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Association of maternal folate use and reduced folate carrier gene polymorphisms with the risk of congenital heart disease in offspring

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Abstract

Although it is generally recognized that genetic and environmental factors are associated with the risk of congenital heart disease (CHD), the mechanism remains largely uncertain. This study aimed to investigate the association of maternal folate use, the time when folate use was started, and polymorphisms of the reduced folate carrier (RFC1) gene with the risk of CHD in offspring of Chinese descent, which can help provide new insight into the etiology of folate-related birth defects. A case-control study of 683 mothers of CHD patients and 740 mothers of healthy children was performed. The present study showed that mothers who did not use folate were at a significantly increased risk of CHD (OR=2.04; 95% CI: 1.42–2.93). When compared with those who started using folate prior to conception, mothers who started using folate from the first trimester of pregnancy (OR=1.90; 95% CI: 1.43–2.54) or from the second trimester of pregnancy (OR=8.92; 95% CI: 4.20–18.97) had a significantly higher risk of CHD. Maternal RFC1 gene polymorphisms at rs2236484 (AG vs AA: OR=1.79 [95% CI: 1.33–2.39]; GG vs AA: OR=1.64 [95% CI: 1.15–2.35]) and rs2330183 (CT vs CC: OR=1.54 [95% CI: 1.14–2.09]) were also significantly associated with CHD risk. Additionally, the risk of CHD was significantly decreased among mothers who had variant genotypes but used folate when compared with those who had variant genotypes and did not use folate.

Conclusion: In those of Chinese descent, maternal folate use and the time when use started are significantly associated with the risk of CHD in offspring. Furthermore, maternal folate supplementation may help to offset some of the risks of CHD in offspring due to maternal RFC1 genetic variants.

What is Known:

• Folate use could help prevent CHD, but the relationship between the time when folate use is started and CHD has not received sufficient attention.

• Studies have assessed the associations of folate metabolism-related genes with CHD, but genes involved in cellular transportation of folate, such as the RFC1 gene, have not garnered enough attention.

What is New:

• In those of Chinese descents, the time when folate use is started is significantly associated with the risk of CHD in offspring.

• Maternal RFC1 polymorphisms were significantly associated with the risk of CHD.

• Folate supplementation may help to offset some risks of CHD due to RFC1 genetic variants.

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Data availability

The authors affirm that all data and materials support their published claims and comply with field standards.

Abbreviations

CHD:

Congenital heart disease

RFC:

Reduced folate carrier

SNP:

Single nucleotide polymorphism

References

  1. Zhao L, Chen L, Yang T, Wang T, Zhang S, Chen L, Ye Z, Luo L, Qin J (2020) Birth prevalence of congenital heart disease in China, 1980-2019: a systematic review and meta-analysis of 617 studies. Eur J Epidemiol 35:631–642

    Article  Google Scholar 

  2. Viswanathan M, Treiman KA, Kish-Doto J, Middleton JC, Coker-Schwimmer EJ, Nicholson WK (2017) Folic acid supplementation for the prevention of neural tube defects: an updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 317:190–203

    Article  Google Scholar 

  3. Millacura N, Pardo R, Cifuentes L, Suazo J (2017) Effects of folic acid fortification on orofacial clefts prevalence: a meta-analysis. Public Health Nutr 20:2260–2268

    Article  Google Scholar 

  4. Qu Y, Lin S, Zhuang J et al (2020) First-trimester maternal folic acid supplementation reduced risks of severe and most congenital heart diseases in offspring: a large case-control study. J Am Heart Assoc 9:e015652

    Article  CAS  Google Scholar 

  5. Shi H, Yang S, Liu Y, Huang P, Lin N, Sun X, Yu R, Zhang Y, Qin Y, Wang L (2015) Study on environmental causes and SNPs of MTHFR, MS and CBS genes related to congenital heart disease. PLoS One 10:e0128646

    Article  Google Scholar 

  6. Li Y, Diao J, Li J, Luo L, Zhao L, Zhang S, Wang T, Chen L, Yang T, Chen L, Zhu P, Qin J (2021) Association of maternal dietary intakes and CBS gene polymorphisms with congenital heart disease in offspring. Int J Cardiol 322:121–128

    Article  Google Scholar 

  7. O'Leary VB, Pangilinan F, Cox C, Parle-McDermott A, Conley M, Molloy AM, Kirke PN, Mills JL, Brody LC, Scott JM (2006) Reduced folate carrier polymorphisms and neural tube defect risk. Mol Genet Metab 87:364–369

    Article  CAS  Google Scholar 

  8. Imani MM, Mozaffari HR, Sharifi R, Sadeghi M (2019) Polymorphism of reduced folate carrier 1 (A80G) and non-syndromic cleft lip/palate: a systematic review and meta-analysis. Arch Oral Biol 98:273–279

    Article  CAS  Google Scholar 

  9. Shaw GM, Zhu H, Lammer EJ, Yang W, Finnell RH (2003) Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial and conotruncal heart defects. Am J Epidemiol 2158:747–752

    Article  Google Scholar 

  10. Pei L, Zhu H, Zhu J, Ren A, Finnell RH, Li Z (2006) Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial defects and congenital heart defects in China. Ann Epidemiol 16:352–356

    Article  Google Scholar 

  11. Wang B, Liu M, Yan W, Mao J, Jiang D, Li H, Chen Y (2013) Association of SNPs in genes involved in folate metabolism with the risk of congenital heart disease. J Matern Fetal Neonatal Med 26:1768–1777

    Article  CAS  Google Scholar 

  12. Zhao M, Diao J, Huang P et al (2020) Association of maternal diabetes mellitus and polymorphisms of the NKX2.5 gene in children with congenital heart disease: a single centre-based case-control study. J Diabetes Res (2020):3854630

  13. Shaw GM, Lu W, Zhu H, Yang W, Briggs FB, Carmichael SL, Barcellos LF, Lammer EJ, Finnell RH (2009) 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. BMC Med Genet 10:49

    Article  Google Scholar 

  14. Wallace HM (2006) A model of gene-gene and gene-environment interactions and its implications for targeting environmental interventions by genotype. Theor Biol Med Model 3:35

    Article  Google Scholar 

  15. Deng C, Deng Y, **e L, Yu L, Liu L, Liu H, Dai L (2019) Genetic polymorphisms in MTR are associated with non-syndromic congenital heart disease from a family-based case-control study in the Chinese population. Sci Rep 9:5065

    Article  Google Scholar 

  16. Yi Y, Lindemann M, Colligs A, Snowball C (2011) Economic burden of neural tube defects and impact of prevention with folic acid: a literature review. Eur J Pediatr 170:1391–1400

    Article  Google Scholar 

  17. Werler MM, Hayes C, Louik C, Shapiro S, Mitchell AA (1999) Multivitamin supplementation and risk of birth defects. Am J Epidemiol 150:675–682

    Article  CAS  Google Scholar 

  18. Bulloch RE, Lovell AL, Jordan V, McCowan L, Thompson J, Wall CR (2018) Maternal folic acid supplementation for the prevention of preeclampsia: a systematic review and meta-analysis. Paediatr Perinat Epidemiol 32:346–357

    Article  Google Scholar 

  19. Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB (2016) Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. J Am Heart Assoc 5:e003768

    PubMed  PubMed Central  Google Scholar 

  20. Stover PJ (2009) One-carbon metabolism-genome interactions in folate-associated pathologies. J Nutr 139:2402–2405

    Article  CAS  Google Scholar 

  21. Leirgul E, Gildestad T, Nilsen RM, Fomina T, Brodwall K, Greve G, Vollset SE, Holmstrøm H, Tell GS, Øyen N (2015) Periconceptional folic acid supplementation and infant risk of congenital heart defects in Norway 1999-2009. Paediatr Perinat Epidemiol 29:391–400

    Article  Google Scholar 

  22. Gómez-Bueno S, Vázquez-López MA, García-Escobar I, Cabrera-Sevilla JE, Ortiz Pérez M, Bonillo-Perales A, Lendinez-Molinos F (2021, 2021) Status of folate in healthy children in Almeria. Eur J Pediatr. https://doi.org/10.1007/s00431-020-03902-2 Online ahead of print

  23. Dang S, Yan H, Zeng L, Wang Q, Li Q, **ao S, Fan X (2014) The status of vitamin B12 and folate among Chinese women: a population-based cross-sectional study in northwest China. PLoS One 9:e112586

    Article  Google Scholar 

  24. Ren A, Zhang L, Li Z, Hao L, Tian Y, Li Z (2006) Awareness and use of folic acid, and blood folate concentrations among pregnant women in northern China--an area with a high prevalence of neural tube defects. Reprod Toxicol 22:431–436

    Article  CAS  Google Scholar 

  25. Soghani B, Ebadifar A, Khorram KH, Kamali K, Hamedi R, Aghakhani MF (2017) The study of association between reduced folate carrier 1 (RFC1) polymorphism and non-syndromic cleft lip/palate in Iranian population. Bioimpacts 7:263–268

    Article  CAS  Google Scholar 

  26. Zhao JY, Qiao B, Duan WY, Gong XH, Peng QQ, Jiang SS, Lu CQ, Chen YJ, Shen HB, Huang GY, ** L, Wang HY (2014) Genetic variants reducing MTR gene expression increase the risk of congenital heart disease in Han Chinese populations. Eur Heart J 35:733–742

    Article  Google Scholar 

  27. Verkleij-Hagoort AC, Verlinde M, Ursem NT et al (2006) Maternal hyperhomocysteinaemia is a risk factor for congenital heart disease. BJOG 113:1412–1418

    Article  CAS  Google Scholar 

  28. Farkas SA, Böttiger AK, Isaksson HS, Finnell RH, Ren A, Nilsson TK (2013) Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia. Epigenetics 8:303–316

    Article  CAS  Google Scholar 

  29. Eudy JD, Spiegelstein O, Barber RC, Wlodarczyk BJ, Talbot J, Finnell RH (2000) Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes. Mol Genet Metab 71:581–590

    Article  CAS  Google Scholar 

  30. Chango A, Emery-Fillon N, de Courcy GP, Lambert D, Pfister M, Rosenblatt DS, Nicolas JP (2000) A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab 70:310–315

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank all pediatricians and parents who participated in the study.

Code availability

The authors affirm that software applications or custom codes that support their published claims comply with field standards.

Funding

Funding for this study was provided by the National Natural Science Foundation of China (grant number: 82073653, 81803313, and 81974019), the China Postdoctoral Science Foundation (grant number: 2020M682644), the Science and Technology Planning Project of Guangdong Province (2020A1414010152), the Hunan Provincial Science and Technology Talent Support Project (grant number: 2020TJ-N07), the Natural Science Foundation of Hunan Province (grant number: 2018JJ2551), the Hunan Provincial Key Research and Development Program (grant number: 2018SK2063 and 2018SK2062), the Open Project from NHC Key Laboratory of Birth Defect for Research and Prevention (grant number: KF2020006), the National Key Research and Development Program of China (grant number: 2018YFA0108700 and 2017YFA0105602), and the Fundamental Research Funds for the Central Universities of Central South University (grant number: 2020zzts238).

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Authors and Affiliations

  1. Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou, 510100, Guangdong, China

    Jiabi Qin & ** Zhu

  2. Department of Epidemiology and Health Statistics, **angya School of Public Health, Central South University, Changsha, Hunan, China

    Jiabi Qin, **qi Li, Fang Li, Mengting Sun, **gyi Diao, Senmao Zhang, Liu Luo, Yihuan Li & Letao Chen

  3. NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China

    Jiabi Qin & Tingting Wang

  4. Hunan Children’s Hospital, 86 Ziyuan Road, Changsha, 410007, Hunan, China

    Peng Huang

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  1. Jiabi Qin
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Contributions

Prof. P. Z. and Prof. P. H. conceptualized the study, coordinated all study phases, and approved the final manuscript as submitted. Dr. J. B. Q. designed the study, carried out the statistical analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. J. Q. L. and Dr. F. L. wrote the paper and approved the final manuscript as submitted. Dr. M. T. S. and Dr. T. T. W. were involved in the design of the study and approved the final manuscript as submitted. Dr. J. Y. D., Dr. S. M. Z., and Dr. L. L. designed the data collection tools, coordinated and supervised data collection, and approved the final manuscript as submitted. Dr. Y. H. L. and Dr. L. T. C. coordinated and supervised data collection, critically reviewed and revised the manuscript, and approved the final manuscript as submitted.

Corresponding authors

Correspondence to Peng Huang or ** Zhu.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Written informed consent was obtained from the parents.

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The authors declare no competing interests.

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Communicated by Gregorio Paolo Milani

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Qin, J., Li, J., Li, F. et al. Association of maternal folate use and reduced folate carrier gene polymorphisms with the risk of congenital heart disease in offspring. Eur J Pediatr 180, 3181–3190 (2021). https://doi.org/10.1007/s00431-021-04087-y

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