Affiliation:
1. The Institute of Cardiovascular Diseases & Department Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University & Chinese Academy of Medical Sciences, Tianjin 300457, China
Abstract
Patent ductus arteriosus (PDA) is a common congenital heart disease. CITED2 plays an important role in the development of the heart, and genetic variants in its coding region are significantly associated with cardiac malformations. However, the role of variants in the promoter region of CITED2 in the development of PDA remains unclear. We extracted the peripheral blood of 646 subjects (including 353 PDA patients and 293 unrelated healthy controls) for sequencing. We identified 13 promoter variants of the CITED2 gene (including 2 novel heterozygous variants). Of the 13 variants, 10 were found only in PDA patients. In mouse cardiomyocytes (HL-1) and rat cardiac myocytes (RCM), the transcriptional activity of the CITED2 gene promoter was significantly changed by the variants (p < 0.05). The results of the experiments of electrophoretic mobility indicated that these variants may affect the transcription of the CITED2 gene by influencing the binding ability of transcription factors. These results, combined with the JASPAR database analysis, showed that the destruction/production of transcription factor binding sites due to the variants in the promoter region of the CITED2 gene may directly or indirectly affect the binding ability of transcription factors. Our results suggest for the first time that variants at the CITED2 promoter region may cause low expression of CITED2 protein related to the formation of PDA.
Funder
National Natural Science Foundation of China
Tianjin Municipal Science and Technology Commission
Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
TEDA International Cardiovascular Hospital Internal Grant
Tianjin Key Medical Discipline (Specialty) Construction Project
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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