About this item:

733 Views | 150 Downloads

Author Notes:

Correspondence: Lora J. H. Bean, Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322; Email: ljbean@emory.edu

Acknowledgments: We thank all the personnel at each NDSP site, as well as the family recruiters and laboratory personnel, particularly Weiya He, Rupa Masse, Maneesha Yadav-Shah, Helen Smith, Tracie Rosser, and Charnan Koller for their continued commitment to this project.

Finally, we thank the many families nationwide whose participation has made this study possible.


Research Funding:

This work was supported by NIH R01 HD38979, NIH R01 HG003618, R01 HL083300, NIH P0 1HD24605, F32 HD046337, Children’s Healthcare of Atlanta Cardiac Research Committee, the American Heart Association, SeattleSNPs PGA (NHLBI U01 HL66682), and by the technical assistance of the General Clinical Research Center at Emory University (NIH/NCRR PHS grant M01 RR00039) and the Emory Biomarker Service Center.


  • Down syndrome
  • atrioventricular septal defect
  • folate
  • trisomy
  • congenital heart defects

Variation in Folate Pathway Genes Contributes to Risk of Congenital Heart Defects Among Individuals With Down Syndrome

Show all authors Show less authors


Journal Title:

Genetic Epidemiology


Volume 34, Number 6


, Pages 613-623

Type of Work:

Article | Post-print: After Peer Review


Cardiac abnormalities are one of the most common congenital defects observed in individuals with Down syndrome. Considerable research has implicated both folate deficiency and genetic variation in folate pathway genes with birth defects, including both congenital heart defects (CHD) and Down syndrome (DS). Here, we test variation in folate pathway genes for a role in the major DS-associated CHD atrioventricular septal defect (AVSD). In a group of 121 case families (mother, father, and proband with DS and AVSD) and 122 control families (mother, father, and proband with DS and no CHD), tag SNPs were genotyped in and around five folate pathway genes: 5,10-methylenetetrahyrdofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine β-synthase (CBS), and the reduced folate carrier (SLC19A1, RFC1). SLC19A1 was found to be associated with AVSD using a multilocus allele-sharing test. Individual SNP tests also showed nominally significant associations with odds ratios of between 1.34 and 3.78, depending on the SNP and genetic model. Interestingly, all marginally significant SNPs in SLC19A1 are in strong linkage disequilibrium (r2≥0.8) with the nonsynonymous coding SNP rs1051266 (c.80A>G), which has previously been associated with nonsyndromic cases of CHD. In addition to SLC19A1, the known functional polymorphism MTHFR c.1298A was over-transmitted to cases with AVSD (P = 0.05) and under-transmitted to controls (P = 0.02). We conclude, therefore, that disruption of the folate pathway contributes to the incidence of AVSD among individuals with DS.

Copyright information:

© 2010 Wiley-Liss, Inc.

Export to EndNote