Polymorphism of rs599839 in the PSRC1 gene is associated with coronary artery disease in an Iranian population.

Introduction: Coronary artery disease (CAD) is the leading health complication worldwide because of its high prevalence and mortality. The association between CAD susceptibility and the rs599839 (C/T) polymorphism in the human proline and serine-rich coiled-coil (PSRC1) was reported in a genome-wide association study. To validate this association, we performed this case-control study to genotype the 1p13.3 (rs599839) locus in a sample of the Iranian population with CAD (stenosis≥70% in≥1 coronary artery). Methods: We performed an association analysis with PCR and Sanger sequencing of rs599839 (C/T) polymorphism and CAD risk in 280 CAD patients and 287 healthy controls defined as a coronary calcium score of zero and no noncalcified plaques in coronary computed tomography angiography. SPSS, version 16.0, was applied for statistical analysis. Results: The rs599839 (C/T) locus showed a significant association with CAD (P value<0.001). TT and CT genotypes were associated with CAD (P value<0.001). Furthermore, the dominant status (TT+CT vs. CC) was associated with an increased risk of CAD (OR, 9.14; 95% CI, 3.77 to 22.15; and P value<0.001). Conclusion: The study findings indicate strong evidence for rs599839 (C/T) association with CAD risk.

High Expression of PSRC1 Predicts Poor Prognosis in Lung Adenocarcinoma.

Background: The incidence of lung cancer is increasing annually, but the mechanism of its occurrence and development requires further study. This study aimed to investigate the biological function and prognostic value of proline- and serine-rich coiled-coil 1 (PSRC1) in lung cancer. Methods: We used data from The Cancer Genome Atlas (TCGA) to analyze the association between clinical features and PSRC1 expression in non-small cell carcinoma. The relationship between PSRC1 expression and prognosis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) was analyzed using Kaplan-Meier curves. The function of PSRC1 was identified using enrichment analysis, and the relationship between PSRC1 expression and immune cell infiltration was studied. In addition, the expression of PSRC1 in 150 patients with non-small cell carcinoma was detected using immunohistochemistry, and its clinical significance was analyzed. Results: It was found that the expression level of PSRC1 was higher in LUAD and LUSC tumor tissues than in normal tissues, and the results were confirmed by immunohistochemistry in 150 patients. TCGA data showed that high PSRC1 expression in LUAD was associated with poorer overall survival (p = 0.003) and progression-free interval (p = 0.012). Multivariable analysis showed that PSRC1 was an independent risk factor for LUAD. Functional enrichment analysis showed that PSRC1 is related to tumor development. Conclusion: High PSRC1 expression is significantly associated with LUAD survival and may be a promising prognostic biomarker.

PSRC1 Regulated by DNA Methylation Is a Novel Target for LGG Immunotherapy.

Proline and serine-rich coiled-coil 1 (PSRC1) has been reported to function as an oncogene in several cancers by regulating mitosis, while there are few reports on the role of PSRC1 in lower-grade glioma (LGG). Thus, this study collected 22 samples and 1126 samples from our institution and several databases, respectively, to explore the function of PSRC1 in LGG. First, the analysis of clinical characteristics showed that PSRC1 was always highly expressed in more malignant clinical characteristics of LGG, such as higher WHO grade, recurrence type, and IDH wild type. Second, the prognosis analysis revealed that the high expression of PSRC1 was an independent risk factor contributing to the shorter overall survival of LGG patients. Third, the analysis of DNA methylation showed that the expression of PSRC1 was associated with its 8 DNA methylation sites, overall negatively regulated by its DNA methylation level in LGG. Fourth, the analysis of immune correlation revealed that the expression of PSRC1 was positively correlated with the infiltration of 6 immune cells and the expression of 4 well-known immune checkpoints in LGG, respectively. Finally, co-expression analysis and KEGG analysis showed the 10 genes most related to PSRC1 and the signaling pathways involved by PSRC1 in LGG, respectively, such as MAPK signaling pathway and focal adhesion. In conclusion, this study identified the pathogenic role of PSRC1 in the pathological progression of LGG, expanding the molecular understanding of PSRC1, and provided a biomarker and potential immunotherapeutic target for the treatment of LGG.

Association between Genetic Variants of CELSR2-PSRC1-SORT1 and Cardiovascular Diseases: A Systematic Review and Meta-Analysis.

A cluster of three genes CELSR2, PSRC1, and SORT1 has been associated with cardiovascular diseases. Thus, the aim of this study was (i) to perform a systematic review and updated meta-analysis of the association of three polymorphisms (rs646776, rs599839, and rs464218) of this cluster with cardiovascular diseases, and (ii) to explore by PheWAS signals of the three SNPs in cardiovascular diseases and to evaluate the effect of rs599839 with tissue expression by in silico tools. Three electronic databases were searched to identify eligible studies. The meta-analysis showed that the rs599839 (allelic OR 1.19, 95% CI 1.13-1.26, dominant OR 1.22, 95% CI 1.06-1.39, recessive OR 1.23, 95% CI 1.15-1.32), rs646776 (allelic OR 1.46, 95% CI 1.17-1.82) polymorphisms showed an increased risk for cardiovascular diseases. PheWas analysis showed associations with coronary artery disease and total cholesterol. Our results suggest a possible involvement of the CELSR2-PSRC1-SORT1 cluster variants in the risk association of cardiovascular diseases, particularly coronary artery disease.

Integrative RNA profiling of TBEV-infected neurons and astrocytes reveals potential pathogenic effectors.

Tick-borne encephalitis virus (TBEV), the most medically relevant tick-transmitted flavivirus in Eurasia, targets the host central nervous system and frequently causes severe encephalitis. The severity of TBEV-induced neuropathogenesis is highly cell-type specific and the exact mechanism responsible for such differences has not been fully described yet. Thus, we performed a comprehensive analysis of alterations in host poly-(A)/miRNA/lncRNA expression upon TBEV infection in vitro in human primary neurons (high cytopathic effect) and astrocytes (low cytopathic effect). Infection with severe but not mild TBEV strain resulted in a high neuronal death rate. In comparison, infection with either of TBEV strains in human astrocytes did not. Differential expression and splicing analyses with an in silico prediction of miRNA/mRNA/lncRNA/vd-sRNA networks found significant changes in inflammatory and immune response pathways, nervous system development and regulation of mitosis in TBEV Hypr-infected neurons. Candidate mechanisms responsible for the aforementioned phenomena include specific regulation of host mRNA levels via differentially expressed miRNAs/lncRNAs or vd-sRNAs mimicking endogenous miRNAs and virus-driven modulation of host pre-mRNA splicing. We suggest that these factors are responsible for the observed differences in the virulence manifestation of both TBEV strains in different cell lines. This work brings the first complex overview of alterations in the transcriptome of human astrocytes and neurons during the infection by two TBEV strains of different virulence. The resulting data could serve as a starting point for further studies dealing with the mechanism of TBEV-host interactions and the related processes of TBEV pathogenesis.

A Genetic Variant in Proline and Serine Rich Coiled-Coil 1 Gene Is Associated with the Risk of Cardiovascular Disease.

Background: Cardiovascular disease is one of the most common causes of morbidity and mortality worldwide. The Proline and Serine Rich Coiled-Coil 1 gene in 1p13.3 locus has been reported to be associated with low density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD). The objective of this study was to investigate the association between the rs599839 polymorphism of the Proline and Serine Rich Coiled-Coil 1 (PSRC1) gene with CVD outcomes in a population sample recruited as part of the Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort. Methods: Five hundred and nine individuals who had an average follow-up period of 10 years were enrolled as part of the MASHAD cohort. DNA was extracted and genotyped using the TaqMan-real-time-PCR based method. Results: The study found individuals with GA/GG genotypes were at a higher risk of CVDs (OR= 4.7; 95% CI, 2.5-8.7; p< 0.001) in comparison to those with AA genotype; however, the result was not significant for GG genotype data. Conclusion: The results suggest that the GA/GG genotypes of the PSRC1gene locus were at increased risk of CVD in a representative population-based cohort, demonstrating further functional analysis to discover the value of emerging marker as a risk stratification biomarker to recognize high risk cases.

The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients.

BACKGROUND AND AIMS: Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet. METHODS: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (n = 125). RESULTS: The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (p < 0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The minor G allele was associated with higher risk of HCC, independently of fibrosis severity (odds ratio (OR): 5.62; 95% c.i. 1.77-17.84, p = 0.003), poor prognosis and advanced tumor stage (p < 0.05) in the overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p < 0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover (p < 0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation (p < 0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development (p < 0.05). CONCLUSIONS: In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively.

Genetically programmed changes in transcription of the novel progranulin regulator.

Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function of Sall > 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P < 1 × 10-7) in one promoter region, which was in line with a significantly lower PSRC1 mRNA expression levels in blood (P = 1 × 10-3). Consistently, rs629301-A allele was associated with lower PSRC1 mRNA expression (P < 1 × 10-7). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription of PSRC1 through alteration of YY1 binding capacity. DNA methylation studies further support the role of PSRC1 in regulation of progranulin serum levels. KEY MESSAGES: PSRC1 (proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels. rs629301 regulates PSRC1 expression by affecting Yin Yang 1 transcription factor (YY1) binding. PSRC1 is also epigenetically regulated in subjects with high progranulin levels.

The impact of PSRC1 overexpression on gene and transcript expression profiling in the livers of ApoE-/- mice fed a high-fat diet.

Our previous studies have confirmed that proline/serine-rich coiled-coil 1 (PSRC1) overexpression can regulate blood lipid levels and inhibit atherosclerosis (AS) development. In the current study, the gene and transcript expression profiles in the livers of ApoE-/- mice overexpressing PSRC1 were investigated. HiSeq X Ten RNA sequencing (RNA-seq) analysis was used to examine the differentially expressed genes (DEGs) and differentially expressed transcripts in the livers of PSRC1-overexpressing ApoE-/- and control mice. Then, Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these DEGs and on long noncoding RNA (lncRNA) predicted target genes. A total of 1892 significant DEGs were identified: 1431 were upregulated (e.g., Cyp2a4, Obp2a, and Sertad4), and 461 were downregulated (e.g., Moxd1, Egr1, and Elovl3). In addition, 8184 significant differentially expressed transcripts were identified, 4908 of which were upregulated and 3276 of which were downregulated. Furthermore, 1106 significant differentially expressed lncRNAs were detected, 713 of which were upregulated and 393 of which were downregulated. Quantitative reverse transcription PCR (qRT-PCR) verified changes in 10 randomly selected DEGs. GO analyses showed that the DEGs and predicted lncRNA target genes were mostly enriched for actin binding and lipid metabolism. KEGG biological pathway analyses showed that the DEGs in the livers of PSRC1-overexpressing ApoE-/- mice were enriched in the mitogen-activated protein kinase (MAPK) pathway. These findings reveal that PSRC1 may affect liver actin polymerization and cholesterol metabolism-related genes or pathways. These mRNAs and lncRNAs may represent new biomarkers and targets for the diagnosis and therapy of lipid metabolism disturbance and AS.

PSRC1 overexpression attenuates atherosclerosis progression in apoE-/- mice by modulating cholesterol transportation and inflammation.

AIMS: Human genome-wide association studies (GWAS) have found that proline/serine-rich coiled-coil 1 (PSRC1) encodes a protein that is associated with serum lipid levels and coronary artery disease. In addition, our previous study showed that the cholesterol efflux capacity is decreased in macrophages following a treatment silencing Psrc1, indicating that PSRC1 has anti-atherosclerotic effects. However, the role of PSRC1 in the development of atherosclerosis is unknown. This study aims to explore the effect of PSRC1 on atherosclerosis and its underlying mechanisms. METHOD AND RESULTS: A recombinant adenovirus expressing Psrc1 (Ad-PSRC1) was constructed and transfected in RAW264.7 cells as well as injected intravenously into apoE-/- mice. The in vitro study showed that PSRC1 overexpression reduced the cellular cholesterol content, increased the cholesterol efflux capacity and inhibited foam cell formation by upregulating the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and liver X receptor α (LXR-α), which are key cholesterol transportation-related proteins. Infecting apoE-/- mice with Ad-PSRC1 inhibited the development of atherosclerotic lesions and enhanced atherosclerotic plaque stability. Consistent with these results, PSRC1 overexpression in apoE-/- mice decreased the plasma levels of TC, TG, LDL-C, TNF-α, IL-1ß and IL-6, increased the plasma HDL-C levels and improved HDL function. Similarly, the PPAR-γ and LXR-α expression levels were upregulated in the liver and in peritoneal macrophages of PSRC1-overexpressing apoE-/- mice. Finally, the liver and peritoneal macrophages of apoE-/- mice displayed elevated expression of ß-catenin, which is a direct downstream gene of PSRC1 and an upstream gene of PPAR-γ and LXR-α, but decreased activity of nuclear transcription factor (NF-κB), which acts as a key gene in the regulation of inflammation. CONCLUSIONS: PSRC1 protects against the development of atherosclerosis and enhances the stability of plaques by modulating cholesterol transportation and inflammation in macrophages and the liver of apoE-/- mice.

Association of variants in CELSR2-PSRC1-SORT1 with risk of serum lipid traits, coronary artery disease and ischemic stroke.

Recent genome-wide association studies (GWAS) have identified genetic variants associated with coronary artery disease (CAD), ischemic stroke (IS) and serum lipid traits in different ethnic groups. Some loci were found to affect the risk of CAD and IS. However, there were no data in the southern Chinese populations. Our study was to assess the association of CELSR2-PSRC1-SORT1 rs599839, rs464218 and rs6698443 SNPs and serum lipid levels and the risk of CAD and IS. The genotypes of 3 SNPs were detected in 561 CAD and 527 IS patients, and in 590 healthy controls. The genotypic and allelic frequencies of the rs599839 SNP were different between the controls and IS patients (P < 0.05). The minor G alleles of rs599839 and rs464218 SNPs were associated with higher high-density lipoprotein cholesterol concentrations in CAD and IS patients (P < 0.05); respectively. No association was found between the SNPs of rs599839, rs464218 and rs6698843 at the CELSR2-PSRC1-SORT1 and the risk of CAD or IS. These results will be replicated in the other Chinese populations.