title: Maternal-fetal metabolic gene-gene interactions and risk of neural tube defects.
abstract: 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.
authors: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.
authors: Philip J
authors: PJ
authors: Lupo
authors: Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX, USA.
authors: Laura E
authors: LE
authors: Mitchell
authors: Texas Department of State Health Services, Austin, TX, USA.
authors: Mark A
authors: MA
authors: Canfield
authors: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors: Gary M
authors: GM
authors: Shaw
authors: Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
authors: Andrew F
authors: AF
authors: Olshan
authors: Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA.
authors: Richard H
authors: RH
authors: Finnell
authors: Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA. Electronic address: hzhu@austin.utexas.edu.
authors: Huiping
authors: H
authors: Zhu
mesh_terms: D000328:Adult; D005260:Female; D005333:Fetus; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D009035:Mothers; D009436:Neural Tube Defects / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012307:Risk Factors; D055815:Young Adult
chemical_list: D005947:Glucose
keywords: BMI; Birth defects; CATI; CI; FDR; GWAS; Gene–gene interactions; LRT; Maternal genetics; Metabolic genes; NBDPS; NTDs; National Birth Defects Prevention Study; Neural tube defects; RR; SNP; body mass index; computer assisted telephone interview; confidence interval; false discovery rate; genome-wide association study; likelihood ratio test; neural tube defects; risk ratio; single nucleotide polymorphism