miR-138 rs139365823多态性与先天性心脏病风险的相关性研究
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摘要
目的探讨miR-138中的遗传多态性是否可能导致先天性心脏病(CHD)的发生和潜在的机制。方法本研究通过miR-138基因分型的方法对100例法洛四联症(TOF)患者及正常对照人群进行病例对照研究。鉴定2个miR-138 SNPs,包括位于pre-miR-138序列中的rs139365823和位于pri-miR-138序列中的rs76987351。结果rs139365823等位基因A的基因型及等位基因频率与TOF风险增加明显相关,但与rs76987351 A/G等位基因无明显相关。PCR数据显示,rs139365823等位基因A明显增加miR-138的表达,而rs76987351等位基因A具有相反的作用。由于TOF是由流出道(OFT)发育异常引起,因此将参与OFT发育有关的Dvl2鉴定为miR-138的直接靶基因。此外,rs139365823等位基因A增强了miR-138对Dvl2的抑制作用。结论本研究证明了miR-138 rs139365823等位基因A增加了miR-138的表达及它对靶基因的抑制作用。
Objective To explore whether a genetic polymorphism in miR-138 may result in the occurrence of congenital heart disease( CHD) and the potential mechanism. Methods A case-control study was performed in 100 patients with tetralogy of Fallot( TOF) and 100 healthy subjects by genotyping miR-138. Two SNPs,including rare rs139365823 located in the pre-miR-138 sequence and rs76987351 located in the pri-miR-138 sequence,were identified by sequencing miR-138. Results The results demonstrated that the genotypes and allele frequencies of the rs139365823 minor allele A were significantly associated with the increased risk of TOF,however,which were not correlated with the rs76987351A/G allele.Real-time PCR data showed that the rs139365823 minor allele A significantly increased the expression of mature miR-138,whereas the rs76987351 minor allele A had the opposite effects. As TOF was caused by severe outflow tract( OFT) abnormal development,the related Dvl2 was regarded as direct target gene of miR-138. In addition rs139365823 minor allele A enhanced the inhibitory efects of miR-138 on Dvl2. Conclusion The miR-138 rs139365823 allele A increases the expression of miR-138 and its inhibitory effect on target genes.
Objective To explore whether a genetic polymorphism in miR-138 may result in the occurrence of congenital heart disease( CHD) and the potential mechanism. Methods A case-control study was performed in 100 patients with tetralogy of Fallot( TOF) and 100 healthy subjects by genotyping miR-138. Two SNPs,including rare rs139365823 located in the pre-miR-138 sequence and rs76987351 located in the pri-miR-138 sequence,were identified by sequencing miR-138. Results The results demonstrated that the genotypes and allele frequencies of the rs139365823 minor allele A were significantly associated with the increased risk of TOF,however,which were not correlated with the rs76987351A/G allele.Real-time PCR data showed that the rs139365823 minor allele A significantly increased the expression of mature miR-138,whereas the rs76987351 minor allele A had the opposite effects. As TOF was caused by severe outflow tract( OFT) abnormal development,the related Dvl2 was regarded as direct target gene of miR-138. In addition rs139365823 minor allele A enhanced the inhibitory efects of miR-138 on Dvl2. Conclusion The miR-138 rs139365823 allele A increases the expression of miR-138 and its inhibitory effect on target genes.
引文
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19 Siegel G,Obernosterer G,Fiore R,et al.A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis.Nat Cell Biol,2009,11:705-716.
2 Di Felice V,Zummo G.Tetralogy of Fallot as a Model to Study Cardiac Progenitor Cell Migration and Differentiation During Heart Development.Trends in Cardiovascular Medicine,2009,19:130-135.
3 Plasterk RHA.Micro RNAs in Animal Development.Cell,2006,124:877-881.
4 Lee Y,Ahn C,Han J,et al.The nuclear RNaseⅢDrosha initiates microRNA processing.Nature,2003,425:415-419.
5 Liu N,Olson EN.MicroRNA Regulatory Networks in Cardiovascular Development.Dev Cell,2010,18:510-525.
6 Liu CM,Wang RY,Saijilafu MD,et al.MicroRNA-138 and SIRT1 form a mutual negative feedback loop to regulate mammalian axon regeneration.Genes Dev,2013,27:1473-1483.
7 Morton SU,Scherz PJ,Cordes KR,et al.microRNA-138 modulates cardiac patterning during embryonic development.Proceedings of the National Academy of Sciences,2008,105:17830-17835.
8 He S,Liu P,Jian Z,et al.miR-138 protects cardiomyocytes from hypoxiainduced apoptosis via ml K3/JNK/c-jun pathway.Biochem Biophys Res Commun,2013,441:763-769.
9 Cordes KR,Srivastava D,Ivey KN.MicroRNAs in cardiac development.Pediatr Cardiol,2010,31:349-356.
10 Abu-Halima M,Meese E,Keller A,et al.Analysis of circulating microRNAs in patients with repaired Tetralogy of Fallot with and without heart failure.Journal of Translational Medicine,2017,15:156.
11 Dorn GW,Matkovich SJ,Eschenbacher WH,et al.A Human 3'miR-499mutation alters cardiac mRNA targeting and function.Circulation Research,2012,110:958-967.
12 Xavier-Neto J,Sousa Costa AM,Figueira ACM,et al.Signaling through retinoic acid receptors in cardiac development:Doing the right things at the right times.Biochim Biophys Acta,2015,1849:94-111.
13 Pavan M,Ruiz VF,Silva FA,et al.ALDH1A2(RALDH2)genetic variation in Human congenital heart disease.BMC Medical Genetics.BioMed Central,2009,10:604.
14 Buckingham M,Meilhac S,Zaffran S.Building the mammalian heart from two sources of myocardial cells.Nat Rev Genet.Nature Publishing Group,2005,6:826-835.
15 Lin L,Cui L,Zhou W,et al.Beta-catenin directly regulates Islet1expression in cardiovascular progenitors and is required for multiple aspects of cardiogenesis.Proc Natl Acad Sci USA.National Acad Sciences,2007,104:9313-9318.
16 Hamblet NS,Lijam N,Ruiz-Lozano P,et al.Dishevelled 2 is essential for cardiac outflow tract development,somite segmentation and neural tube closure.Development,2002,129:5827-5838.
17 Watanabe Y,Shibuya M,Nunokawa A,et al.A rare MIR138-2 gene variation is associated with schizophrenia in a Japanese population.Psychiatry Res,2014,215:801-802.
18 Sarkar A,Marchetto MC,Gage FH.Synaptic activity:An emerging player in schizophrenia.Brain Res,2017,1656:68-75.
19 Siegel G,Obernosterer G,Fiore R,et al.A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis.Nat Cell Biol,2009,11:705-716.