Putative regulatory functions of SNPs associated with bronchial asthma, arterial hypertension and their comorbid phenotype

Linkage disequilibrium (LD) of single nucleotide polymorphisms (SNPs) of TLR4/AL160272.2 (rs1927914, rs1928298, rs7038716, rs7026297, rs7025144) was estimated in the Slavs of West Siberia. We further investigated an association of SNPs in TLR4/AL160272.2 (rs1927914, rs7038716, rs7025144), SERPINA1 (rs1980616), ATXN2/BRAP (rs11065987), IL2RB (rs2284033), NT5C2 (rs11191582), CARD8 (rs11669386), ANG/RNASE4 (rs1010461), and ABTB2/ САТ (rs2022318) genes with bronchial asthma (BA), arterial hypertension (AH) and their comorbidity. Then, the disease-associated SNPs were annotated in silico in relation to their potential regulatory functions. Strong LD was detected between rs1928298 and rs1927914, as well as rs7026297 and rs7038716 in the Slavs of West Siberia. It was found that the rs1927914 G allele of the TLR4 gene and the rs1980616 C allele of the SERPINA1 gene are associated with the predisposition to BA. These SNPs can affect binding affinity of transcription factors of the Pou and Klf4 families, as well as the expression levels of the TLR4 and SERPINA1 genes. The rs11065987 allele A of the ATXN2/BRAP genes, the rs11669386 A allele of the CARD8 gene, the rs2284033 allele G of the IL2RB gene, and the rs11191582 allele G of the NT5C2 gene were associated with the risk of AH. These variants can alter binding affinity of the Hoxa9, Irf, RORalpha1 and HMG-IY transcription factors, as well as the expression levels of the ALDH2, CARD8, NT5C2, ARL3, and SFXN2 genes in blood cells/vessels/heart, respectively. The risk of developing a comorbid phenotype of AD and AH is associated with the A allele of rs7038716 and the T allele of rs7025144 of the TLR4/AL160272.2 genes, the A allele of rs1010461 of the ANG gene and the C allele of rs2022318 of the ABTB2/CAT genes. Variants rs7038716 and rs7025144 can change the expression levels of the TLR4 gene in blood cells, while rs1010461 and rs2022318 influence the expression levels of the ANG and RNASE4 genes as well as the CAT and ABTB2 genes in blood cells, lungs/vessels/heart.

Download Full-text

Enhancement of Plasminogen Binding to U937 Cells and Fibrin by Complestatin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655921 ◽

1997 ◽

Vol 77 (01) ◽

pp. 137-142 ◽

Cited By ~ 20

Author(s):

Kiyoshi Tachikawa ◽

Keiji Hasurni ◽

Akira Endo

Keyword(s):

Binding Site ◽

Binding Affinity ◽

Blood Cells ◽

Aminocaproic Acid ◽

U937 Cells ◽

Biochemical Basis ◽

Equilibrium Binding ◽

Pharmacological Stimulation ◽

Endogenous Fibrinolysis ◽

Stimulation Of

SummaryPlasminogen binds to endothelial and blood cells as well as to fibrin, where the zymogen is efficiently activated and protected from inhibition by α2-antiplasmin. In the present study we have found that complestatin, a peptide-like metabolite of a streptomyces, enhances binding of plasminogen to cells and fibrin. Complestatin, at concentrations ranging from 1 to 5 μM, doubled 125I-plasminogen binding to U937 cells both in the absence and presence of lipoprotein(a), a putative physiological competitor of plasminogen. The binding of 125I-plasminogen in the presence of complestatin was abolished by e-aminocaproic acid, suggesting that the lysine binding site(s) of the plasminogen molecule are involved in the binding. Equilibrium binding analyses indicated that complestatin increased the maximum binding of 125I-plasminogen to U937 cells without affecting the binding affinity. Complestatin was also effective in increasing 125I-plasminogen binding to fibrin, causing 2-fold elevation of the binding at ~1 μM. Along with the potentiation of plasminogen binding, complestatin enhanced plasmin formation, and thereby increased fibrinolysis. These results would provide a biochemical basis for a pharmacological stimulation of endogenous fibrinolysis through a promotion of plasminogen binding to cells and fibrin.

Download Full-text

Anti-glioma Efficacy and Mechanism of Action of Tripolinolate A from Tripolium pannonicum

Planta Medica ◽

10.1055/s-0044-101038 ◽

2018 ◽

Vol 84 (11) ◽

pp. 786-794

Author(s):

Weiyun Chai ◽

Lu Chen ◽

Xiao-Yuan Lian ◽

Zhizhen Zhang

Keyword(s):

Cell Cycle ◽

Transcription Factors ◽

Glioma Cells ◽

Inhibitory Effect ◽

Cell Cycle Regulators ◽

Expression Levels ◽

Multiple Tumor ◽

Glioma Growth

AbstractTripolinolate A as a new bioactive phenolic ester was previously isolated from a halophyte of Tripolium pannonicum. However, the in vitro and in vivo anti-glioma effects and mechanism of tripolinolate A have not been investigated. This study has demonstrated that (1) tripolinolate A inhibited the proliferation of different glioma cells with IC50 values of 7.97 to 14.02 µM and had a significant inhibitory effect on the glioma growth in U87MG xenograft nude mice, (2) tripolinolate A induced apoptosis in glioma cells by downregulating the expressions of antiapoptotic proteins and arrested glioma cell cycle at the G2/M phase by reducing the expression levels of cell cycle regulators, and (3) tripolinolate A also remarkably reduced the expression levels of several glioma metabolic enzymes and transcription factors. All data together suggested that tripolinolate A had significant in vitro and in vivo anti-glioma effects and the regulation of multiple tumor-related regulators and transcription factors might be responsible for the activities of tripolinolate A against glioma.

Download Full-text

The concerted regulatory functions of the transcription factors nuclear factor-1 and upstream stimulatory factor on a composite element in the promoter of the hepatocyte growth factor gene

Oncogene ◽

10.1038/sj.onc.1203581 ◽

2000 ◽

Vol 19 (23) ◽

pp. 2786-2790 ◽

Cited By ~ 10

Author(s):

Jie-Gen Jiang ◽

Bin Gao ◽

Reza Zarnegar

Keyword(s):

Transcription Factors ◽

Growth Factor ◽

Nuclear Factor ◽

Upstream Stimulatory Factor ◽

Factor Gene ◽

Growth Factor Gene ◽

Nuclear Factor 1 ◽

Regulatory Functions ◽

Stimulatory Factor ◽

Hepatocyte Growth

Download Full-text

Characterization and risk association of polymorphisms in Aurora kinases A, B and C with genetic susceptibility to gastric cancer development

BMC Cancer ◽

10.1186/s12885-019-6133-z ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Aner Mesic ◽

Marija Rogar ◽

Petra Hudler ◽

Nurija Bilalovic ◽

Izet Eminovic ◽

...

Keyword(s):

Gastric Cancer ◽

Transcription Factors ◽

In Silico ◽

In Silico Analysis ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Mitotic Kinases ◽

Genes Encoding ◽

Silico Analysis ◽

Control Study

Abstract Background Single nucleotide polymorphisms (SNPs) in genes encoding mitotic kinases could influence development and progression of gastric cancer (GC). Methods Case-control study of nine SNPs in mitotic genes was conducted using qPCR. The study included 116 GC patients and 203 controls. In silico analysis was performed to evaluate the effects of polymorphisms on transcription factors binding sites. Results The AURKA rs1047972 genotypes (CT vs. CC: OR, 1.96; 95% CI, 1.05–3.65; p = 0.033; CC + TT vs. CT: OR, 1.94; 95% CI, 1.04–3.60; p = 0.036) and rs911160 (CC vs. GG: OR, 5.56; 95% CI, 1.24–24.81; p = 0.025; GG + CG vs. CC: OR, 5.26; 95% CI, 1.19–23.22; p = 0.028), were associated with increased GC risk, whereas certain rs8173 genotypes (CG vs. CC: OR, 0.60; 95% CI, 0.36–0.99; p = 0.049; GG vs. CC: OR, 0.38; 95% CI, 0.18–0.79; p = 0.010; CC + CG vs. GG: OR, 0.49; 95% CI, 0.25–0.98; p = 0.043) were protective. Association with increased GC risk was demonstrated for AURKB rs2241909 (GG + AG vs. AA: OR, 1.61; 95% CI, 1.01–2.56; p = 0.041) and rs2289590 (AC vs. AA: OR, 2.41; 95% CI, 1.47–3.98; p = 0.001; CC vs. AA: OR, 6.77; 95% CI, 2.24–20.47; p = 0.001; AA+AC vs. CC: OR, 4.23; 95% CI, 1.44–12.40; p = 0.009). Furthermore, AURKC rs11084490 (GG + CG vs. CC: OR, 1.71; 95% CI, 1.04–2.81; p = 0.033) was associated with increased GC risk. A combined analysis of five SNPs, associated with an increased GC risk, detected polymorphism profiles where all the combinations contribute to the higher GC risk, with an OR increased 1.51-fold for the rs1047972(CT)/rs11084490(CG + GG) to 2.29-fold for the rs1047972(CT)/rs911160(CC) combinations. In silico analysis for rs911160 and rs2289590 demonstrated that different transcription factors preferentially bind to polymorphic sites, indicating that AURKA and AURKB could be regulated differently depending on the presence of particular allele. Conclusions Our results revealed that AURKA (rs1047972 and rs911160), AURKB (rs2241909 and rs2289590) and AURKC (rs11084490) are associated with a higher risk of GC susceptibility. Our findings also showed that the combined effect of these SNPs may influence GC risk, thus indicating the significance of assessing multiple polymorphisms, jointly. The study was conducted on a less numerous but ethnically homogeneous Bosnian population, therefore further investigations in larger and multiethnic groups and the assessment of functional impact of the results are needed to strengthen the findings.

Download Full-text

Molecular Relationships between Bronchial Asthma and Hypertension as Comorbid Diseases

Journal of Integrative Bioinformatics ◽

10.1515/jib-2018-0052 ◽

2018 ◽

Vol 15 (4) ◽

Cited By ~ 4

Author(s):

Elena Yu. Bragina ◽

Irina A. Goncharova ◽

Anna F. Garaeva ◽

Evgeniy V. Nemerov ◽

Anastasija A. Babovskaya ◽

...

Keyword(s):

Bronchial Asthma ◽

Genetic Background ◽

Regulation Of Gene Expression ◽

Common Phenomenon ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Multiple Factors ◽

Comorbid Diseases ◽

Set Up ◽

Molecular Relationships

AbstractComorbidity, a co-incidence of several disorders in an individual, is a common phenomenon. Their development is governed by multiple factors, including genetic variation. The current study was set up to look at associations between isolated and comorbid diseases of bronchial asthma and hypertension, on one hand, and single nucleotide polymorphisms associated with regulation of gene expression (eQTL), on the other hand. A total of 96 eQTL SNPs were genotyped in 587 Russian individuals. Bronchial asthma alone was found to be associated with rs1927914 (TLR4), rs1928298 (intergenic variant), and rs1980616 (SERPINA1); hypertension alone was found to be associated with rs11065987 (intergenic variant); rs2284033 (IL2RB), rs11191582 (NT5C2), and rs11669386 (CARD8); comorbidity between asthma and hypertension was found to be associated with rs1010461 (ANG/RNASE4), rs7038716, rs7026297 (LOC105376244), rs7025144 (intergenic variant), and rs2022318 (intergenic variant). The results suggest that genetic background of comorbidity of asthma and hypertension is different from genetic backgrounds of both diseases manifesting isolated.

Download Full-text

ETS-Related Gene (ERG) and Friend leukemia integration – 1 (FLI-1) Transcription Factors in the Precision Treatment of Pulmonary Arterial Hypertension and Pulmonary Fibrosis

Journal of Cancer Epidemiology & Treatment ◽

10.24218/jcet.2019.21 ◽

2019 ◽

Vol 3 (1) ◽

pp. 1-4

Author(s):

E Shyam P. Reddy

Keyword(s):

Transcription Factors ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Fibrosis ◽

Arterial Hypertension ◽

Related Gene ◽

Friend Leukemia ◽

Pulmonary Arterial

Download Full-text

Association of single‐nucleotide polymorphisms in TLR4 gene and gene–environment interaction with primary open angle glaucoma in a Chinese northern population

The Journal of Gene Medicine ◽

10.1002/jgm.3139 ◽

2019 ◽

Vol 22 (1) ◽

Author(s):

Huijuan Liu ◽

Shixin Qi ◽

Wei He ◽

Cuirong Chang ◽

Yanhui Chen ◽

...

Keyword(s):

Primary Open Angle Glaucoma ◽

Open Angle Glaucoma ◽

Environment Interaction ◽

Nucleotide Polymorphisms ◽

Open Angle ◽

Northern Population ◽

Single Nucleotide ◽

Gene Environment Interaction ◽

Gene Environment ◽

Tlr4 Gene

Download Full-text

Genetically Determined Physical Activity and Its Association with Circulating Blood Cells

Genes ◽

10.3390/genes10110908 ◽

2019 ◽

Vol 10 (11) ◽

pp. 908 ◽

Cited By ~ 2

Author(s):

Femke M. Prins ◽

M. Abdullah Said ◽

Yordi J. van de Vegte ◽

Niek Verweij ◽

Hilde E. Groot ◽

...

Keyword(s):

Physical Activity ◽

Blood Cells ◽

Fixed Effects ◽

Mendelian Randomization ◽

P Value ◽

Nucleotide Polymorphisms ◽

Increased Risk ◽

Inflammatory State ◽

The Uk ◽

Genetically Determined

Lower levels of physical activity (PA) have been associated with increased risk of cardiovascular disease. Worldwide, there is a shift towards a lifestyle with less PA, posing a serious threat to public health. One of the suggested mechanisms behind the association between PA and disease development is through systemic inflammation, in which circulating blood cells play a pivotal role. In this study we investigated the relationship between genetically determined PA and circulating blood cells. We used 68 single nucleotide polymorphisms associated with objectively measured PA levels to perform a Mendelian randomization analysis on circulating blood cells in 222,645 participants of the UK Biobank. For inverse variance fixed effects Mendelian randomization analyses, p < 1.85 × 10−3 (Bonferroni-adjusted p-value of 0.05/27 tests) was considered statistically significant. Genetically determined increased PA was associated with decreased lymphocytes (β = –0.03, SE = 0.008, p = 1.35 × 10−3) and decreased eosinophils (β = –0.008, SE = 0.002, p = 1.36 × 10−3). Although further mechanistic studies are warranted, these findings suggest increased physical activity is associated with an improved inflammatory state with fewer lymphocytes and eosinophils.

Download Full-text