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

• Type of Material: Article
• Authors: Adam E. Locke, Emory University; Kenneth J Dooley, Emory University; Stuart W. Tinker, Emory University; Soo Yeon Cheong, University of Pittsburgh; Eleanor Feingold, University of Pittsburgh; Emily Graves Allen, Emory University; Sallie Boineau Freeman, Emory University; Claudine P. Torfs, Public Health Institute; Clifford L. Cua, Nationwide Children’s Hospital; Michael Epstein, Emory University; Michael C. Wu, Harvard University; Xihong Lin, Harvard University; George Capone, Kennedy Krieger Institute; Stephanie Sherman, Emory University; Lora J. H. Bean, Emory University
• Language: English
• Date: 2010-09
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 Wiley-Liss, Inc.
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/gepi.20518/abstract
• Title of Journal or Parent Work: Genetic Epidemiology
• ISSN: 0741-0395
• Volume: 34
• Issue: 6
• Start Page: 613
• End Page: 623
• Grant/Funding Information: 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.
• Keywords: trisomy; folate; atrioventricular septal defect; Down syndrome; congenital heart defects
• Research Categories: Biology, Biostatistics; Biology, Genetics

Abstract

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.