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Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways.

ABSTRACT: We investigated the association between conotruncal heart defects (CTDs) and maternal and fetal single nucleotide polymorphisms (SNPs) in 60 genes in the folate, homocysteine, and transsulfuration pathways. We also investigated whether periconceptional maternal folic acid supplementation modified associations between CTDs and SNPsParticipants were enrolled in the National Birth Defects Prevention Study between 1997 and 2008. DNA samples from 616 case-parental triads affected by CTDs and 1645 control-parental triads were genotyped using an Illumina® Golden Gate custom SNP panel. A hybrid design analysis, optimizing data from case and control trios, was used to identify maternal and fetal SNPs associated with CTDsAmong 921 SNPs, 17 maternal and 17 fetal SNPs had a Bayesian false-discovery probability of <0.8. Ten of the 17 maternal SNPs and 2 of the 17 fetal SNPs were found within the glutamate-cysteine ligase, catalytic subunit (GCLC) gene. Fetal SNPs with the lowest Bayesian false-discovery probability (rs2612101, rs2847607, rs2847326, rs2847324) were found within the thymidylate synthetase (TYMS) gene. Additional analyses indicated that the risk of CTDs associated with candidate SNPs was modified by periconceptional folic acid supplementation. Nineteen maternal and nine fetal SNPs had a Bayesian false-discovery probability <0.8 for gene-by-environment (G × E) interactions with maternal folic acid supplementation.These results support previous studies suggesting that maternal and fetal SNPs within folate, homocysteine, and transsulfuration pathways are associated with CTD risk. Maternal use of supplements containing folic acid may modify the impact of SNPs on the developing heart.

SUBMITTER: Hobbs CA

PROVIDER: S-EPMC4118819 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways.

Hobbs Charlotte A CA Cleves Mario A MA Macleod Stewart L SL Erickson Stephen W SW Tang Xinyu X Li Jingyun J Li Ming M Nick Todd T Malik Sadia S

Birth defects research. Part A, Clinical and molecular teratology 20140218 2

<h4>Background</h4>We investigated the association between conotruncal heart defects (CTDs) and maternal and fetal single nucleotide polymorphisms (SNPs) in 60 genes in the folate, homocysteine, and transsulfuration pathways. We also investigated whether periconceptional maternal folic acid supplementation modified associations between CTDs and SNPs<h4>Methods</h4>Participants were enrolled in the National Birth Defects Prevention Study between 1997 and 2008. DNA samples from 616 case-parental t ...[more]

PMID: 24535845

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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.

Project description:Folate, vitamin B12, and homocysteine concentrations during pregnancy are important factors for early development and may persistently influence kidney function in the offspring. We examined the associations of folate, vitamin B12, and homocysteine concentrations during pregnancy with kidney outcomes in school-aged children.Population-based prospective cohort study from fetal life onward.This study was performed among 4,226 pregnant women and their children.Folate, vitamin B12, and homocysteine blood concentrations measured in early pregnancy (median gestational age, 13.2 [IQR, 12.2-14.8] weeks) and at birth (cord blood).At the median age of 6.0 (IQR, 5.9-6.3) years, we measured combined kidney volume with ultrasound, estimated glomerular filtration rate based on creatinine (eGFRcr) and cystatin C (eGFRcys) concentrations, and microalbuminuria.We observed that higher maternal folate concentrations were associated with larger childhood combined kidney volume, whereas higher maternal vitamin B12 concentrations were associated with higher childhood eGFRcys (P for both <0.05). These associations were independent of homocysteine concentrations. Higher maternal homocysteine concentrations were associated with smaller combined kidney volume and lower childhood eGFRcys (P for both < 0.05). The association of maternal homocysteine concentrations with childhood eGFRcys was largely explained by combined kidney volume. Higher cord blood homocysteine concentrations were associated with larger combined kidney volume and lower eGFRcys (P for both < 0.05). Folate, vitamin B12, or homocysteine concentrations were not associated with microalbuminuria.Observational study, so causality cannot be established.Our findings suggest that folate, vitamin B12, and homocysteine concentrations during fetal life are associated with offspring kidney development. However, effect sizes are small. Further studies to replicate these findings and assess the causality and consequences for kidney health in later life are needed.

Dataset Information

Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways.

Publications

Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways.

Similar Datasets

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