Variants in the Regulatory Region of WNT5A Reduced Risk of Cardiac Conotruncal Malformations in the Chinese Population.
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.
1] The State Key Laboratory of Genetic Engineering, Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China [2] Institute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou City 730000, Gansu Province, China.
Peiqiang
P
Li
Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan 250022, China.
Haijie
H
Li
The State Key Laboratory of Genetic Engineering, Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
Yufang
Y
Zheng
Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan 250022, China.
Bin
B
Qiao
Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan 250022, China.
Wenyuan
W
Duan
The State Key Laboratory of Genetic Engineering, Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
Lijuan
L
Huang
The State Key Laboratory of Genetic Engineering, Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
Weiqi
W
Liu
1] The State Key Laboratory of Genetic Engineering, Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China [2] Children's Hospital Shanghai, Fudan University, 399 Wanyuan Road, Shanghai 201102, China.
Hongyan
H
Wang
D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002681:China; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006239:Haplotypes; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D016297:Mutagenesis, Site-Directed; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000737:chemistry / Q000378:metabolism; D051153:Wnt Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000071818:Wnt-5a Protein
D011518:Proto-Oncogene Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein