs. Birth Defects Res A Clin Mol Teratol 2008; 82: 474–481.CrossRefGoogle ScholarPubMed
34. Hobbs, CA, Cleves, MA, Karim, MA, Zhao, W, MacLeod, SL. Maternal folate-related gene environment interactions and congenital heart defects. Obstet Gynecol 2010; 116: 316–322.CrossRefGoogle ScholarPubMed
35. Leclerc, D, Sibani, S, Rozen, R. Molecular Biology of methylenetetrahydrofolate reductase (MTHFR) and overview of mutation/polymorphisms. In: Ueland PM and Rozen R (eds). MTHFR Polymorphisms and Disease. Landes Bioscience, Georgetown, Texas, 2005, pp 1–20.Google Scholar
36. Ananth, CV, Elsasser, DA, Kinzler, WL, et al. Polymorphisms in methionine synthase reductase and betaine-homocysteine S-methyltransferase genes: risk of placental abruption. Mol Genet Metab 2007; 91: 104–110.CrossRefGoogle ScholarPubMed
37. Shaw, GM, Zhu, H, Lammer, EJ, Yang, W, Finnell, RH. Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial and conotruncal heart defects. Am J Epidemiol 2003; 158: 747–752.CrossRefGoogle ScholarPubMed
38. Westfall, PH, Young, SS. Resampling-based multiple testing. John Wiley & Sons, Inc., New York, 1993.Google Scholar
39. Guo, SW, Thompson, EA. Performing the exact test of Hardy–Weinberg proportion for multiple alleles. Biometrics 1992; 48: 361–372.CrossRefGoogle ScholarPubMed
40. Boot, MJ, Steegers-Theunissen, RP, Poelmann, RE, Van Iperen, L, Lindemans, J, Gittenberger-de Groot, AC. Folic acid and homocysteine affect neural crest and neuroepithelial cell outgrowth and differentiation in vitro. Dev Dyn 2003; 227: 301–308.CrossRefGoogle ScholarPubMed
41. Tang, LS, Wlodarczyk, BJ, Santillano, DR, Miranda, RC, Finnell, RH. Developmental consequences of abnormal folate transport during murine heart morphogenesis. Birth Defects Res A Clin Mol Teratol 2004; 70: 449–458.CrossRefGoogle ScholarPubMed
42. Czeizel, AE. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Am J Med Genet 1996; 62: 179–183.3.0.CO;2-L>CrossRefGoogle ScholarPubMed
43. Goldmuntz, E, Woyciechowski, S, Renstrom, D, Lupo, PJ, Mitchell, LE. Variants of folate metabolism genes and the risk of conotruncal cardiac defects. Circ Cardiovasc Genet 2008; 1: 126–132.CrossRefGoogle ScholarPubMed
44. Mitchell, LE, Long, J, Garbarini, J, Paluru, P, Goldmuntz, E. Variants of folate metabolism genes and risk of left-sided cardiac defects. Birth Defects Res A Clin Mol Teratol 2010; 88: 48–53.CrossRefGoogle ScholarPubMed
45. Shaw, GM, Lu, W, Zhu, H, et al. 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. BMC Med Genet 2009; 10: 49.CrossRefGoogle ScholarPubMed
46. van Beynum, IM, Kouwenberg, M, Kapusta, L, et al. MTRR 66A > G polymorphism in relation to congenital heart defects. Clin Chem Lab Med 2006; 44: 1317–1323.CrossRefGoogle ScholarPubMed
47. Verkleij-Hagoort, AC, van Driel, LM, Lindemans, J, et al. Genetic and lifestyle factors related to the periconception vitamin B12 status and congenital heart defects: a Dutch case–control study. Mol Genet Metab 2008; 94: 112–119.CrossRefGoogle Scholar
48. Olteanu, H, Wolthers, KR, Munro, AW, Scrutton, NS, Banerjee, R. Kinetic and thermodynamic characterization of the common polymorphic variants of human methionine synthase reductase. Biochemistry 2004; 43: 1988–1997.CrossRefGoogle ScholarPubMed
49. Junker, R, Kotthoff, S, Vielhaber, H, et al. Infant methylenetetrahydrofolate reductase 677TT genotype is a risk factor for congenital heart disease. Cardiovasc Res 2001; 51: 251–254.CrossRefGoogle ScholarPubMed
50. Lee, CN, Su, YN, Cheng, WF, et al. Association of the C677T methylenetetrahydrofolate reductase mutation with congenital heart diseases. Acta Obstet Gynecol Scand 2005; 84: 1134–1140.CrossRefGoogle ScholarPubMed
51. Shaw, GM, Iovannisci, DM, Yang, W, et al. Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes. Am J Med Genet A 2005; 138: 21–26.CrossRefGoogle ScholarPubMed
52. Storti, S, Vittorini, S, Lascone, MR, et al. Association between 5,10-methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and conotruncal heart defects. Clin Chem Lab Med 2003; 41: 276–280.CrossRefGoogle Scholar
53. Xu, J, Xu, X, Xue, L, et al. MTHFR c.1793G > A polymorphism is associated with congenital cardiac disease in a Chinese population. Cardiol Young 2010; 20: 318–326.CrossRefGoogle ScholarPubMed
54. Hobbs, CA, James, SJ, Parsian, A, et al. Congenital heart defects and genetic variants in the methylenetetrahydroflate reductase gene. J Med Genet 2006; 43: 162–166.CrossRefGoogle ScholarPubMed
55. McBride, KL, Fernbach, S, Menesses, A, et al. A family-based association study of congenital left-sided heart malformations and 5,10 methylenetetrahydrofolate reductase. Birth Defects Res A Clin Mol Teratol 2004; 70: 825–830.CrossRefGoogle Scholar
56. Pei, L, Zhu, H, Zhu, J, Ren, A, Finnell, RH, Li, Z. Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial defects and congenital heart defects in China. Ann Epidemiol 2006; 16: 352–356.CrossRefGoogle ScholarPubMed
57. Henderson, GI, Perez, T, Schenker, S, Mackins, J, Antony, AC. Maternal-to-fetal transfer of 5-methyltetrahydrofolate by the perfused human placental cotyledon: evidence for a concentrative role by placental folate receptors in fetal folate delivery. J Lab Clin Med 1995; 126: 184–203.Google ScholarPubMed
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