Susceptibility to congenital heart defects associated with a polymorphism in TBX2 3' untranslated region in the Han Chinese population.
3' Untranslated Regions
Alleles
Animals
Asian People
Binding Sites
Case-Control Studies
Child
China
/ ethnology
Echocardiography
Female
Gene Expression Regulation
Genetic Predisposition to Disease
Genotype
HEK293 Cells
Heart Defects, Congenital
/ ethnology
Heart Ventricles
Humans
Male
MicroRNAs
/ genetics
Phenotype
Plasmids
/ metabolism
Polymorphism, Single Nucleotide
Rats
Risk Assessment
T-Box Domain Proteins
/ genetics
Journal
Pediatric research
ISSN: 1530-0447
Titre abrégé: Pediatr Res
Pays: United States
ID NLM: 0100714
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
28
12
2017
accepted:
19
06
2018
revised:
15
06
2018
pubmed:
29
9
2018
medline:
9
6
2020
entrez:
29
9
2018
Statut:
ppublish
Résumé
Tbx2 plays a critical role in determining fates of cardiomyocytes. Little is known about the contribution of TBX2 3' untranslated region (UTR) variants to the risk of congenital heart defect (CHD). Thus, we aimed to determine the association of single-nucleotide polymorphisms (SNPs) in TBX2 3' UTR with CHD susceptibility. We recruited 1285 controls and 1241 CHD children from China. SNPs identification and genotyping were detected using Sanger Sequencing and SNaPshot. Stratified analysis was conducted to explore the association between rs59382073 polymorphism and CHD subtypes. Functional analyses were performed by luciferase assays in HEK-293T and H9c2 cells. Among five TBX2 3'UTR variants identified, rs59382073 minor allele T carriers had a 1.89-fold increased CHD risk compared to GG genotype (95% CI = 1.48-2.46, P = 4.48 × 10 T allele of rs59382073 in TBX2 3'UTR contributed to greater CHD risk in the Han Chinese population. G to T variation created binding sites for miR-3940 and miR-708 to inhibit gene expression.
Sections du résumé
BACKGROUND
Tbx2 plays a critical role in determining fates of cardiomyocytes. Little is known about the contribution of TBX2 3' untranslated region (UTR) variants to the risk of congenital heart defect (CHD). Thus, we aimed to determine the association of single-nucleotide polymorphisms (SNPs) in TBX2 3' UTR with CHD susceptibility.
METHODS
We recruited 1285 controls and 1241 CHD children from China. SNPs identification and genotyping were detected using Sanger Sequencing and SNaPshot. Stratified analysis was conducted to explore the association between rs59382073 polymorphism and CHD subtypes. Functional analyses were performed by luciferase assays in HEK-293T and H9c2 cells.
RESULTS
Among five TBX2 3'UTR variants identified, rs59382073 minor allele T carriers had a 1.89-fold increased CHD risk compared to GG genotype (95% CI = 1.48-2.46, P = 4.48 × 10
CONCLUSION
T allele of rs59382073 in TBX2 3'UTR contributed to greater CHD risk in the Han Chinese population. G to T variation created binding sites for miR-3940 and miR-708 to inhibit gene expression.
Identifiants
pubmed: 30262811
doi: 10.1038/s41390-018-0181-y
pii: 10.1038/s41390-018-0181-y
doi:
Substances chimiques
3' Untranslated Regions
0
MIRN3940 microRNA, human
0
MIRN708 microRNA, human
0
MicroRNAs
0
T-Box Domain Protein 2
0
T-Box Domain Proteins
0
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
378-383Références
Triedman, J. K. & Newburger, J. W. Trends in congenital heart disease: the next decade. Circulation 133, 2716–2733 (2016).
doi: 10.1161/CIRCULATIONAHA.116.023544
Pradat, P. et al. The epidemiology of cardiovascular defects, part I: a study based on data from three large registries of congenital malformations. Pediatr. Cardiol. 24, 195–221 (2003).
doi: 10.1007/s00246-002-9401-6
Zaidi, S. et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220–223 (2013).
doi: 10.1038/nature12141
Christoffels, V. M. et al. Development of the pacemaker tissues of the heart. Circ. Res. 106, 240–254 (2010).
doi: 10.1161/CIRCRESAHA.109.205419
Cai, C. L. et al. T-box genes coordinate regional rates of proliferation and regional specification during cardiogenesis. Development 132, 2475–2487 (2005).
doi: 10.1242/dev.01832
Ma, L. et al. Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development 132, 5601–5611 (2005).
doi: 10.1242/dev.02156
Sakabe, M. et al. Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgfβ2 pathway. Development 139, 385–395 (2012).
doi: 10.1242/dev.067058
Singh, M. K. et al. Tbx20 is essential for cardiac chamber differentiation and repression of Tbx2. Development 132, 2697–2707 (2005).
doi: 10.1242/dev.01854
Habets, P. E. M. H. et al. Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes Dev. 16, 1234–1246 (2002).
doi: 10.1101/gad.222902
Boogerd, K.-J. et al. Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43. Cardiovasc. Res. 78, 485–493 (2008).
doi: 10.1093/cvr/cvn049
Barron, M. R. et al. Serum response factor, an enriched cardiac mesoderm obligatory factor, is a downstream gene target for Tbx genes. J. Biol. Chem. 280, 11816–11828 (2005).
doi: 10.1074/jbc.M412408200
Harrelson, Z. et al. Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development. Development 131, 5041–5052 (2004).
doi: 10.1242/dev.01378
Wang, F. et al. A TBX5 3’UTR variant increases the risk of congenital heart disease in the Han Chinese population. Cell Discov. 3, 17026 (2017).
doi: 10.1038/celldisc.2017.26
Pang, S. et al. Novel and functional sequence variants within the TBX2 gene promoter in ventricular septal defects. Biochimie 95, 1807–1809 (2013).
doi: 10.1016/j.biochi.2013.05.007
Houyel, L. et al. Population-based evaluation of a suggested anatomic and clinical classification of congenital heart defects based on the International Paediatric and Congenital Cardiac Code. Orphanet. J. Rare Dis. 6, 64 (2011).
doi: 10.1186/1750-1172-6-64
Botto, L. D. et al. Seeking causes: classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Res. Part A Clin. Mol. Teratol. 79, 714–727 (2007).
doi: 10.1002/bdra.20403
Campbell, C. et al. Cloning and mapping of a human gene (TBX2) sharing a highly conserved protein motif with the Drosophila omb gene. Genomics 28, 255–260 (1995).
doi: 10.1006/geno.1995.1139
Campbell, C. E., Casey, G. & Goodrich, K. Genomic structure of TBX2 indicates conservation with distantly related T-box genes. Mamm. Genome. 9, 70–73 (1998).
doi: 10.1007/s003359900682
Law, D. J. et al. Identification, characterization, and localization to Chromosome 17q21-22 of the human TBX2 homolog, member of a conserved developmental gene family. Mamm. Genome. 6, 793–797 (1995).
doi: 10.1007/BF00539006
Radio, F. C., et al., TBX2 gene duplication associated with complex heart defect and skeletal malformations. Am. J. Med. Genet. A 152A, 2061–2066 (2010).
Yamada, M. et al. Expression of chick Tbx-2, Tbx-3, and Tbx-5 genes during early heart development: evidence for BMP2 induction of Tbx2. Dev. Biol. 228, 95–105 (2000).
doi: 10.1006/dbio.2000.9927
Sizarov, A. et al. Formation of the building plan of the human heart: morphogenesis, growth, and differentiation. Circulation 123, 1125–1135 (2011).
doi: 10.1161/CIRCULATIONAHA.110.980607
Aanhaanen, W. T. J. et al. The Tbx2+ primary myocardium of the atrioventricular canal forms the atrioventricular node and the base of the left ventricle. Circ. Res. 104, 1267–1274 (2009).
doi: 10.1161/CIRCRESAHA.108.192450
Moorman, A. F. M. et al. The heart-forming fields: one or multiple? Philos. Trans. R. Soc. Lond. B. Biol. Sci. 362, 1257–1265 (2007).
doi: 10.1098/rstb.2007.2113
Shirai, M., et al., T-box 2, a mediator of Bmp-Smad signaling, induced hyaluronan synthase 2 and Tgfbeta2 expression and endocardial cushion formation. Proc. Natl Acad. Sci. USA 106, 18604-18609 (2009).
Kiriakidou, M. et al. An mRNA m7G cap binding-like motif within human Ago2 represses translation. Cell 129, 1141–1151 (2007).
doi: 10.1016/j.cell.2007.05.016
Nikolova, E., Jordanov, I. & Vitanov, N. Dynamical analysis of the microRNA – mediated protein translation process. BIOMATH 2, 1210071 (2013).
doi: 10.11145/j.biomath.2012.10.071
Pillai, R. S. et al. Inhibition of translational initiation by Let-7 MicroRNA in human cells. Science 309, 1573–1576 (2005).
doi: 10.1126/science.1115079
Pelletier, C. & Weidhaas, J. B. MicroRNA binding site polymorphisms as biomarkers of cancer risk. Expert. Rev. Mol. Diagn. 10, 817–829 (2014).
doi: 10.1586/erm.10.59
Liang, D. et al. Genetic variants in MicroRNA biosynthesis pathways and binding sites modify ovarian cancer risk, survival, and treatment response. Cancer Res. 70, 9765–9776 (2010).
doi: 10.1158/0008-5472.CAN-10-0130
Sabina, S. et al. Germline hereditary, somatic mutations and microRNAs targeting-SNPs in congenital heart defects. J. Mol. Cell. Cardiol. 60, 84–89 (2013).
doi: 10.1016/j.yjmcc.2013.04.002