Associations between maternal genotypes and metabolites implicated in congenital heart defects

Details

• Alternative Title:
  Mol Genet Metab
• Personal Author:
  Chowdhury, Shimul ; Hobbs, Charlotte A. ; MacLeod, Stewart L. ; Cleves, Mario A. ; Melnyk, Stepan ; James, S. Jill ; Hu, Ping ; Erickson, Stephen W.
• Description:
  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. ; Design ; 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.
• Subjects:
  • Article
  • Adult
  • Asymptomatic Diseases
  • Carbon-Nitrogen Ligases
  • Case-Control Studies
  • Catalase
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Modification Methylases
  • DNA Repair Enzymes
  • Female
  More +
• Source:
  Mol Genet Metab. 2012; 107(3):596-604
• Pubmed ID:
  23059056
• Pubmed Central ID:
  PMC3523122
• Document Type:
  Journal Article
• Funding:
  U01 DD000491/DD/NCBDD CDC HHS/United States ; 2R01HD039054-11A1/HD/NICHD NIH HHS/United States ; 5U01 DD000491-04/DD/NCBDD CDC HHS/United States ; R01 HD039054/HD/NICHD NIH HHS/United States ; U50 DD613236/DD/NCBDD CDC HHS/United States
• Volume:
  107
• Issue:
  3
• Download URL:
  https://stacks.cdc.gov/view/cdc/33495/cdc_33495_DS1.pdf
• File Type:
  [PDF - 1.53 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:385813e4d2be6ccd8b05c42071376cb4a5c1bf323a5787fdd648df1097a5e201