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Mol Genet Metab. 2014 Jan;111(1):46-51. doi: 10.1016/j.ymgme.2013.11.004. Epub 2013 Nov 18.

Maternal-fetal metabolic gene-gene interactions and risk of neural tube defects.

Author information

1
Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.
2
Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX, USA.
3
Texas Department of State Health Services, Austin, TX, USA.
4
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
5
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
6
Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA.
7
Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA. Electronic address: hzhu@austin.utexas.edu.

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.

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

PMID:
24332798
PMCID:
PMC4394735
DOI:
10.1016/j.ymgme.2013.11.004
[Indexed for MEDLINE]
Free PMC Article
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