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Association of MTHFR A1298C polymorphism with conotruncal heart disease

Published online by Cambridge University Press:  30 December 2014

Beyza D. Sayin Kocakap ,
Cihat Sanli ,
Feryal Cabuk ,
Murat Koc  and
Ali Kutsal
Beyza D. Sayin Kocakap*
Affiliation:
Faculty of Medicine, Department of Medical Genetics, Kirikkale University, Kirikkale, Turkey
Cihat Sanli
Affiliation:
Department of Pediatric Cardiology, Faculty of Medicine, Kirikkale University, Kirikkale, Turkey
Feryal Cabuk
Affiliation:
Faculty of Medicine, Department of Medical Genetics, Kirikkale University, Kirikkale, Turkey
Murat Koc
Affiliation:
Department of Cardiovascular Surgery, Ankara Dr Sami Ulus Obstetrics and Gynecology, Children’s Health and Diseases Training and Research Hospital, Ankara, Turkey
Ali Kutsal
Affiliation:
Department of Cardiovascular Surgery, Ankara Dr Sami Ulus Obstetrics and Gynecology, Children’s Health and Diseases Training and Research Hospital, Ankara, Turkey
*
Correspondence to: Dr D. B. Sayin Kocakap, Department of Medical Genetics, Faculty of Medicine, Kirikkale University, 71450 Yahsihan, Kirikkale, Turkey. Tel: +90-318-333-5000/5784; Fax: +90-318-225-2819; E-mail: dsayin@yahoo.com
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Abstract

Congenital heart diseases are common congenital anomalies with 1% prevalence worldwide and are associated with significant childhood morbidity and mortality. Among a wide range of aetiologically heterogeneous conditions, conotruncal anomalies account for approximately one-third of all congenital heart defects. The aetiology of conotruncal heart diseases is complex, with both environmental and genetic causes. Hyperhomocysteinaemia, which is often accompanied by the defects of folic acid metabolism, is known to cause conotruncal heart anomalies. In this study, we have evaluated three polymorphisms in the following two hyperhomocysteinaemia-related genes: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and nicotinamide N-methyl transferase (NNMT rs694539) in 79 children with conotruncal heart disease and 99 children without conotruncal heart disease. Genotype distribution of the MTHFR A1298C polymorphism showed a statistically significant difference between the two groups. In the case group, AC and CC genotypes were higher than the control group (p<0.05). We have found that MTHFR A1298C polymorphism is associated with conotruncal heart disease; C allele (p=0.028), AC (OR[95% CI]=2.48[1.24–4.95], p=0.010), CC (OR[95% CI]=3.01[1.16–7.83], p=0.023), and AC+CC (OR[95% CI]=2.60[1.36–4.99], p=0.004) genotypes are more frequent in the patient group. Genotype distributions of the MTHFR C677T and NNMT rs694539 polymorphisms were similar in the two groups when evaluated separately and also according to the dominant genetic model (p>0.05). Our results suggest that MTHFR 1298C allele is a risk factor for conotruncal heart disease.

Keywords

Conotruncal heart diseaseMTHFR geneC677T polymorphismA1298C polymorphismNNMT geners694539 polymorphism
Type
Original Articles
Information
Cardiology in the Young , Volume 25 , Issue 7 , October 2015 , pp. 1326 - 1331
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Copyright
© Cambridge University Press 2014 

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References

1. Agopian, AJ, Mitchell, LE, Glessner, J, et al. Genome-wide association study of maternal and inherited loci for conotruncal heart defects. PLoS One 2014; 9: e96057.CrossRefGoogle ScholarPubMed
2. 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: 536–545.CrossRefGoogle ScholarPubMed
3. Souto, JC, Blanco-Vaca, F, Soria, JM, et al. A genomewide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: results from the GAIT project. Am J Hum Genet 2005; 76: 925–933.CrossRefGoogle ScholarPubMed
4. Robien, K, Ulrich, CM. 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemiol 2003; 157: 571–582.CrossRefGoogle Scholar
5. Storti, S, Vittorini, S, Iascone, 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
6. 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
7. 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.CrossRefGoogle ScholarPubMed
8. Lu, W, Zhu, H, Wen, S, et al. Nicotinamide N-methyl transferase (NNMT) gene polymorphisms and risk for spina bifida. Birth Defects Res A Clin Mol Teratol 2008; 82: 670–675.CrossRefGoogle ScholarPubMed
9. Zhang, L, Miyaki, K, Araki, J, Nakayama, T, Muramatsu, M. The relation between nicotinamide N-methyltransferase gene polymorphism and plasma homocysteine concentration in healthy Japanese men. Thromb Res 2007; 121: 55–58.CrossRefGoogle ScholarPubMed
10. Shrubsole, MJ, Gao, YT, Cai, Q, et al. MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai breast cancer study. Cancer Epidemiol Biomarkers Prev 2004; 13: 190–196.CrossRefGoogle ScholarPubMed
11. 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
12. Kluijtmans, LA, Young, IS, Boreham, CA, et al. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults. Blood 2003; 101: 2483–2488.CrossRefGoogle ScholarPubMed
13. Gong, D, Gu, H, Zhang, Y, et al. Methylenetetrahydrofolate reductase C677T and reduced folate carrier 80 G>A polymorphisms are associated with an increased risk of conotruncal heart defects. Clin Chem Lab Med 2012; 50: 1455–1461.CrossRefGoogle ScholarPubMed
14. 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
15. Zidan, HE, Rezk, NA, Mohammed, D. MTHFR C677T and A1298C gene polymorphisms and their relation to homocysteine level in Egyptian children with congenital heart diseases. Gene 2013; 529: 119–124.CrossRefGoogle ScholarPubMed
16. Sahiner, UM, Alanay, Y, Alehan, D, Tuncbilek, E, Alikasifoglu, M. Methylene tetrahydrofolate reductase polymorphisms and homocysteine level in heart defects. Pediatr Int 2013; 56: 167–172.CrossRefGoogle Scholar
17. 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
18. 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
19. van Driel, LM, Smedts, HP, Helbing, WA, et al. Eight-fold increased risk for congenital heart defects in children carrying the nicotinamide N-methyltransferase polymorphism and exposed to medicines and low nicotinamide. Eur Heart J 2008; 29: 1424–1431.CrossRefGoogle ScholarPubMed
20. Lupo, PJ, Goldmuntz, E, Mitchell, LE. Gene-gene interactions in the folate metabolic pathway and the risk of conotruncal heart defects. J Biomed Biotechnol 2010; 20: 630940.Google Scholar
21. Kotby, A, Anwar, M, El-Masry, OA, Awady, M, El-Nashar, A, Meguid, NA. Genetic variants in the methylenetetrahydrofolate reductase gene in Egyptian children with conotruncal heart defects and their mothers. Maced J Med Sci 2012; 5: 78–84.CrossRefGoogle Scholar
22. Chao, CS, Wei, J, Huang, HW, Yang, SC. Correlation between methyltetrahydrofolate reductase (MTHFR) polymorphisms and isolated patent ductus arteriosus in Taiwan. Heart Lung Circ 2014; 23: 655–660.CrossRefGoogle ScholarPubMed
23. 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
24. Chen, L, Liu, L, Hong, K, Hu, J, Cheng, X. Three genetic polymorphisms of homocysteine-metabolizing enzymes and risk of coronary heart disease: a meta-analysis based on 23 case-control studies. DNA Cell Biol 2012; 31: 238–249.CrossRefGoogle ScholarPubMed
25. Christensen, KE, Zada, YF, Rohlicek, CV, et al. Risk of congenital heart defects is influenced by genetic variation in folate metabolism. Cardiol Young 2013; 23: 89–98.CrossRefGoogle ScholarPubMed
26. Pereira, AC, Xavier-Neto, J, Mesquita, SM, Mota, GF, Lopes, AA, Krieger, JE. Lack of evidence of association between MTHFR C677T polymorphism and congenital heart disease in a TDT study design. Int J Cardiol 2005; 105: 15–18.CrossRefGoogle Scholar
27. Wintner, S, Hafner, E, Stonek, F, Stuempflen, I, Metzenbauer, M, Philipp, K. Association of congenital cardiac defects and the C677T methylenetetrahydrofolate reductase polymorphism. Prenat Diagn 2007; 27: 704–708.CrossRefGoogle ScholarPubMed
28. García-Fragoso, L, García-García, I, Leavitt, G, Renta, J, Ayala, MA, Cadilla, CL. MTHFR polymorphisms in Puerto Rican children with isolated congenital heart disease and their mothers. Int J Genet Mol Biol 2010; 2: 43–47.Google ScholarPubMed