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The GTEx dataset revealed a significant eQTL association between the rs1719153 genotype and expression of the CCL4 gene in peripheral whole blood cells.
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Chemokine C-C motif ligand 4 ( CCL4 ) gene is a chemokine-encoding gene, and the polymorphism of CCL4 gene has been shown to predict risk of various diseases. We want to investigate whether the single nucleotide polymorphisms (SNPs) of the CCL4 gene can predict the risk of rheumatoid arthritis (RA). Between 2007 and 2015, we recruited 217 patients...
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Key message
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Citations
... In autoimmune diseases, studies have found a correlation between CCL4 polymorphisms and the risk of rheumatoid arthritis (RA). Modulating CCL4 expression could be a promising therapeutic strategy for treating RA (53). MMPs are a A B FIGURE 9 Ust reduces impaired colonic mucosal in UC patients by regulating the ERSRGs (A, B (54). ...
Background
Endoplasmic reticulum stress (ERS) is a critical factor in the development of ulcerative colitis (UC); however, the underlying molecular mechanisms remain unclear. This study aims to identify pivotal molecular mechanisms related to ERS in UC pathogenesis and provide novel therapeutic targets for UC.
Methods
Colon tissue gene expression profiles and clinical information of UC patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database, and the ERS-related gene set was downloaded from GeneCards for analysis. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were utilized to identify pivotal modules and genes associated with UC. A consensus clustering algorithm was used to classify UC patients. The CIBERSORT algorithm was employed to evaluate the immune cell infiltration. Gene Set Variation Analysis (GSVA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. The external sets were used to validate and identify the relationship of ERS-related genes with biologics. Small molecule compounds were predicted using the Connectivity Map (CMap) database. Molecular docking was performed to simulate the binding conformation of small molecule compounds and key targets.
Results
The study identified 915 differentially expressed genes (DEGs) and 11 ERS-related genes (ERSRGs) from the colonic mucosa of UC patients and healthy controls, and these genes had good diagnostic value and were highly correlated. Five potential small-molecule drugs sharing tubulin inhibitors were identified, including albendazole, fenbendazole, flubendazole, griseofulvin, and noscapine, among which noscapine exhibited the highest correlation with a high binding affinity to the targets. Active UC and 10 ERSRGs were associated with a large number of immune cells, and ERS was also associated with colon mucosal invasion of active UC. Significant differences in gene expression patterns and immune cell infiltration abundance were observed among ERS-related subtypes.
Conclusion
The results suggest that ERS plays a vital role in UC pathogenesis, and noscapine may be a promising therapeutic agent for UC by affecting ERS.
... Several chemokines (CCL3, CCL4, CCL5, CCL3L1, CCL21, CCL26, CXCL8, CXCL9, CXCL10, CXCL12, and CXCL13) have been reported as risk factors for RA development (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Certain chemokines (CCL2, CCL5, CCL20, CCL23, CCL25, CXCL2, CXCL5, CXCL7, CXCL8, CXCL9, CXCL11, CXCL12, and CXCL13) are associated with disease activity and/or severity (40-58). ...
Rheumatoid arthritis (RA) is an autoimmune disease that commonly causes inflammation and bone destruction in multiple joints. Inflammatory cytokines, such as IL-6 and TNF-α, play important roles in RA development and pathogenesis. Biological therapies targeting these cytokines have revolutionized RA therapy. However, approximately 50% of the patients are non-responders to these therapies. Therefore, there is an ongoing need to identify new therapeutic targets and therapies for patients with RA. In this review, we focus on the pathogenic roles of chemokines and their G-protein-coupled receptors (GPCRs) in RA. Inflamed tissues in RA, such as the synovium, highly express various chemokines to promote leukocyte migration, tightly controlled by chemokine ligand-receptor interactions. Because the inhibition of these signaling pathways results in inflammatory response regulation, chemokines and their receptors could be promising targets for RA therapy. The blockade of various chemokines and/or their receptors has yielded prospective results in preclinical trials using animal models of inflammatory arthritis. However, some of these strategies have failed in clinical trials. Nonetheless, some blockades showed promising results in early-phase clinical trials, suggesting that chemokine ligand-receptor interactions remain a promising therapeutic target for RA and other autoimmune diseases.
... In an analysis of cartilage specimens from RA patients and multiorgan donors who served as controls, RT-PCR and flow cytometry revealed higher intracellular CCL4 expression levels among RA patients. Other researchers have also noticed higher CCL4 expression levels in T cells from RA patients (6,(9)(10)(11) . Single nucleotide polymorphisms (SNPs) denote the single nucleotide variations occurring at specific sites in the genome with appreciable frequency within the population. ...
... Single nucleotide polymorphisms (SNPs) denote the single nucleotide variations occurring at specific sites in the genome with appreciable frequency within the population. Genotyping SNPs of a population and comparing the distribution frequency of SNPs among subgroups (e.g., controls and patients) are frequently utilized to exam-ine disease risk and prognosis, including RA (11) . The present study is a case-control study, aimed to investigate whether the single nucleotide polymorphisms (SNPs) of the CCL4 gene can predict the risk of RA disease and whether the studied gene can predict disease activity ...
... Hu et al 2020 reported that in individuals carrying the Tcontaining genotype of the CCL4 rs1719153 polymorphism were not susceptible to RA in Asian population (16) . Kuo et al (2018) recruited between 2007 and 2015, 217 RA patients and 371 control participants. They found that those with the A/T genotype were less likely to develop RA. ...
... Following mitogenic and antigen entry into individual cells, ccl4 is secreted in inflammatory environments or compromised tissue, ultimately contributing to the chemical uptake of immune cells such as natural killers and monocyte to the inflammation and injury site (10,12). The association of ccl4 with liver carcinoma, rheumatoid arthritis, AIDS, breast and oral cancer has been investigated and confirmed in previous studies (10,(12)(13)(14)(15)(16). It is a pro-inflammatory chemokine involved in macrophage recruitment to the site of infection and stimulation of regulatory T cells, and induction of mast cell degranulation. ...
Background & objective:
CCL4 (C-C chemokine ligand4) is a chemoattractant involved in tumors' development, progression, and metastasis. The relationship between the ccl4 gene polymorphisms and the risk of OSCC has not been studied in Iran. This study aimed to identify the effect of ccl4 gene polymorphism on OSCC susceptibility in the population of Southeastern Iran.
Methods:
In this case-control study, a total of 100 participants, 50 patients with OSCC who were referred to the Department of Oral Pathology, Faculty of Dentistry, Zahedan University of Medical Sciences, Iran, and 50 healthy people were included. The DNA was extracted from the tissue blocks of OSCC patients. The rs10491121 and rs1634507 in the ccl4 gene were evaluated by the tetra-ARMS (Amplification Refractory Mutation System)- PCR technique. Data were analyzed in SPSS (version 21) using the Chi-square and logistic regression test.
Results:
CCL4 genotyping showed that AA+AG genotype in rs10491121 and AA+CA genotype in rs1634507 were slightly higher in control than in the case. Still, the risk of OSCC in both polymorphisms was not significantly different. The minor allele (A) in the rs10491121 and rs1634507 polymorphisms were more common in OSCC compared to the control group (OR = 1.2, 95% CI: 0.66 - 2.22, P=0.54) (OR = 1.6, 95% CI: 0.85-3.07, P=0.15). There was no association between OSCC histopathological grades and CCL4 genotypes at these two sites.
Conclusion:
Our results showed no association between ccl4 gene polymorphism and the risk of oral cancer in the population of Southeastern Iran.
... String showed that CD209 was majorly located on plasma membrane ( Figure S1), and from there, it was found that decrease of CD209 downstream induces high levels of chemokine C-C motif ligand 3 and 4 (CCL3 and CCL4). A study showed that high level of CCL4 is associated with susceptibility of RA, 33 and another study found that using CCL3 null mice model showed that CCL3 is essential for joint inflammation and destruction in mice. 34 Furthermore, our study found protein-protein interaction between CD209 and other subcellular molecules such as Dectin-1, also known as CLEC7A ...
Single nucleotide polymorphisms (SNPs) in the promoter region of CD209 (cluster of differentiation 209) may influence expression levels, and higher expression of CD209 on immune cells correlate with severity of cartilage destruction in patients with rheumatoid arthritis (RA). Due to the lack of a comprehensive study, this study aimed to investigate the CD209 promoter variants and haplotypes in a Taiwanese population and the association with RA development. Deoxyribonucleic acid (DNA) of peripheral blood mononuclear cells from 126 RA patients and 124 healthy controls was purified, and the CD209 gene promoter was amplified by polymerase chain reaction and analyzed by Sanger sequencing. Results showed that a novel variant −96C>A polymorphism in CD209 promoter was identified in the Taiwanese population, and the frequency was significantly higher in RA patients than in controls (11.51% vs. 2.42%, P < .0001). The odds ratio (OR) for the development of RA was 5.88 (95% CI 2.35–14.74, P < .0001). Other known variants were also evaluated; for instance, −1180 T/T (rs7359874) was increased in RA patients, and the OR for the development of RA was 3.26, 95% CI 0.85–12.52, P = .07). Besides, the haplotype frequencies were calculated; −1180A‐939C‐871 T‐336 T‐139 T‐96A and −1180 T‐939 T‐871C‐336 T‐139C‐96A were increased in RA patients (P = .004 and 0.05, respectively). In summary, CD209‐96A variant could be an important factor for the development of RA in the Taiwanese population.
... [15][16][17] SNPs in the CCL4 chemokine gene are known to be associated with breast cancer, oral cancer, and hepatocellular carcinoma, [18][19][20] while a recent study has reported a protective effect against the risk of developing rheumatoid arthritis in individuals carrying the T-containing genotype of the CCL4 rs1719153 polymorphism. [21] Thus, the evidence suggests that it is worth seeking associations between CCL4 gene polymorphisms and lung cancer diagnosis. Our case-control study therefore sought to determine possible associations between three SNPs (rs1634507, rs1719153, and rs10491121) in the CCL4 gene and lung cancer. ...
Lung cancer is the most common malignancy in China and has a low survival rate amongst Han Chinese. The high mortality is largely attributed to late-stage diagnosis, when treatment is largely ineffective. Identification of genetic variants could potentially assist with earlier diagnosis and thus more effective treatment. Chemokine (C-C motif) ligand 4 (CCL4) plays a critical role as a chemoattractant in tumor development, metastasis and angiogenesis. In this study, we explored three CCL4 single nucleotide polymorphisms (SNPs) (rs1634507, rs1719153, and rs10491121) in 538 patients with lung cancer and 370 healthy, cancer-free controls. Carriers of the GT + TT heterozygote of rs1634507 had a lower risk of lung cancer than wild-type (GG) carriers, while the presence of the AG + GG heterozygote at rs10491121 was associated with a higher risk of lung cancer compared with having the AA genotype. The G/A/G and T/A/A CCL4 haplotypes significantly reduced and increased the risks for lung cancer, respectively. Our study is the first to document correlations between CCL4 polymorphisms and lung cancer development and progression in people of Han Chinese ethnicity.
... Hu et al. have found an association between CCL4 gene polymorphisms and clinical aspects of breast cancer (18). In addition, SNPs belonging to the gene have also been investigated in relation to several immunologic and infectious diseases such as rheumatoid arthritis (40), psoriasis (41), susceptibility to tuberculosis (42), HIV infection (43) and AIDS progression (44). The rs1719217 is situated around 23 kb from CCL4 and it is predicted to alter its expression in several tissues including whole blood. ...
There is overwhelming evidence that inflammation plays a key role in the pathogenesis of cancer and its progression. Inflammation is regulated through a complex network of genes and polymorphic variants in these genes have been found to be associated to risk of various human cancers, alone or in combination with environmental variables. Despite this, not much is known on the genetic variability of genes that regulate inflammation and risk of pancreatic ductal adenocarcinoma (PDAC). We performed a two-phase association study considering the genetic variability of 76 genes that are key players in inflammatory response. We analysed tagging single nucleotide polymorphisms (SNPs) and regulatory SNPs on 7207 PDAC cases and 7063 controls and observed several associations with PDAC risk. The most significant association was between the carriers of the A allele of the CCL4-rs1719217 polymorphism, which was reported to be also associated with the expression level of the CCL4 gene, and increased risk of developing PDAC (odds ratio = 1.12, 95% confidence interval = 1.06-1.18, P = 3.34 × 10 −5). This association was significant also after correction for multiple testing, highlighting the importance of using potentially functional SNPs in order to discover more genetic variants associated with PDAC risk.
... Rheumatoid arthritis (RA) presents with prominent hypertrophy and hypervascularity of the synovial tissues and consequent joint destruction, and affects around 1% of the global population. [1][2][3] Anti-inflammation drugs are most common for RA treatment. [4,5] In spite of the recent advent of biological agents enabling some RA patients to reach disease remission or at least low disease activity, a substantial proportion remain treatment-refractory and suffer from progressive joint destruction, functional deterioration or even premature mortality. ...
... Single nucleotide polymorphisms (SNPs) are single nucleotide variations occurring at specific sites in the genome with substantial frequency within the general population. [1,2,10,11] Genotyping SNPs and comparing the frequency of SNPs among subgroups (e.g., controls and patients) are frequently used to stratify the risk and prognosis of human diseases, including RA. [1,2,12] The SNPs of high-mobility group box protein 1 (HMGB1), resistin (RETN), chemokine C-C motif ligand 4 (CCL4), and angiopoietin-2 (Ang2) genes have been shown to be associated with RA susceptibility. [1,2,12,13] WNT1 inducible signaling pathway protein-1 (WISP-1), also known as CCN4 or Elm1, is a cysteine-rich protein belonging to the CCN superfamily. ...
... Single nucleotide polymorphisms (SNPs) are single nucleotide variations occurring at specific sites in the genome with substantial frequency within the general population. [1,2,10,11] Genotyping SNPs and comparing the frequency of SNPs among subgroups (e.g., controls and patients) are frequently used to stratify the risk and prognosis of human diseases, including RA. [1,2,12] The SNPs of high-mobility group box protein 1 (HMGB1), resistin (RETN), chemokine C-C motif ligand 4 (CCL4), and angiopoietin-2 (Ang2) genes have been shown to be associated with RA susceptibility. [1,2,12,13] WNT1 inducible signaling pathway protein-1 (WISP-1), also known as CCN4 or Elm1, is a cysteine-rich protein belonging to the CCN superfamily. ...
This study genotyped blood samples from 214 patients with rheumatoid arthritis (RA) and 293 healthy controls for single nucleotide polymorphisms (SNPs) rs2977537, rs2929970, rs2929973, rs2977530, rs1689334 and rs62514004. We want to investigate whether the SNPs in the WNT1-inducible signaling pathway protein 1 (WISP-1) gene may increase the risk of developing RA. We showed that RA disease was more likely with the AA genotype compared with the AG genotype of SNP rs2977537 (adjusted odds ratio [AOR]: 0.54; 95% confidence interval [CI]: 0.34-0.84), and with the TT genotype (AOR: 0.24; 95% CI: 0.13-0.39) or the GG genotype (AOR: 0.05; 95% CI: 0.03-0.10) compared with the GT genotype of rs2929973, and with the AA genotype (AOR: 0.34; 95% CI: 0.22-0.54) or GG genotype (AOR: 0.52; 95% CI: 0.31 to 0.87) vs the AG genotype of rs2977530. Rheumatoid factor positivity was more likely with the AA genotype than with the AG genotype of the rs2977537 polymorphism (AOR: 0.16; 95% CI: 0.16-0.94). High CRP (>8 mg/L) was more likely with the non-AG genotype (AA + GG) than the AG genotype of rs2977537 (AOR: 1.84; 95% CI: 1.05-3.21) and with the AA genotype vs the AG genotype of rs2977530 (AOR: 2.62; 95% CI: 1.35-5.09). Compared with the AG genotype, the AA genotype of rs2929970 was more likely to require prednisolone (AOR: 0.49; 95% CI: 0.27-0.88), while the AG genotype was more likely than the AA genotype of SNP rs2977530 to require TNF-α inhibitors (AOR: 2.07; 95% CI: 1.08 to 3.98). WISP-1 may be a diagnostic marker and therapeutic target for RA therapy.
... The Friedman test was used for repeated measures analysis of repeated within-group comparisons for continuous variables, and the Wilcoxon signed-rank test was used for post hoc analysis. All statistical analyses were performed using SPSS software, and a p-value of < 0.05 was considered to indicate statistical significance [2,29,30]. ...
Background:
Venous thromboembolism (VTE) is a major sequela after total knee arthroplasty (TKA). We prospectively compared the differences in the perioperative plasma D-dimer and fibrinogen levels between the individuals undergoing TKA via computer-assisted navigation and via a conventional method as the surrogate comparison for VTE. There were 174 patients fulfilling the inclusion criteria and providing valid informed consent between September 2011 and November 2013. There were 69 females and 20 males in the navigation-assisted group (median age: 71.00 years), while the conventional group was composed of 59 females and 26 males (median age: 69.00 years). Blood samples were obtained prior to and at 24 and 72 h after surgery for measurement of the levels of plasma D-dimer and fibrinogen.
Results:
A significantly lower plasma D-dimer level 24 h after TKA (p = 0.001) and a milder postoperative surge 24 h after TKA (p = 0.002) were observed in patients undergoing navigation-assisted TKA. The proportions of subjects exceeding the plasma D-dimer cut-off values of 7.5, 8.6 and 10 mg/L 24 h after TKA were all significantly higher in the conventional group than in the navigation-assisted group (p = 0.024, 0.004, and 0.004, respectively).
Conclusions:
A lower plasma D-dimer level and a milder surge in the plasma D-dimer level were observed in patients undergoing navigation-assisted TKA in comparison with patients undergoing conventional TKA 24 h after surgery. These findings may supplement the known advantages of navigation-assisted TKA.
... Rheumatoid arthritis (RA) is an autoimmune disease that manifests hypertrophy and hypervascularity in synovial tissues and leads to joint destruction, affecting approximately 1% of the global population [1][2][3][4]. Despite several treatment regimens emerging in recent years that have enabled a substantial portion of RA patients to achieve disease remission with minimal symptoms, some patients remain treatment-refractory and continue to experience progressive joint deterioration and increasing functional limitations, or even premature mortality [5][6][7]. When compared with the general population, RA patients face higher risks of major morbidities, including infection and pulmonary and renal disease, and an approximate 1.5-fold higher risk of mortality [8]. ...
... When compared with the general population, RA patients face higher risks of major morbidities, including infection and pulmonary and renal disease, and an approximate 1.5-fold higher risk of mortality [8]. The fact that genetic factors account for around 60% of the overall susceptibility to RA highlights the importance of research into the genetic basis for RA [5,9]. Research into RA genetics may facilitate risk prediction and enable individually Ivyspring International Publisher tailored treatment [6,10]. ...
Vascular endothelial growth factor C (VEGF-C) promotes angiogenesis, a prominent feature in rheumatoid synovitis, contributing to the perpetuation of the global burden of rheumatoid arthritis (RA). VEGF-C gene polymorphisms predict the risk of developing various human diseases, such as urothelial cell carcinoma, oral cancer and coronary artery disease. We sought to determine whether single nucleotide polymorphisms (SNPs) of the VEGF-C gene can predict the risk of RA. Our study recruited 210 patients with RA and 373 healthy controls between 2007 and 2015, and performed comparative genotyping for SNPs rs7664413, rs11947611, rs1485766, rs2046463 and rs3775194. In analyses adjusted for potential covariates, we found that compared with subjects with the A/A genotype of SNP rs11947611, those with the A/G genotype were 40% more likely to develop RA (adjusted odds ratio [AOR] 0.61; 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In addition, subjects lacking the A/A genotype (A/G, G/G) of SNP rs2046463 were more than twice as likely as those with the A/A genotype to require methotrexate (AOR 2.23, 95% CI 1.25 to 3.98; p = 0.01), while those who lacked the G/G genotype (G/C, C/C) in the SNP rs3775194 had a significantly lower risk of requiring prednisolone as compared with those with the G/G genotype (AOR 0.39, 95% CI 0.19 to 0.79; p = 0.01). Our findings suggest that VEGF-C gene polymorphisms might serve as a diagnostic marker and therapeutic target for RA therapy. Pharmacotherapies that modulate the activity of the VEGF-C gene may be promising for RA treatment.
