Dataset Information

Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease.

ABSTRACT: Congenital heart defects (CHDs) represent the most common human birth defects. Our previous study indicates that the malfunction of microRNAs (miRNAs) in cardiac neural crest cells (NCCs), which contribute to the development of the heart and the connected great vessels, is likely linked to the pathogenesis of human CHDs. In this study, we attempt to further search for causative single-nucleotide variants (SNVs) from CHD patients that mediate the mis-regulating of miRNAs on their downstream target genes in the pathogenesis of CHDs. As a result, a total of 2,925 3'UTR SNVs were detected from a CHD cohort. In parallel, we profiled the expression of miRNAs in cardiac NCCs and found 201 expressed miRNAs. A combined analysis with these data further identified three 3'UTR SNVs, including NFATC1 c.^*654C>T, FGFRL1 c.^*414C>T, and CTNNB1 c.^*729_^*730insT, which result in the malfunction of miRNA-mediated gene regulation. The dysregulations were further validated experimentally. Therefore, our study indicates that miRNA-mediated gene dysregulation in cardiac NCCs could be an important etiology of congenital heart disease, which could lead to a new direction of diagnostic and therapeutic investigation on congenital heart disease.

SUBMITTER: Liu W

PROVIDER: S-EPMC8460875 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease.

Liu Wangkai W Cheng Liangping L Chen Ken K Wu Jialing J Peng Rui R Tang Yan-Lai YL Chen Jinghai J Yang Yuedong Y Li Peiqiang P Huang Zhan-Peng ZP

Frontiers in cardiovascular medicine 20210910

Congenital heart defects (CHDs) represent the most common human birth defects. Our previous study indicates that the malfunction of microRNAs (miRNAs) in cardiac neural crest cells (NCCs), which contribute to the development of the heart and the connected great vessels, is likely linked to the pathogenesis of human CHDs. In this study, we attempt to further search for causative single-nucleotide variants (SNVs) from CHD patients that mediate the mis-regulating of miRNAs on their downstream targe ...[more]

PMID: 34568467

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Project description:Background: MicroRNAs (miRNAs) are important regulators in a variety of biological processes, and their dysregulation is associated with multiple human diseases. Single nucleotide variants (SNVs) in genes involved in the processing of microRNAs may alter miRNA regulation and could present high allele heterogeneity in populations from different ethnic groups. Thus, the aim of this study was to genotype 15 SNVs in eight genes involved in the miRNA processing pathway in Mexican individuals and compare their frequencies across 21 populations from five continental groups. Methods: Genomic DNA was obtained from 399 healthy Mexican individuals. SNVs in AGO2 (rs2293939 and rs4961280), DGCR8 (rs720012), DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), GEMIN3 (rs197388 and rs197414), GEMIN4 (rs7813, rs2740349, and rs4968104), TNRC6B (rs9611280), and XP05 (rs11077 and rs34324334) were genotyped using TaqMan probes. The minor allele frequency of each SNV was compared to those reported in the 1,000 Genomes database using chi-squared. Sankey plot was created in the SankeyMATIC package to visualize the frequency range of each variant in the different countries analyzed. Results: In Mexican individuals, all 15 SNVs were found in Hardy-Weinberg equilibrium, with frequencies ranging from 0.04 to 0.45. The SNVs rs4961280, rs2740349, rs34324334, and rs720012 in Mexican individuals had the highest minor allele frequencies worldwide, whereas the minor allele frequencies of rs197388, rs10719, rs197414, and rs1107 were among the lowest in Mexican individuals. The variants had high allele heterogeneity among the sub-continental populations, ranging from monomorphic, as was the case for rs9611280 and rs34324334 in African groups, to >0.50, which was the case for variants rs11077 and rs10719 in most of the populations. Importantly, the variants rs197388, rs720012, and rs197414 had FST values > 0.18, indicating a directional selective process. Finally, the SNVs rs13078 and rs10719 significantly correlated with both latitude and longitude. Conclusion: These data indicate the presence of high allelic heterogeneity in the worldwide distribution of the frequency of SNVs located in components of the miRNA processing pathway, which could modify the genetic susceptibility associated with human diseases in populations with different ancestry.

Dataset Information

Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease.

Publications

Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease.

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