Maternal-Fetal Metabolic Gene-Gene Interactions and Risk of Neural Tube Defects

Details

• Alternative Title:
  Mol Genet Metab
• Personal Author:
  Lupo, Philip J. ; Mitchell, Laura E. ; Canfield, Mark A. ; Shaw, Gary M. ; Olshan, Andrew F. ; Finnell, Richard H. ; Zhu, Huiping
• Corporate Authors:
  The National Birth Defects Prevention Study
• Description:
  Single-gene analyses indicate that maternal genes associated with metabolic conditions (e.g., obesity) may influence the risk of neural tube defects (NTDs). However, to our knowledge, there have been no assessments of maternal-fetal metabolic gene-gene interactions and NTDs. We investigated 23 single nucleotide polymorphisms among 7 maternal metabolic genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, and TCF7L2) and 2 fetal metabolic genes (SLC2A2 and UCP2). Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study for birth years 1999-2007. We used a 2-step approach to evaluate maternal-fetal gene-gene interactions. First, a case-only approach was applied to screen all potential maternal and fetal interactions (n = 76), as this design provides greater power in the assessment of gene-gene interactions compared to other approaches. Specifically, ordinal logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each maternal-fetal gene-gene interaction, assuming a log-additive model of inheritance. Due to the number of comparisons, we calculated a corrected p-value (q-value) using the false discovery rate. Second, we confirmed all statistically significant interactions (q < 0.05) using a log-linear approach among case-parent triads. In step 1, there were 5 maternal-fetal gene-gene interactions with q < 0.05. The "top hit" was an interaction between maternal ENPP1 rs1044498 and fetal SLC2A2 rs6785233 (interaction OR = 3.65, 95% CI: 2.32-5.74, p = 2.09×10(-8), q=0.001), which was confirmed in step 2 (p = 0.00004). Our findings suggest that maternal metabolic genes associated with hyperglycemia and insulin resistance and fetal metabolic genes involved in glucose homeostasis may interact to increase the risk of NTDs.
• Subjects:
  Adult Article Birth Defects Female Fetus Gene-Environment Interaction Gene-gene Interactions Genetic Predisposition To Disease Genetic Variation Glucose Humans Hypoglycemia Insulin Resistance Logistic Models Male Maternal Genetics Metabolic Genes Mothers Neural Tube Defects Obesity Polymorphism, Single Nucleotide Pre-gestational Diabetes Pregnancy Risk Factors Young Adult

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• Source:
  Mol Genet Metab. 111(1):46-51.
• Pubmed ID:
  24332798
• Pubmed Central ID:
  PMC4394735
• Document Type:
  Journal Article
• Funding:
  L40 DE023736/DE/NIDCR NIH HHS/United States ; P30 ES010126/ES/NIEHS NIH HHS/United States ; P30ES010126/ES/NIEHS NIH HHS/United States ; R01 NS 050249/NS/NINDS NIH HHS/United States ; R01 NS050249/NS/NINDS NIH HHS/United States ; R21 HD 058912/HD/NICHD NIH HHS/United States ; R21 HD058912/HD/NICHD NIH HHS/United States ; U01/DD000494/DD/NCBDD CDC HHS/United States ; U50/CCU925286/PHS HHS/United States
• Volume:
  111
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:58aab8791b08c1cd70884e01d102481927a41791c591e193004a9d8a565bc29c
• Download URL:
  https://stacks.cdc.gov/view/cdc/30382/cdc_30382_DS1.pdf
• File Type:
  [PDF - 254.80 KB ]