Characterization of nodal/TGF-lefty signaling pathway gene variants for possible roles in congenital heart diseases

Xia Deng; Jing Zhou; Fei-Feng Li; Peng Yan; Er-Ying Zhao; Ling Hao; Kai-Jiang Yu; Shu-Lin Liu

doi:10.1371/journal.pone.0104535

Characterization of nodal/TGF-lefty signaling pathway gene variants for possible roles in congenital heart diseases

PLoS One. 2014 Aug 11;9(8):e104535. doi: 10.1371/journal.pone.0104535. eCollection 2014.

Authors

Xia Deng¹, Jing Zhou², Fei-Feng Li¹, Peng Yan³, Er-Ying Zhao¹, Ling Hao⁴, Kai-Jiang Yu², Shu-Lin Liu⁵

Affiliations

¹ Genomics Research Center (one of the State-Province Key Laboratory of Biopharmaceutical Engineering, China), Harbin Medical University, Harbin, China.
² Intensive Care Unit, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
³ Department of Colorectal Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
⁴ Department of Oncology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
⁵ Genomics Research Center (one of the State-Province Key Laboratory of Biopharmaceutical Engineering, China), Harbin Medical University, Harbin, China; Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Canada.

Abstract

Background: Nodal/TGF-Lefty signaling pathway has important effects at early stages of differentiation of human embryonic stem cells in directing them to differentiate into different embryonic lineages. LEFTY, one of transforming growth factors in the Nodal/TGF-Lefty signaling pathway, plays an important role in the development of heart. The aim of this work was to find evidence on whether Lefty variations are associated with congenital heart diseases (CHD).

Methods: We sequenced the Lefty gene for 230 Chinese Han CHD patients and evaluated SNPs rs2295418, rs360057 and g.G169A, which are located within the translated regions of the genes. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0). The Hardy-Weinberg equilibrium test of the population was carried out using online software OEGE, and multiple-sequence alignments of LEFTY proteins were carried out using the Vector NTI software.

Results: Two heterozygous variants in Lefty1 gene, g.G169A and g.A1035C, and one heterozygous variant in Lefty2 gene, g.C925A, were identified. Statistical analyses showed that the rs2295418 (g.C925A) variant in Lefty2 gene was obviously associated with the risk of CHD (P value = 0.016<0.05). The genotype frequency of rs360057 (g.A1035C) variant in Lefty1 gene was associated with the risk of CHD (P value = 0.007<0.05), but the allele frequency was not (P value = 0.317>0.05).

Conclusions: The SNP rs2295418 in the Lefty2 gene is associated with CHD in Chinese Han populations.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Amino Acid Sequence
Animals
Asian People / ethnology
Asian People / genetics
Base Sequence
Child
Ethnicity / genetics
Female
Genetic Predisposition to Disease / genetics
Heart Defects, Congenital / genetics*
Heart Defects, Congenital / pathology*
Humans
Left-Right Determination Factors / chemistry
Left-Right Determination Factors / genetics
Left-Right Determination Factors / metabolism*
Male
Molecular Sequence Data
Nodal Protein / metabolism*
Polymorphism, Single Nucleotide*
RNA Splice Sites / genetics
Signal Transduction*
Transcription, Genetic / genetics
Transforming Growth Factors / metabolism*

Substances

Left-Right Determination Factors
Nodal Protein
RNA Splice Sites
Transforming Growth Factors

Grants and funding

This work was supported by a grant from Heilongjiang Innovation Research Foundation for Graduate Studies (YJSCX2012-199HLJ) to XD; a grant from Heilongjiang Province (ZD200917) to KJY; a grant from Pharmacy College of Harbin Medical University to FFL for training undergraduate students; and grants of National Natural Science Foundation of China (NSFC81271786, 81110378, 30970119, 81030029) to SLL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.