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Variants of folate metabolism genes and the risk of conotruncal cardiac defects.

ABSTRACT: Although congenital heart defects (CHD) are the most common and serious group of birth defects, relatively little is known about the causes of these conditions and there are no established prevention strategies. There is evidence suggesting that the risk of CHD in general, and conotruncal and ventricular septal defects in particular, may be related to maternal folate status as well as genetic variants in folate-related genes. However, efforts to establish the relationships between these factors and CHD risk have been hampered by a number of factors including small study sample sizes and phenotypic heterogeneity.The present study examined the relationships between variation in 9 folate-related genes and a subset of CHD phenotypes (ie, conotruncal defects, perimembranous and malalignment type ventricular septal defects, and isolated aortic arch anomalies) in a cohort of >700 case-parent triads. Further, both maternal and embryonic genetic effects were considered. Analyses of the study data confirmed an earlier reported association between embryonic genotype for MTHFR A1298C and disease risk (unadjusted P=0.002).These results represent the most comprehensive and powerful analysis of the relationship between CHD and folate-related genes reported to date, and provide additional evidence that, similar to neural tube defects, this subset of CHD is folate related.

SUBMITTER: Goldmuntz E

PROVIDER: S-EPMC3035562 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Variants of folate metabolism genes and the risk of conotruncal cardiac defects.

Goldmuntz Elizabeth E Woyciechowski Stacy S Renstrom Daniel D Lupo Philip J PJ Mitchell Laura E LE

Circulation. Cardiovascular genetics 20081209 2

<h4>Background</h4>Although congenital heart defects (CHD) are the most common and serious group of birth defects, relatively little is known about the causes of these conditions and there are no established prevention strategies. There is evidence suggesting that the risk of CHD in general, and conotruncal and ventricular septal defects in particular, may be related to maternal folate status as well as genetic variants in folate-related genes. However, efforts to establish the relationships bet ...[more]

PMID: 20031554

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Project description:Folic acid taken in early pregnancy reduces risks for delivering offspring with several congenital anomalies. The mechanism by which folic acid reduces risk is unknown. Investigations into genetic variation that influences transport and metabolism of folate will help fill this data gap. We focused on 118 SNPs involved in folate transport and metabolism.Using data from a California population-based registry, we investigated whether risks of spina bifida or conotruncal heart defects were influenced by 118 single nucleotide polymorphisms (SNPs) associated with the complex folate pathway. This case-control study included 259 infants with spina bifida and a random sample of 359 nonmalformed control infants born during 1983-86 or 1994-95. It also included 214 infants with conotruncal heart defects born during 1983-86. Infant genotyping was performed blinded to case or control status using a designed SNPlex assay. We examined single SNP effects for each of the 118 SNPs, as well as haplotypes, for each of the two outcomes.Few odds ratios (ORs) revealed sizable departures from 1.0. With respect to spina bifida, we observed ORs with 95% confidence intervals that did not include 1.0 for the following SNPs (heterozygous or homozygous) relative to the reference genotype: BHMT (rs3733890) OR = 1.8 (1.1-3.1), CBS (rs2851391) OR = 2.0 (1.2-3.1); CBS (rs234713) OR = 2.9 (1.3-6.7); MTHFD1 (rs2236224) OR = 1.7 (1.1-2.7); MTHFD1 (hcv11462908) OR = 0.2 (0-0.9); MTHFD2 (rs702465) OR = 0.6 (0.4-0.9); MTHFD2 (rs7571842) OR = 0.6 (0.4-0.9); MTHFR (rs1801133) OR = 2.0 (1.2-3.1); MTRR (rs162036) OR = 3.0 (1.5-5.9); MTRR (rs10380) OR = 3.4 (1.6-7.1); MTRR (rs1801394) OR = 0.7 (0.5-0.9); MTRR (rs9332) OR = 2.7 (1.3-5.3); TYMS (rs2847149) OR = 2.2 (1.4-3.5); TYMS (rs1001761) OR = 2.4 (1.5-3.8); and TYMS (rs502396) OR = 2.1 (1.3-3.3). However, multiple SNPs observed for a given gene showed evidence of linkage disequilibrium indicating that the observed SNPs were not individually contributing to risk. We did not observe any ORs with confidence intervals that did not include 1.0 for any of the studied SNPs with conotruncal heart defects. Haplotype reconstruction showed statistical evidence of nonrandom associations with TYMS, MTHFR, BHMT and MTR for spina bifida.Our observations do not implicate a particular folate transport or metabolism gene to be strongly associated with risks for spina bifida or conotruncal defects.

Dataset Information

Variants of folate metabolism genes and the risk of conotruncal cardiac defects.

Publications

Variants of folate metabolism genes and the risk of conotruncal cardiac defects.

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