Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations

Abstract

ATP-binding cassette (ABC) proteins in the placenta regulate fetal exposure to xenobiotics. We hypothesized that functional polymorphisms in ABC genes influence risk for non-syndromic oral clefts (NSOC). Both family-based and case-control studies were undertaken to evaluate the association of nine potentially functional single-nucleotide polymorphisms within four ABC genes with risk of NSOC. Peripheral blood DNA from a total of 150 NSOC case-parent trios from Singapore and Taiwan were genotyped, as was cord blood DNA from 189 normal Chinese neonates used as controls. In trios, significant association was observed between the ABCB1 single-nucleotide polymorphisms and NSOC (Po0.05). Only ABCB1 rs1128503 retained significant association after Bonferroni correction (odds ratio (OR) ¼ 2.04; 95% confidence interval (CI) ¼ 1.42-2.98), while rs2032582 and rs1045642 showed nominal significance. Association with rs1128503 was replicated in a case-control analysis comparing NSOC probands with controls (OR ¼ 1.58; 95% CI ¼ 1.12-2.23). A comparison between the mothers of probands and controls showed no evidence of association, suggesting NSOC risk is determined by fetal and not maternal ABCB1 genotype. The two studies produced a combined OR of 1.79 (95% CI ¼ 1.38-2.30). The T-allele at rs1128503 was associated with higher risk. This study thus provides evidence that potentially functional polymorphisms in fetal ABCB1 modulate risk for NSOC, presumably through suboptimal exclusion of xenobiotics at the fetal-maternal interface.

The important role of MDM2, RPL5, and TP53 in mycophenolic acid-induced cleft lip and palate

“…The haplotype of ABCB1 in conjunction with sex is correlated with the risk of extrarenal adverse effects resulting from MPA [49] . Mothers who carry the ABCB1 3435C > T polymorphism are at significantly increased risk for having offspring with CLP, especially mothers using medication in the periconceptional period; [50] this risk is presumably attributable to suboptimal exclusion of xenobiotics at the fetal–maternal interface [51] …”

“…[49] Mothers who carry the ABCB1 3435C > T polymorphism are at significantly increased risk for having offspring with CLP, especially mothers using medication in the periconceptional period; [50] this risk is presumably attributable to suboptimal exclusion of xenobiotics at the fetal-maternal interface. [51] 4.3. COL1A1 could be involved in Stickler syndrome, similar to MPA-induced CLP COL1A1 encodes the alpha 1 chain of collagen type I, which can be inhibited by MPA.…”

Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention

“…Additionally, el-Ashmawy, I. M. et al, [28] observed that verapamil could dramatically enhance the susceptibility of fetal developmental disorders induced by ivermectin via P-gp inhibition. With regard to clinical studies, two researches [31, 32] have reported that 3435C>T polymorphism of ABCB1 gene could affect the risk of toxicants-induced birth defects, which might be explained by the alteration of placental P-gp expression and efflux activity. Moreover, a recent epidemiological case-control survey [33] documented that several drug classes that are substrates for P-gp were shown to have a higher user rate in mothers of cases with specific anomalies.…”

Genetic Predictors for the Development of Congenital Orofacial Clefts

“…Reliable associations of gene variations (IRF6, MDR1, and MTHFR) with an increased risk for CLP, CL, and CP have been obtained in different populations. (1)(2)(3)(4)(5) IRF6 is a protein encoded by the IRF6 gene in humans. This gene encodes a member of the interferon regulatory transcription factor family.…”

“…These proteins are able to remove toxins or drugs from the environment that enter the mother's body, into the mother's bloodstream, and can lead to an altered response of the fetus on xenobiotics and a subsequent increase in the risk of complex genetic disorders or birth defects. (3) The MTHFR gene, encoding the synthesis of the MTHFR enzyme, is located on chromosome 1p36.3. MTHFR plays a key role in folic acid metabolism.…”