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

• Published in: Genetic epidemiology Vol. 34; no. 6; pp. 613 - 623
• Main Authors: Locke, Adam E., Dooley, Kenneth J., Tinker, Stuart W., Cheong, Soo Yeon, Feingold, Eleanor, Allen, Emily G., Freeman, Sallie B., Torfs, Claudine P., Cua, Clifford L., Epstein, Michael P., Wu, Michael C., Lin, Xihong, Capone, George, Sherman, Stephanie L., Bean, Lora J.H.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2010
• Subjects: African Continental Ancestry Group - genetics; African Continental Ancestry Group - statistics & numerical data; atrioventricular septal defect; Case-Control Studies; Causality; Chromosomes, Human, Pair 21 - genetics; Comorbidity; congenital heart defects; Down syndrome; Down Syndrome - epidemiology; Down Syndrome - genetics; European Continental Ancestry Group - genetics; European Continental Ancestry Group - statistics & numerical data; folate; Folic Acid - genetics; Genetic Association Studies; Genetic Variation; Genotype; Heart Defects, Congenital - epidemiology; Heart Defects, Congenital - genetics; Heart Septal Defects - epidemiology; Heart Septal Defects - genetics; Humans; Incidence; Polymorphism, Single Nucleotide; trisomy
• ISSN: 0741-0395; 1098-2272; 1098-2272
• DOI: 10.1002/gepi.20518

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. Genet. Epidemiol. 34: 603–612, 2010. © 2010 Wiley‐Liss, Inc.