Variants in the Regulatory Region of WNT5A Reduced Risk of Cardiac Conotruncal Malformations in the Chinese Population

Abstract

WNT5A is one of the most highly investigated non-canonical Wnt ligands and is involved in the embryonic heart development, especially in formation of the cardiac conotruncal region by regulating the migration and differentiation of cardiac neural crest (CNC) and second heart field (SHF) cells. No study to date has comprehensively characterized the WNT5A regulatory variants in patients with congenital heart malformations (CHMs). The association between regulatory variants of the WNT5A gene and CHMs was examined in case-control association study in 1,210 CHMs and 798 controls. Individuals carrying a homozygous genotype CC (rs524153) or GG (rs504849) had a similarly reduced risk of conotruncal malformations. The homozygous genotypes (CC for rs524153 and GG for rs504849) were associated with a lower WNT5A transcriptional level compared with the transcriptional level of those with wild-type genotypes. Further functional analysis revealed that an additional upstream single nucleotide polymorphisms (SNP) rs371954924 (–5244GCCA > CC) in a linkage disequilibrium (LD) block with the above genotyped SNPs decreased WNT5A expression through the attenuated binding affinity with the transcription factor SOX9. This is the first demonstration that genetic variants in the regulatory regions of WNT5A play a vital role in sporadic conotruncal malformations susceptibility through the changeable expression of the WNT5A gene.

The role of histone modification and a regulatory single-nucleotide polymorphism (rs2071166) in the Cx43 promoter in patients with TOF

“…et al . observed that rs371954924 in WNT5A reduced gene expression by attenuating the binding affinity of the transcription factor SOX9 43 . In our previous study, we identified a functional RARE in the Cx43 promoter 23 .…”

Variants in a cis-regulatory element of TBX1 in conotruncal heart defect patients impair GATA6-mediated transactivation

“…There are also reports of TBX1 cis -regulatory elements being involved in cardiac development [ 32 , 33 , 51 , 62 ], such as a mutation of the Fox-binding site upstream of Tbx1 abolishing Tbx1 expression in the pharyngeal endoderm [ 32 , 33 ] and heterozygous variants NC_000022.11:g.19756055C > T and NC_000022.11: g.19756212A > C upstream of the TBX1 TSS in VSD patients significantly decreasing the activity of the TBX1 gene promoter [ 51 ]. In addition, studies have reported that variants in the regulatory region of other OFT development-related genes are also associated with CTD, such as WNT5A [ 63 ].…”

Human 3p14.3: A Regulatory Region in Transposition of the Great Arteries

“…This would further support the finding that Wnt5a misexpression is a key contributor to D-TGA. In a previous study of 1210 patients with congenital heart malformations, Li et al 12 also found that reduced levels of Wnt5a lead to lower rates of conotruncal malformation. While this study did not specifically examine patients with D-TGA, the results support the work described by Škorić-Milosavljević et al Interestingly, the authors did not find evidence of any affected ciliary genes at their pathogenic locus, despite prior studies finding several ciliary genes as a key component of TGA.…”