To better understand the biologic mechanisms underpinning gene-environment interaction, core to NIDCR’s mission.
The etiology of most dental, oral, and craniofacial diseases and conditions involves the interplay of genetic and environment factors. Epidemiologic and statistical methods provide evidence of a role for specific environmental risk factors on disease risk or expression; the effects of these factors may vary based on genotype. By extension, some genetic variants may be important only in the presence of specific environmental factors. However, little is known about how environmental factors work at a biologic level, such as affecting gene expression through epigenetic changes. Model organisms, such as zebrafish or mice, and in vitro studies may be used to understand the molecular details of gene-environment interactions identified in human epidemiologic studies.
Through this initiative, we encourage research to identify pathways affected by environmental exposures by taking advantage of recent scientific advances including new technologies, such as CRISPR/Cas, that facilitate the introduction of human genetic variants into the genomes of model organisms, as well as progress in constructing gene regulatory networks.
Examples of research areas encouraged under this concept include:
- Using animal models or in vitro approaches to study craniofacial birth defects, genetics or epigenetics, and maternal exposures identified in humans such as
- Exposure through medical conditions or medical treatment (e.g., thyroxine levels, exposure to retinoids)
- Exposure through behaviors (e.g., alcohol use, smoking, other substance use, diet and other nutrients)
- Exogenous exposures (e.g., pollutant levels)
- Using animal models or in vitro approaches to study the interplay between candidate genes identified in human research and fluoride exposure on dental caries development
- Using animal models or in vitro approaches to study the interplay between candidate genes identified in human research and composition of the oral microbiome on oral health
- Developing new animal or organoid models that will inform mechanisms of gene-environment interaction
This concept is not intended to include epidemiologic or other human studies of gene-environment interaction. Genetic epidemiologic research may be supported under PA-14-347 [Building Genetics and Genomic Knowledge about Dental, Oral, and Craniofacial Diseases and Disorders (R01)] or PAR-17-154 [NIDCR Prospective Observational or Biomarker Clinical Validation Study Cooperative Agreement (U01)].
Current Portfolio Overview
Current research includes a few projects related to mechanisms of gene-environment interaction in craniofacial development:
- 5R01DE024584-04; Epigenetic Control of Human Neural Crest Formation: Impact on Neurocristopathies; Bajpai, Ruchi; University of Southern California
- 5R01DE020884-07; Causes of Variability in Craniofacial Disease; Eberhart, Johann K; University of Texas, Austin
- 5U01DE024430-04; Epigenetic landscapes and regulatory divergence of human craniofacial traits; Wysocka, Joanna (Contact); Selleri, Licia; Stanford University
- 5U01DE024427-04; Genomic, Transgenic and Knockout Resources for Craniofacial Enhancer Studies; Visel, Axel; University of Calif-Lawrence Berkeley Lab
Individuals and Groups Whose Input was Solicited for This Initiative
Input from the research community on mechanisms of gene-environment interaction in cleft lip/cleft palate was obtained through a workshop held September 6-7, 2016; the planning committee included staff from the CDC, NIAAA, NICHD, NIDA, and NIDCR. Public comments specific for this concept were solicited on NIDCR website from August 4-September 5, 2017.
Alignment with Institute Goals and Strategic Plan
This initiative is aligned with the NIDCR Strategic Plan 2014-2019, Goals 1 and 2, “Support the best science to improve dental, oral, and craniofacial health.” Specifically, the initiative aligns with objectives 1-1 and 1-2 that “Enable basic research to advance knowledge of dental, oral, and craniofacial health” and “Promote development and use of comprehensive, interoperable databases and informatics resources to advance prevention, diagnosis, and treatment of dental, oral, and craniofacial diseases.”
- Durham EL, Howie RN, Black L, Bennfors G, Parsons TE, Elsalanty M, Yu JC, Weinberg SM, Cray JJ Jr. Effects of thyroxine exposure on the Twist 1 +/- phenotype: A test of gene-environment interaction modeling for craniosynostosis. Birth Defects Res A Clin Mol Teratol. 2016 Oct;106(10):803-813. doi: 10.1002/bdra.23543. Epub 2016 Jul 20.
- Durham EL, Howie RN, Cray JJ. Gene/environment interactions in craniosynostosis: A brief review. Orthod Craniofac Res. 2017 Jun;20 Suppl 1:8-11. doi: 10.1111/ocr.12153
- Hoyt AT, Canfield MA, Romitti PA, Botto LD, Anderka MT, Krikov SV, Tarpey MK, Feldkamp ML. Associations between maternal periconceptional exposure to secondhand tobacco smoke and major birth defects. Am J Obstet Gynecol. 2016 Nov;215(5):613.e1-613.e11. doi: 10.1016/j.ajog.2016.07.022. Epub 2016 Jul 18.
- Joubert BR, Felix JF, Yousefi P, Bakulski KM, Just AC, Breton C, Reese SE, Markunas CA, Richmond RC, Xu CJ, Küpers LK, Oh SS, Hoyo C, Gruzieva O, Söderhäll C, Salas LA, Baïz N, Zhang H, Lepeule J, Ruiz C, Ligthart S, Wang T, Taylor JA, Duijts L, Sharp GC, Jankipersadsing SA, Nilsen RM, Vaez A, Fallin MD, Hu D, Litonjua AA, Fuemmeler BF, Huen K, Kere J, Kull I, Munthe-Kaas MC, Gehring U, Bustamante M, Saurel-Coubizolles MJ, Quraishi BM, Ren J, Tost J, Gonzalez JR, Peters MJ, Håberg SE, Xu Z, van Meurs JB, Gaunt TR, Kerkhof M, Corpeleijn E, Feinberg AP, Eng C, Baccarelli AA, Benjamin Neelon SE, Bradman A, Merid SK, Bergström A, Herceg Z, Hernandez-Vargas H, Brunekreef B, Pinart M, Heude B, Ewart S, Yao J, Lemonnier N, Franco OH, Wu MC, Hofman A, McArdle W, Van der Vlies P, Falahi F, Gillman MW, Barcellos LF, Kumar A, Wickman M, Guerra S, Charles MA, Holloway J, Auffray C, Tiemeier HW, Smith GD, Postma D, Hivert MF, Eskenazi B, Vrijheid M, Arshad H, Antó JM, Dehghan A, Karmaus W, Annesi-Maesano I, Sunyer J, Ghantous A, Pershagen G, Holland N, Murphy SK, DeMeo DL, Burchard EG, Ladd-Acosta C, Snieder H, Nystad W, Koppelman GH, Relton CL, Jaddoe VW, Wilcox A, Melén E, London SJ. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis. Am J Hum Genet. 2016 Apr 7;98(4):680-96. doi: 10.1016/j.ajhg.2016.02.019. Epub 2016 Mar 31.
- Shaffer JR, Carlson JC, Stanley BO, Feingold E, Cooper M, Vanyukov MM, Maher BS, Slayton RL, Willing MC, Reis SE, McNeil DW, Crout RJ, Weyant RJ, Levy SM, Vieira AR, Marazita ML. Effects of enamel matrix genes on dental caries are moderated by fluoride exposures. Hum Genet. 2015 Feb;134(2):159-67. doi: 10.1007/s00439-014-1504-7. Epub 2014 Nov 6.
- Wu T, Schwender H, Ruczinski I, Murray JC, Marazita ML, Munger RG, Hetmanski JB, Parker MM, Wang P, Murray T, Taub M, Li S, Redett RJ, Fallin MD, Liang KY, Wu-Chou YH, Chong SS, Yeow V, Ye X, Wang H, Huang S, Jabs EW, Shi B, Wilcox AJ, Jee SH, Scott AF, Beaty TH. Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate. PLoS One. 2014 Feb 6;9(2):e88088. doi: 10.1371/journal.pone.0088088. eCollection 2014.