Journal article
Gene-by-Environment Interactions Involving Maternal Exposures with Orofacial Cleft Risk in Filipinos
Genes, Vol.16(8), p.876
07/25/2025
DOI: 10.3390/genes16080876
PMCID: PMC12386167
PMID: 40869924
Abstract
Background/Objectives: Maternal exposures are known to influence the risk of isolated cleft lip with or without cleft palate (CL/P)-a common and highly heritable birth defect with a multifactorial etiology. Methods: To identify new risk loci, we conducted a genome-wide gene-environment interaction (GEI) analysis of CL/P with maternal smoking and vitamin use in Filipinos (Ncases = 540, Ncontrols = 260). Since GEI analyses are typically low in power and the results can be difficult to interpret, we applied multiple testing frameworks to evaluate potential GEI effects: a one degree-of-freedom (1df) GxE test, the 3df joint test, and the two-step EDGE approach. Results: While no genome-wide significant interactions were detected, we identified 11 suggestive GEIs with smoking and 24 with vitamin use. Several implicated loci contain biologically plausible genes. Notable interactions with smoking include loci near FEZF1, TWIST2, and NET1. While FEZF1 is involved in early neuronal development, TWIST2 and NET1 regulate epithelial-mesenchymal transition, which is required for proper lip and palate fusion. Interactions with vitamins encompass CECR2-a chromatin remodeling protein required for neural tube closure-and FURIN, a critical protease during early embryogenesis that activates various growth factors and extracellular matrix proteins. The activity of both proteins is influenced by folic acid. Conclusions: Our findings highlight the critical role of maternal exposures in identifying genes associated with structural birth defects such as CL/P and provide new paths to explore for CL/P genetics.
Details
- Title: Subtitle
- Gene-by-Environment Interactions Involving Maternal Exposures with Orofacial Cleft Risk in Filipinos
- Creators
- Zeynep Erdogan-Yildirim - University of PittsburghJenna C. Carlson - University of PittsburghNandita Mukhopadhyay - University of PittsburghElizabeth J. Leslie-Clarkson - Emory UniversityCarmencita D. Padilla - University of the Philippines ManilaJeffrey C. Murray - University of IowaTerri H. Beaty - Johns Hopkins UniversitySeth M. Weinberg - University of PittsburghMary L. Marazita - University of PittsburghJohn R. Shaffer - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Genes, Vol.16(8), p.876
- DOI
- 10.3390/genes16080876
- PMID
- 40869924
- PMCID
- PMC12386167
- NLM abbreviation
- Genes (Basel)
- ISSN
- 2073-4425
- eISSN
- 2073-4425
- Publisher
- Mdpi
- Number of pages
- 18
- Grant note
- S10OD028483 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA SCR_022735 / University of Pittsburgh Center for Research Computing (CRC) T90-DE030853 / National Institute of Dental & Craniofacial Research of the National Institutes of Health National Institute of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 07/25/2025
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985035883502771
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