Gene×environment associations in orofacial clefting.

This chapter reviews the evidence of gene×environment interactions (G×E) in the etiology of orofacial cleft birth defects (OFCs), specifically cleft lip (CL), cleft palate (CP), and cleft lip with or without cleft palate (CL/P). We summarize the current state of our understanding of the genetic architecture of nonsyndromic OFCs and the evidence that maternal exposures during pregnancy influence risk of OFCs. Further, we present possible candidate gene pathways for these exposures including metabolism of folates, metabolism of retinoids, retinoic acid receptor signaling, aryl hydrocarbon receptor signaling, glucocorticoid receptor signaling, and biotransformation and transport. We review genes in these pathways with prior evidence of association with OFCs, genes with evidence from prior candidate gene G×E studies, and genes identified from genome-wide searches specifically for identifying G×E. Finally, we suggest future directions for G×E research in OFCs.