Associations between maternal genotypes and metabolites implicated in congenital heart defects.
BACKGROUND
The development of non-syndromic congenital heart defects (CHDs) involves a complex interplay of genetics, metabolism, and lifestyle. Previous studies have implicated maternal single nucleotide polymorphisms (SNPs) and altered metabolism in folate-related pathways as CHD risk factors.


OBJECTIVE
We sought to discover associations between maternal SNPs and metabolites involved in the homocysteine, folate, and transsulfuration pathways, and determine if these associations differ between CHD cases and controls.


METHODS
Genetic, metabolic, demographic, and lifestyle information was available for 335 mothers with CHD-affected pregnancies and 263 mothers with unaffected pregnancies. Analysis was conducted on 1160 SNPs, 13 plasma metabolites, and 2 metabolite ratios. A two-stage multiple linear regression was fitted to each combination of SNP and metabolite/ratio.


RESULTS
We identified 4 SNPs in the methionine adenosyltransferase II alpha (MAT2A) gene that were associated with methionine levels. Three SNPs in tRNA aspartic acid methyltransferase 1 (TRDMT1) gene were associated with total plasma folate levels. Glutamylcysteine (GluCys) levels were associated with multiple SNPs within the glutathione peroxidase 6 (GPX6) and O-6-methylguanine-DNA methyltransferase (MGMT) genes. The regression model revealed interactions between genotype and case-control status in the association of total plasma folate, total glutathione (GSH), and free GSH, to SNPs within the MGMT, 5,10-methenyltetrahydrofolate synthetase (MTHFS), and catalase (CAT) genes, respectively.


CONCLUSIONS
Our study provides further evidence that genetic variation within folate-related pathways accounts for inter-individual variability in key metabolites. We identified specific SNP-metabolite relationships that differed in mothers with CHD-affected pregnancies, compared to controls. Our results underscore the importance of multifactorial studies to define maternal CHD risk.
Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, 13 Children's Way, Slot 512, Little Rock, AR 72202, USA.
Shimul
S
Chowdhury
Charlotte A
CA
Hobbs
Stewart L
SL
MacLeod
Mario A
MA
Cleves
Stepan
S
Melnyk
S Jill
SJ
James
Ping
P
Hu
Stephen W
SW
Erickson
D000328:Adult; D058070:Asymptomatic Diseases; D019731:Carbon-Nitrogen Ligases / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005838:Genotype; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008019:Life Style; D008297:Male; D008715:Methionine / Q000378:metabolism; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D025521:Tumor Suppressor Proteins; D006710:Homocysteine; D005492:Folic Acid; D008715:Methionine; D002374:Catalase; D005979:Glutathione Peroxidase; D015254:DNA Modification Methylases; D004248:DNA (Cytosine-5-)-Methyltransferases; C112218:TRDMT1 protein, human; C515491:MGMT protein, human; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase; D019731:Carbon-Nitrogen Ligases; C021557:5,10-methenyltetrahydrofolate synthetase; D045643:DNA Repair Enzymes; D005978:Glutathione