Gene-environment interactions (GEI) play a critical role in the etiology of neural tube defect (NTDs). Definitive conclusions regarding the association amongst environmental exposures, genetic factors and NTD risk have been hampered by the rarity of this outcome (e.g., <1/1000 births in the US), and differences in exposure assessment between studies, as well as adherence to overly simplistic etiological models. It is now appreciated that the toxic effects of environmental exposures are mediated by chemicals that alter critical molecules, cells, and physiological processes inside the human body. In the proposed research project, we intend to explore the maternal and embryonic exposomes, i.e., the internal chemical environment in NTD etiology by measuring relevant analytes and biomarkers using biological samples and data collected through an established infrastructure in an area known for its high NTD rate (~10/1000 live birth), extremely heavy pollution, and poor nutritional status in Shanxi Province, China. To identify the human gene(s) that predispose the embryo to a neural tube closure failure during embryonic development has been challenging. Hypothesis-driven candidate gene studies were not successful in identifying common variants that may be predictive for NTD risk. Re-sequencing of a limited number of candidate genes has yielded few genetic variants, although none of these variants alone is a robust predictor of human NTDs. This leads us to postulate that NTDs, like other complex diseases, may arise from combinatorial effects of rare variants. We propose to use next-generation sequencing technologies to screen the complete protein coding regions on the genome (the exome). We anticipate the yield of a spectrum of gene variants including single nucleotide variations (SNV), insertion/deletion (Indel) and structural variations (SV) that contribute to the expression of NTDs. The results of our studies will help defining the relationships among maternal exposure, maternal nutrition, immune responses, maternal/embryonic genetics, and NTD risk. Moreover, the biological sample and data bank will allow us to continuously explore the genome and exposome of NTDs as our toolkit of investigation continues to mature. Exposure and genetic markers will be identified through our effort. The information derived from these studies could provide the foundation for population-based or targeted, exposure-based and genotype-based risk-assessment strategies.

Public Health Relevance

Neural tube defects (NTDs) are common, serious birth defects that affect approximately 324,000 births worldwide and 3,000 pregnancies in the United States annually. Both environmental exposures and genetic factors contribute to NTD etiology. We propose explore the exposome-an individual's internal chemical environment as well as genomic variants-using biological samples and data collected in an area known for its high NTD rate, heavy pollution, and poor nutrition status in Shanxi Province, China. We expect the information derived from these studies to provide the foundation for population-based or targeted, exposure-based and genotype-based risk-assessment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES021006-03
Application #
8694034
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Mcallister, Kimberly A
Project Start
2012-08-16
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Social Sciences
Type
Schools of Arts and Sciences
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
Ahsanuddin, Sofia; Afshinnekoo, Ebrahim; Gandara, Jorge et al. (2017) Assessment of REPLI-g Multiple Displacement Whole Genome Amplification (WGA) Techniques for Metagenomic Applications. J Biomol Tech 28:46-55
Afshinnekoo, Ebrahim; Chou, Chou; Alexander, Noah et al. (2017) Precision Metagenomics: Rapid Metagenomic Analyses for Infectious Disease Diagnostics and Public Health Surveillance. J Biomol Tech 28:40-45
Tighe, Scott; Afshinnekoo, Ebrahim; Rock, Tara M et al. (2017) Genomic Methods and Microbiological Technologies for Profiling Novel and Extreme Environments for the Extreme Microbiome Project (XMP). J Biomol Tech 28:31-39
McIntyre, Alexa B R; Ounit, Rachid; Afshinnekoo, Ebrahim et al. (2017) Comprehensive benchmarking and ensemble approaches for metagenomic classifiers. Genome Biol 18:182
Toriyama, Manami; Toriyama, Michinori; Wallingford, John B et al. (2017) Folate-dependent methylation of septins governs ciliogenesis during neural tube closure. FASEB J 31:3622-3635
Castro-Wallace, Sarah L; Chiu, Charles Y; John, Kristen K et al. (2017) Nanopore DNA Sequencing and Genome Assembly on the International Space Station. Sci Rep 7:18022
Li, Sheng; Garrett-Bakelman, Francine E; Chung, Stephen S et al. (2016) Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat Med 22:792-9
Yang, Na; Wang, Linlin; Finnell, Richard H et al. (2016) Levels of folate receptor autoantibodies in maternal and cord blood and risk of neural tube defects in a Chinese population. Birth Defects Res A Clin Mol Teratol 106:685-95
Afshinnekoo, Ebrahim; Mason, Christopher E (2016) Epigenetic therapy in a new era of medicine: creating and integrating molecular profiles of patients. Ann Transl Med 4:436
Gokhale, Nandan S; McIntyre, Alexa B R; McFadden, Michael J et al. (2016) N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection. Cell Host Microbe 20:654-665

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