Gene-Gene Interactions in the Folate Metabolic Pathway and the Risk of Conotruncal Heart Defects

Philip J Lupo,Laura E Mitchell,Elizabeth Goldmuntz

doi:10.1155/2010/630940

Abstract

Conotruncal and related heart defects (CTRD) are common, complex malformations. Although there are few established risk factors, there is evidence that genetic variation in the folate metabolic pathway influences CTRD risk. This study was undertaken to assess the association between inherited (i.e., case) and maternal gene-gene interactions in this pathway and the risk of CTRD. Case-parent triads (n = 727), ascertained from the Children's Hospital of Philadelphia, were genotyped for ten functional variants of nine folate metabolic genes. Analyses of inherited genotypes were consistent with the previously reported association between MTHFR A1298C and CTRD (adjusted P = .02), but provided no evidence that CTRD was associated with inherited gene-gene interactions. Analyses of the maternal genotypes provided evidence of a MTHFR C677T/CBS 844ins68 interaction and CTRD risk (unadjusted P = .02). This association is consistent with the effects of this genotype combination on folate-homocysteine biochemistry but remains to be confirmed in independent study populations.

Highlights

Congenital heart defects (CHDs) are a heterogeneous group of malformations with a birth prevalence that approaches 1 per 100 [1]
Since CHDs develop during gestation, studies aimed at identifying genetic risk factors should consider the effects of both the maternal genotype and the inherited genotype [6]
Our results using Multifactor dimensionality reduction-phenomics (MDR-P) are consistent with these previous findings and provide evidence that this association is similar across the seven component Conotruncal and related heart defects (CTRD) phenotypes (TOF, DTGA, ventricular septal defect (VSD), double outlet right ventricle (DORV), arch anomaly (AAA), truncus arteriosus (TA), and interrupted aortic arch (IAA))

Summary

Introduction

Congenital heart defects (CHDs) are a heterogeneous group of malformations with a birth prevalence that approaches 1 per 100 [1]. In addition to being the most common type of structural birth defect, CHDs have a major impact on pediatric morbidity and mortality [2]. Relatively little is known about the specific risk factors for non-syndromic CHDs, and there are currently no strategies for reducing the public health impact of these conditions [3]. As CHDs are complex conditions, the identification of risk factors may require the simultaneous assessment of multiple factors (e.g., gene-gene interactions). Since CHDs are a heterogeneous group of conditions, analyses may need to be restricted to subgroups of phenotypes that are likely to be relatively homogeneous [7]

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Discussion

Conclusion