Functional rare variant in a C/EBP beta binding site in NINJ2 gene increases the risk of coronary artery disease

Wang, Pengyun; Wang, Yifan; Peng, Huixin; Wang, Jingjing; Zheng, Qian; Wang, Pengxia; Wang, Jing; Zhang, Hongfu; Huang, Yufeng; Xiong, Liang; Zhang, Rongfeng; Xia, Yunlong; Wang, Qing Kenneth; Xu, Chengqi

doi:10.18632/aging.203755

Cited by 12 publications

(5 citation statements)

References 61 publications

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“…Sequencing of MEF2A exon 11 revealed a rare 21-bp deletion in five CAD patients, indicating that this deletion might be a specific cause of CAD [44]. Wang et al genotyped the rare variant rs34166160 in NINJ2 and demonstrated that rs34166160 significantly confers risk of CAD [45].…”

Section: Discussionmentioning

confidence: 99%

Rare and common coding variants in lipid metabolism-related genes and their association with coronary artery disease

Li,

Wang,

Huang

et al. 2024

BMC Cardiovasc Disord

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Background Coronary artery disease (CAD) is a complex disease that is influenced by environmental and genetic factors. In this study, we aimed to investigate the relationship between coding variants in lipid metabolism-related genes and CAD in a Chinese Han population. Methods A total of 252 individuals were recruited for this study, including 120 CAD patients and 132 healthy control individuals. Rare and common coding variants in 12 lipid metabolism-related genes (ANGPTL3, ANGPTL4, APOA1, APOA5, APOC1, APOC3, CETP, LDLR, LIPC, LPL, PCSK9 and SCARB1) were detected via next-generation sequencing (NGS)-based targeted sequencing. Associations between common variants and CAD were evaluated by Fisher’s exact test. A gene-based association test of rare variants was performed by the sequence kernel association test-optimal (SKAT-O test). Results We found 51 rare variants and 17 common variants in this study. One common missense variant, LIPC rs6083, was significantly associated with CAD after Bonferroni correction (OR = 0.47, 95% CI = 0.29–0.76, p = 1.9 × 10− 3). Thirty-three nonsynonymous rare variants were identified, including two novel variants located in the ANGPTL4 (p.Gly47Glu) and SCARB1 (p.Leu233Phe) genes. We did not find a significant association between rare variants and CAD via gene-based analysis via the SKAT-O test. Conclusions Targeted sequencing is a powerful tool for identifying rare and common variants in CAD. The common missense variant LIPC rs6083 confers protection against CAD. The clinical relevance of rare variants in CAD aetiology needs to be investigated in larger sample sizes in the future.

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Section: Discussionmentioning

confidence: 99%

Rare and common coding variants in lipid metabolism-related genes and their association with coronary artery disease

Li,

Wang,

Huang

et al. 2024

BMC Cardiovasc Disord

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“…Several genomic variants have been associated to date with either risk or severity of PAH, 58 but the mechanisms underlying these associations, particularly those involving the common noncoding variants, are poorly understood. 59 In the case of the tag SNP rs2856830, 60 we investigated associated SNPs, determined functional capacity 61 of those SNPs, and identified differentially binding transcription factors. In doing so, we defined the pathogenic genomic architecture containing SNP rs9277336 including allele‐specific binding of ACTN4 and identified targets that can drive PAH pathogenesis, explaining the association between this genetic locus and PAH outcomes 62 (Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

Single Nucleotide Polymorphism rs9277336 Controls the Nuclear Alpha Actinin 4‐Human Leukocyte Antigen‐DPA1 Axis and Pulmonary Endothelial Pathophenotypes in Pulmonary Arterial Hypertension

Hafeez

Kirillova

Yue

et al. 2023

JAHA

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Background Pulmonary arterial hypertension (PAH) is a complex, fatal disease where disease severity has been associated with the single nucleotide polymorphism (SNP) rs2856830, located near the human leukocyte antigen DPA1 (HLA‐DPA1) gene. We aimed to define the genetic architecture of functional variants associated with PAH disease severity by identifying allele‐specific binding transcription factors and downstream targets that control endothelial pathophenotypes and PAH. Methods and Results Electrophoretic mobility shift assays of oligonucleotides containing SNP rs2856830 and 8 SNPs in linkage disequilibrium revealed functional SNPs via allele‐imbalanced binding to human pulmonary arterial endothelial cell nuclear proteins. DNA pulldown proteomics identified SNP‐binding proteins. SNP genotyping and clinical correlation analysis were performed in 84 patients with PAH at University of Pittsburgh Medical Center and in 679 patients with PAH in the All of Us database. SNP rs9277336 was identified as a functional SNP in linkage disequilibrium ( r 2 >0.8) defined by rs2856830, and the minor allele was associated with decreased hospitalizations and improved cardiac output in patients with PAH, an index of disease severity. SNP pulldown proteomics showed allele‐specific binding of nuclear ACTN4 (alpha actinin 4) protein to rs9277336 minor allele. Both ACTN4 and HLA‐DPA1 were downregulated in pulmonary endothelium in human patients and rodent models of PAH. Via transcriptomic and phenotypic analyses, knockdown of HLA‐DPA1 phenocopied knockdown of ACTN4, both similarly controlling cell structure pathways, immune pathways, and endothelial dysfunction. Conclusions We defined the pathogenic activity of functional SNP rs9277336, entailing the allele‐specific binding of ACTN4 and controlling expression of the neighboring HLA‐DPA1 gene. Through inflammatory or genetic means, downregulation of this ACTN4‐HLA‐DPA1 regulatory axis promotes endothelial pathophenotypes, providing a mechanistic explanation for the association between this SNP and PAH outcomes.

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“…GPCR ligand binding [60], extracellular matrix organization [61], cytokine signaling in immune system [62], interferon signaling [63], signaling by GPCR [64], neuronal system [65] and platelet activation, signaling and aggregation [66] plays an important role in the schizophrenia. Studies have revealed that SIX1 [67], VIP (vasoactive intestinal peptide) [68], GATA6 [69], FRZB (frizzled related protein) [70], CD40 [71], WT1 [72], PCDHGA3 [73], TFAP2B [74], HFE (homeostatic iron regulator) [75], NKX2-5 [76], IGFBP7 [77], HLA-F [78], CCL2 [79], COL1A2 [80], RUNX1 [81], TFF3 [82], IRX4 [83], NOS1 [84], DKK2 [85], IL18R1 [86], ADAM12 [87], NPPC (natriuretic peptide C) [88], COL1A1 [89], ABCG2 [90], SIX2 [91], CSRP1 [92], MR1 [93], NINJ2 [94], ACE (angiotensin I converting enzyme) [95], TBX1 [96], CTSC (cathepsin C) [97], DLX6 [98], KCNE1 [99], AZGP1 [100], CYP1B1 [101], PRRX1 [102], CD34 [103], A2M [104], CDKN2A [105], SERPINE1 [106], CD44 [107], FABP4 [108], ITGB3 [109], ALOX5AP [110], DAND5 [111], SFRP4 [112], RUNX2 [113], TACR3 [114], MYD88 [115], CYBA (cytochrome b-245 alpha chain) [116], STAT6 [117], FOXC1 [118], FN1 [119], TLR6 [120], CAV1 [121], RGS4 [122], TPM2 [123], TNFSF4 [124], LOX (lysyl oxidase) [125], SMOC2 [126], SPHK1 [127], FOLH1 [128], CYP2C8 [129], CD163 [130], DIRAS3 [131], OSMR (oncostatin M receptor) [132], POSTN (peri...…”

Section: Discussionmentioning

confidence: 99%

Screening of the Key Genes and Signaling Pathways for Schizophrenia Using Bioinformatics and Next Generation Sequencing Data Analysis

Vastrad,

Vastrad

2023

Preprint

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Schizophrenia is thought to be the most prevalent chronic psychiatric disorder. Numerous proteins have been identified that are associated with the occurrence and development of schizophrenia. This study aimed to identify potential core genes and pathways involved in schizophrenia, through exhaustive bioinformatic and next generation sequencing (NGS) data analyses using GSE20966 NGS data of neural progenitor cells and neurons obtained from healthy controls and patients with schizophrenia. The NGS data were downloaded from the Gene Expression Omnibus database. NGS data was processed by the DESeq2 package in R software and the differentially expressed genes (DEGs) were identified. Gene Ontology (GO) enrichment analysis and REACTOME pathway enrichment analysis were carried out to identify potential biological functions and pathways of the DEGs. Protein-protein interaction (PPI) network, module, miRNA-hub gene regulatory network and TF-hub gene regulatory network analysis were performed to identify the hub genes, miRNA and TFs. Potential hub genes were analyzed using receiver operating characteristic (ROC) curves in the R package (pROC). In this investigation, an overall 955 DEGs were identified: 478 genes were remarkably up regulated and 477 genes were distinctly down regulated. These genes were enriched for GO terms and pathways mainly involved in the multicellular organismal process, GPCR ligand binding, regulation of cellular process and amine ligand-binding receptors. MYC, FN1, CDKN2A, EEF1G, CAV1, ONECUT1, SYK, MAPK13, TFAP2A and BTK were considered the potential hub genes. miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed successfully. On the whole, the findings of this investigation enhance our understanding of the potential molecular mechanisms of schizophrenia and provide potential targets for further investigation.

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Functional rare variant in a C/EBP beta binding site in NINJ2 gene increases the risk of coronary artery disease

Cited by 12 publications

References 61 publications

Rare and common coding variants in lipid metabolism-related genes and their association with coronary artery disease

Rare and common coding variants in lipid metabolism-related genes and their association with coronary artery disease

Single Nucleotide Polymorphism rs9277336 Controls the Nuclear Alpha Actinin 4‐Human Leukocyte Antigen‐DPA1 Axis and Pulmonary Endothelial Pathophenotypes in Pulmonary Arterial Hypertension

Screening of the Key Genes and Signaling Pathways for Schizophrenia Using Bioinformatics and Next Generation Sequencing Data Analysis

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