Candidate genes and non-syndromic cleft lip with or without cleft palate among case-parent trios from Chinese populations

As a complex and heterogeneous birth defect, the etiology of non-syndromic cleft lip with/without cleft palate (CL/P) remains largely unknown. Chinese Han is among the populations with highest prevalence rates of CL/P. Besides conventional genetic mechanisms, gene---environment (GxE) interaction and parent-of-origin effects may also influence the risk to CL/P. Our objective was to investigate association between markers in interferon regulatory factor 6 gene (IRF6) and Runt-related transcription factor 2 gene (RUNX2), and non-syndromic CL/P among 326 Chinese case-parent trios, while considering parent-of-origin effects and GxE interaction.;CL/P case-parent trios were genotyped for 22 single nucleotide polymorphisms (SNPs) in IRF6 and 49 SNPs in RUNX2. After Bonferroni correction, fourteen SNPs of IRF6 showed statistically significant association with CL/P. Significant GxE interaction was found for multivitamin supplementation and environmental tobacco smoke (ETS). Two SNPs showed significant interaction with multivitamin supplementation ( rs2076153: P =0.019; rs17015218: P =0.012). In addition, rs1044516 yielded significant interaction with maternal ETS ( P=0.041). Haplotype analysis also suggested interaction between SNPs in IRF6 and both multivitamin supplementation and ETS. However, no maternal genotypic effects or significant parent-of-origin effects were seen in these data.;For RUNX2, one SNP (rs545289) showed statistically significant linkage and association with CL/P (permuted P=0.035). Another SNP (rs675613) yielded statistically significant imprinting [RR (imprinting) = 2.2]. Eight SNPs showed statistical significance when considering possible interaction with ETS. In addition, three SNPs yielded significant GxE interaction with maternal multivitamin supplementation. Haplotype analysis also suggested interaction between SNPs in RUNX2 and both maternal exposures. We conducted a replication study using a genome wide scan sample to confirm the findings of RUNX2. Independent samples from European populations showed consistent results of significant association and GxE interaction with ETS and multivitamin supplementation.;In conclusion, these results indicate the variation of markers in these two candidate genes contributes to the etiology of non-syndromic CL/P among Chinese populations. Our study also demonstrates gene-by-ETS and gene-by-multivitamin supplementation interactions for non-syndromic CL/P. With previous findings, our study suggests the presence of imprinting effect of RUNX2. Further comfirmation of these results in other populations or studies will be important.