Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome

Adam E. Locke, Kenneth J. Dooley, Stuart W. Tinker, Soo Yeon Cheong, Eleanor Feingold, Emily G. Allen, Sallie B. Freeman, Claudine P. Torfs, Clifford L. Cua, Michael P. Epstein, Michael C. Wu, Xihong Lin, George Capone, Stephanie L. Sherman, Lora J.H. Bean

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56 Scopus citations


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 b-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.80 > 4G), which has previously been associated with nonsyndromic cases of CHD. In addition to SLC19A1, the known functional polymorphism MTHFR c.1298A was overtransmitted 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.

Original languageEnglish (US)
Pages (from-to)613-623
Number of pages11
JournalGenetic epidemiology
Issue number6
StatePublished - Sep 2010


  • Atrioventricular septal defect
  • Congenital heart defects
  • Down syndrome
  • Folate
  • Trisomy

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)


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