Hostname: page-component-cd9895bd7-lnqnp Total loading time: 0 Render date: 2024-12-27T08:10:12.088Z Has data issue: false hasContentIssue false
  • English
  • Français

MTHFR c.1793G>A polymorphism is associated with congenital cardiac disease in a Chinese population

Published online by Cambridge University Press:  07 April 2010

Jing Xu ,
Xiaohan Xu ,
Lei Xue ,
Xiang Liu ,
Haiyong Gu ,
Hailong Cao ,
Wanshan Qiu ,
Zhibin Hu ,
Hongbing Shen  and
Yijiang Chen
Jing Xu
Affiliation:
Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Peoples Republic of China
Xiaohan Xu
Affiliation:
Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Peoples Republic of China
Lei Xue
Affiliation:
Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Peoples Republic of China
Xiang Liu
Affiliation:
Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Peoples Republic of China
Haiyong Gu
Affiliation:
Department of Thoracic and Cardiovascular Surgery, Zhenjiang First People's Hospital, Peoples Republic of China
Hailong Cao
Affiliation:
Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Peoples Republic of China
Wanshan Qiu
Affiliation:
Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Nanjing Medical University, Peoples Republic of China
Zhibin Hu
Affiliation:
Department of Epidemiology and Biostatistics, Nanjing Medical University, Peoples Republic of China
Hongbing Shen
Affiliation:
Department of Epidemiology and Biostatistics, Nanjing Medical University, Peoples Republic of China
Yijiang Chen*
Affiliation:
Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Peoples Republic of China
*
Correspondence to: Dr Y. Chen, Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Peoples Republic of China, 210029. Tel: +86 25 85038012; Fax: +86 25 83719809; E-mail: YJChen@njmu.edu.cn
Get access Rights & Permissions [Opens in a new window]

Abstract

Objectives

To investigate whether genetic variants in methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD) genes are associated with risk of congenital cardiac disease.

Background

Accumulative evidence suggests that hyperhomocysteinaemia is associated with risk of congenital cardiac disease. Inherited polymorphisms in key folate metabolic pathway genes, MTHFR and MTHFD, may influence the efficiency of folate metabolism and plasma level of homocysteine.

Methods

A two-stage case–control study of congenital cardiac disease was conducted by genotyping MTHFR c.1793G>A and four other variants – MTHFR c.677C>T, c.1298A>C, and MTHFD c.1958G>A, c.401C>T – in a Chinese population consisting of 1033 congenital cardiac disease patients and 1067 non-congenital cardiac disease patients.

Results

The variant genotypes of MTHFR c.1793GA/AA were associated with a significantly decreased risk of congenital cardiac disease in two stages combined, with an adjusted odds ratio of 0.67 and a 95% confidence interval of 0.54–0.84 (p = 0.0004). In comparison with wild-type homozygote c.1793GG, the effect was significant in isolated perimembranous ventricular septal defect patients with an adjusted odds ratio of 0.60 and a 95% confidence interval of 0.43–0.83 (p = 0.0003).

Conclusion

These findings indicate that MTHFR c.1793G>A may have a role in susceptibility to sporadic congenital cardiac disease.

Keywords

Geneticshomocysteinemalformationvariant
Type
Original Articles
Information
Cardiology in the Young , Volume 20 , Issue 3 , June 2010 , pp. 318 - 326
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Hoffman, JI, Kaplan, S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890–1900.CrossRefGoogle ScholarPubMed
2. Goh, YI, Bollano, E, Einarson, TR, Koren, G. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can 2006; 28: 680–689.Google Scholar
3. Botto, LD, Mulinare, J. Occurrence of congenital heart defects in relation to maternal mulitivitamin use. Am J Epidemiol 2000; 151: 878–884.CrossRefGoogle ScholarPubMed
4. Jenkins, KJ, Correa, A, Feinstein, JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007; 115: 2995–3014.CrossRefGoogle Scholar
5. Boot, MJ, Steegers-Theunissen, RP, Poelmann, RE, van Iperen, L, Gittenberger-de Groot, AC. Cardiac outflow tract malformations in chick embryos exposed to homocysteine. Cardiovasc Res 2004; 64: 365–373.CrossRefGoogle ScholarPubMed
6. 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
7. 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
8. Hol, FA, van der Put, NM, Geurds, MP, et al. Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolatecyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects. Clin Genet 1998; 53: 119–125.CrossRefGoogle ScholarPubMed
9. Christensen, KE, Patel, H, Kuzmanov, U, Mejia, NR, Mackenzie, RE. Disruption of the mthfd1 gene reveals a monofunctional 10-formyltetrahydrofolate synthetase in mammalian mitochondria. J Biol Chem 2005; 280: 7597–7602.CrossRefGoogle ScholarPubMed
10. Parle-McDermott, A, Kirke, PN, Mills, JL, et al. Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population. Eur J Hum Genet 2006; 14: 768–772.CrossRefGoogle ScholarPubMed
11. Shi, M, Caprau, D, Romitti, P, Christensen, K, Murray, JC. 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 2003; 67: 545–549.CrossRefGoogle ScholarPubMed
12. Vizcaino, G, Diez-Ewald, M, Herrmann, FH, Schuster, G, Torres-Guerra, E, Arteaga-Vizcaino, M. Homocysteinemia and its relationship with the methylentetrahydrofolate reductase polymorphism in various ethnic groups from western Venezuela. Invest Clin 2005; 46: 347–355.Google ScholarPubMed
13. Weisberg, IS, Jacques, PF, Selhub, J, et al. The 1298A-->C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis 2001; 156: 409–415.CrossRefGoogle Scholar
14. Rady, PL, Szucs, S, Grady, J, et al. Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, 1793G>A. Am J Med Genet 2002; 107: 162–168.CrossRefGoogle Scholar
15. van Beynum, IM, den Heijer, M, Blom, HJ, Kapusta, L. The MTHFR 677C->T polymorphism and the risk of congenital heart defects: a literature review and meta-analysis. QJM 2007; 100: 743–753.CrossRefGoogle Scholar
16. Hobbs, CA, Cleves, MA, Melnyk, S, Zhao, W, James, SJ. Congenital heart defects and abnormal maternal biomarkers of methionine and homocysteine metabolism. Am J Clin Nutr 2005; 81: 147–153.CrossRefGoogle ScholarPubMed
17. 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
18. 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
19. Nurk, E, Tell, GS, Refsum, H, Ueland, PM, Vollset, SE. Associations between maternal methylenetetrahydrofolate reductase polymorphisms and adverse outcomes of pregnancy: the Hordaland Homocysteine study. Am J Med 2004; 117: 26–31.CrossRefGoogle ScholarPubMed
20. 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
21. Brody, LC, Conley, M, Cox, C, et al. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group. Am J Hum Genet 2002; 71: 1207–1215.CrossRefGoogle ScholarPubMed
22. Cheng, J, Zhu, WL, Dao, JJ, Li, SQ, Li, Y. Relationship between polymorphism of methylenetetrahydrofolate dehydrogenase and congenital heart defect. Biomed Environ Sci 2005; 18: 58–64.Google ScholarPubMed
23. Wang, L, Ke, Q, Chen, W, et al. Polymorphisms of MTHFD, plasma homocysteine levels, and risk of gastric cancer in a high-risk Chinese population. Clin Cancer Res 2007; 13: 2526–2532.CrossRefGoogle Scholar
24. Shen, H, Newmann, AS, Hu, Z, et al. Methylenetetrahydrofolate reductase polymorphisms/haplotypes and risk of gastric cancer: a case-control analysis in China. Oncol Rep 2005; 13: 355–360.Google ScholarPubMed
25. 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 Genet A 2005; 138: 21–26.CrossRefGoogle ScholarPubMed
26. van, B, Kapusta, L, Den, H, 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.Google Scholar
27. Pereira, AC, Xavier-Neto, J, Mesquita, SM, Mota, GFA, Lopes, AA, Krieger, JE. Lack of evidence of association between MTHFR 677C>T polymorphism and congenital heart disease in a TDT study design. Int J Cardiol 2005; 105: 15–18.CrossRefGoogle Scholar
28. Verkleij-Haqoort, A, Bliek, J, Sayed-Tabatabaei, F, Ursem, N, Steeqers, E, Steegers-Theunissen, R. Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: a meta-analysis. Am Med Genet A 2007; 143: 952–960.CrossRefGoogle Scholar