Biological and epidemiological evidence of interaction of infant genotypes at Rs7205289 and maternal passive smoking in cleft palate

Abstract

The noncoding SNP rs7205289, located in the microRNA-140 gene has been associated with cleft palate risk. MiR-140 was found to regulate zebrafish palatal development in vivo and its expression level be reduced by environmental smoke exposure in vitro. Therefore, we sought to investigate whether the A allele of rs7205289 and maternal smoke exposure during the first trimester might contribute to cleft palate risk by regulating microRNA-140. We used in situ hybridization to explore the microRNA-140 expression pattern. A luciferase reporting system and Western blot were used to validate the target of microRNA-140. Mouse palatal mesenchymal cells (MPMC) were transfected with microRNA-140 expression vectors, or treated with cigarette smoke extract. In addition, we performed a hospital-based case-control study in 169 patients with nonsyndromic cleft palate and 306 unaffected controls. We demonstrated microRNA-140 expression in mouse palatal shelves from embryonic days 12 to 15. Pdgfrα was the target of microRNA-140 in MPMC. When these cells were transfected with the minor allele vector or exposed to cigarette smoke extract, they showed a decrease in microRNA-140 expression. Epidemiological analyses showed that infants with CA/AA genotypes and exposed to maternal passive smoking during pregnancy had evidence of synergistic interaction in contributing to cleft palate risk. We concluded that infants with CA/AA genotypes at rs7205289 and maternal passive smoking during the first trimester may synergistically contribute to cleft palate risk by decreasing microRNA-140 during palatal development.

PDGFRa mutations in humans with isolated cleft palate

“…17 In addition, a subsequent publication has revealed possible synergistic interaction between infants with CA/AA at rs7205289 located in the microRNA (miR)-140 and maternal passive smoking in contributing to cleft palate risk. 18 We therefore investigated whether PDGFRa and miR-140 had a role in human CP. Seven different mutations in PDGFRa were identified.…”

8 Epidemiology of Cleft Lip and Palate

“…Recognized teratogens included rare exposures such as phenytoin, valproic acid, thalidomide, and herbicides such as dioxin. As mentioned previously, risk of CL/P or CPO conferred by these exposures-in particular tobacco-may be modulated by the presence or absence of certain genetic factors [19,88,89].…”

Identification of the Differentially Expressed microRNAs Involved in Cleft Palate Induced by Retinoic Acid (RA) in Mouse Model

“…Although several genetic and environmental factors have been reported for this disorder, the biological mechanism remains intricate 3) . The process of embryonic palatal development in mice is coordinated with the one in mammals temporally and spatially.…”