The potential up-regulation risk of 3' UTR SNP (rs10787760 G > A) for the VAX1 gene is associated with NSCLP in the northwest Chinese population.

Aims: To investigate the association between single nucleotide polymorphisms (SNPs) in 3'UTR region of VAX1, SYT14 and PAX7 genes and the risk of non-syndromic cleft palate (NSCLP) in a northwest Chinese population.

Main Methods: A case-control study was conducted in 406 normal controls and 399 NSCLP patients. Using iMLDRTM genotyping technology, eight SNPs of three genes ((rs10787760, rs7086344 at VAX1), (rs1010113, rs851114, and rs485874 at PAX7), and (rs61820397, rs4609425, rs12133399 at SYT14)) were genotyped to investigate the differences in alleles and genotype distribution frequencies between NSCLP patients and healthy controls. RNA Folding Form software was used to predict RNA secondary structure and expression vectors were constructed to explore the function of the relevant SNP. The effect of SNP polymorphism of gene transcription and translation was assessed using qPCR and Western blot analysis.

Key Findings: Among the eight SNPs of three genes, rs10787760 of VAX1 gene was found to be associated with an increased risk of NSCLP (OR = 1.341, CI = 1.004-1.790) and the GA genotype of rs10787760 increased the risk of cleft lip and/or palate (CL/P) about 1.42 times (p < 0.05), and carrying the A allele might increase the risk of NSCL/P in male (OR = 1.356, 95 % CI = 1.010-1.823). But there was no association observed with cleft palate only (CPO). Cell function experiments revealed that the G to A mutation in rs10787760 up-regulated GFP-VAX1 transcriptional level by 2.39 and 3.13 times in two cell lines respectively, and enhance the protein expression of the VAX1 gene further. RNA secondary structure study showed that the rs10787760 (G > A) had two different secondary structures in 3'UTR region.

Significance: The rs10787760 variant in the 3'UTR region of VAX1 gene is associated with CL/P in northwest Chinese population. We hypothesize that the machanism of it might be caused by the RNA differenct fold in the 3'UTR region caused by the polymorphism of the gene.

Level Of Evidence: Original Reports.