scholarly journals IL-6R protective variant rs7529229 reduces interleukin-6 signaling and contributes to decreased ischemic stroke risk

2020 ◽  
Author(s):  
Haihua Zhang ◽  
Wenbo Zhao ◽  
Bian Liu ◽  
Tao Wang ◽  
Zhifa Han ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ischemic Stroke ◽  
Expression Analysis ◽  
Interleukin 6 ◽  
Whole Blood ◽  
Gene Expression Analysis ◽  
Minor Allele ◽  
Healthy Controls ◽  
Increased Risk ◽  
Stage 1

Abstract BackgroundInterleukin-6 (IL-6) signaling is associated with the increased risk of coronary artery disease (CAD) and ischemic stroke (IS). Growing evidence shows that the minor allele of IL-6R rs7529229 variant could significantly increase the soluble IL-6 receptor levels and reduce CAD risk. However, it is largely unknown about the role of rs7529229 in IS, which promotes us to perform a comprehensive analysis. MethodsIn stage 1, we performed a meta-analysis of three GWAS datasets from MEGASTROKE, UK Biobank, and Million Veteran Program to evaluate the association of rs7529229 with IS. In stage 2, we conducted an expression quantitative trait loci analysis to examine the effects of rs7529229 on IL-6R expression in neuropathologically normal individuals from UK Brain Expression Consortium, GTEx project and eQTLGen Consortium. In stage 3, a tissue-specific gene expression analysis is used to evaluate the potential difference of IL-6R expression across the human tissues using gene expression data from GTEx. In stage 4, a case-control gene expression analysis is used to explore the potentially differential expression of IL-6R in IS and healthy controls in whole blood. ResultsOur results show that (1) rs7529229 minor allele could significantly reduce the risk of IS (OR=0.97, 95% CI 0.95-0.99, P=2.30E-03); (2) rs7529229 minor allele could significantly reduce IL-6R expression in relevant tissues especially in blood vessels and whole blood; (3) IL-6R is mainly expressed in skeletal muscle and whole blood; (4) expression of IL-6R is significantly reduced in healthy controls compared with IS cases in whole blood. Importantly, the biological senses in stage 1-4 are all convergent. ConclusionsCollectively, these findings indicate that rs7529229 minor allele may first reduce IL-6R expression in relevant tissues, further reduce IL-6 signaling, and eventually reduce the IS risk. Hence, IL-6R may be a potential therapeutic target, and blocking IL-6 signaling might be effective in treatment of IS.

scholarly journals IL-6R Protective Variant rs7529229 Reduces Interleukin-6 Signaling and Contributes To A Decreased Ischemic Stroke Risk

2020 ◽  
Author(s):  
Haihua Zhang ◽  
Wenbo Zhao ◽  
Bian Liu ◽  
Tao Wang ◽  
Zhifa Han ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ischemic Stroke ◽  
Expression Analysis ◽  
Interleukin 6 ◽  
Whole Blood ◽  
Gene Expression Analysis ◽  
Minor Allele ◽  
Specific Gene ◽  
Healthy Controls ◽  
Increased Risk

Abstract Background Interleukin-6 (IL-6) signaling is associated with an increased risk of coronary artery disease (CAD) and ischemic stroke (IS). Growing evidence shows that the minor alleles of IL-6 receptor gene (IL-6R) variants rs2228145, rs7529229, and rs4129267 significantly increase soluble IL-6R levels and reduce CAD risk. However, the role of IL-6R variants in IS is largely unknown, prompting us to perform a comprehensive analysis. Methods In stage 1 of this study, we performed a meta-analysis of three genome-wide association study datasets from MEGASTROKE, UK Biobank, and the Million Veteran Program to evaluate the association of rs7529229 with IS. In stage 2, we conducted an expression quantitative trait loci analysis to examine the effects of rs7529229 on IL-6R expression in neuropathologically healthy individuals from the UK Brain Expression Consortium, GTEx project, and the eQTLGen Consortium. In stage 3, we used a tissue-specific gene expression analysis to evaluate differences in IL-6R expression across human tissues using gene expression data from GTEx. In stage 4, we conducted a case–control gene expression analysis to explore the differential expression of IL-6R in the whole blood of IS patients and healthy controls. Results We found that: (1) the rs7529229 minor allele significantly reduced the risk of developing IS (odds ratio=0.97, 95% confidence interval 0.95–0.99, P=2.30E-03); (2) the rs7529229 minor allele significantly reduced IL-6R expression in relevant tissues especially in blood vessels and whole blood; (3) IL-6R was mainly expressed in skeletal muscle and whole blood; and (4) IL-6R expression was significantly reduced in the whole blood of healthy controls compared with IS patients. Importantly, the biological senses in stages 1–4 were all convergent. Conclusions Taken together, our findings indicate that the rs7529229 minor allele decreases IL-6R expression in relevant tissues, diminishes IL-6 signaling, and eventually reduces the IS risk. Hence, IL-6R may be a potential therapeutic target for IS. Tocilizumab, a monoclonal antibody that blocks both membrane-bound and circulating IL-6R, might be effective in treating IS or lowering its risk of development, so warrants further testing in suitably powered randomized controlled trials.

scholarly journals Gene Expression Analysis of the Effect of Ischemic Infarction in Whole Blood

2017 ◽  
Vol 18 (11) ◽  
pp. 2335 ◽  
Author(s):  
Ayako Takuma ◽  
Arata Abe ◽  
Yoshikazu Saito ◽  
Chikako Nito ◽  
Masayuki Ueda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Analysis ◽  
Whole Blood ◽  
Gene Expression Analysis ◽  
Ischemic Infarction

scholarly journals Gene expression analysis of whole blood RNA from pigs infected with low and high pathogenic African swine fever viruses

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Crystal Jaing ◽  
Raymond R. R. Rowland ◽  
Jonathan E. Allen ◽  
Andrea Certoma ◽  
James B. Thissen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Analysis ◽  
Whole Blood ◽  
Gene Expression Analysis ◽  
African Swine Fever ◽  
High Pathogenic

scholarly journals Sensitive and Quantitative Measurement of Gene Expression Directly from a Small Amount of Whole Blood

2006 ◽  
Vol 52 (7) ◽  
pp. 1294-1302 ◽  
Author(s):  
Zhi Zheng ◽  
Yuling Luo ◽  
Gary K McMaster
Keyword(s):  
Gene Expression ◽  
Expression Analysis ◽  
Reverse Transcription ◽  
Whole Blood ◽  
Quantitative Measurement ◽  
Gene Expression Analysis ◽  
Rna Isolation ◽  
Multiplex Assay ◽  
Quality Data ◽  
Branched Dna

Abstract Background: Accurate and precise quantification of mRNA in whole blood is made difficult by gene expression changes during blood processing, and by variations and biases introduced by sample preparations. We sought to develop a quantitative whole-blood mRNA assay that eliminates blood purification, RNA isolation, reverse transcription, and target amplification while providing high-quality data in an easy assay format. Methods: We performed single- and multiplex gene expression analysis with multiple hybridization probes to capture mRNA directly from blood lysate and used branched DNA to amplify the signal. The 96-well plate singleplex assay uses chemiluminescence detection, and the multiplex assay combines Luminex-encoded beads with fluorescent detection. Results: The single- and multiplex assays could quantitatively measure as few as 6000 and 24 000 mRNA target molecules (0.01 and 0.04 amoles), respectively, in up to 25 μL of whole blood. Both formats had CVs <10% and dynamic ranges of 3–4 logs. Assay sensitivities allowed quantitative measurement of gene expression in the minority of cells in whole blood. The signals from whole-blood lysate correlated well with signals from purified RNA of the same sample, and absolute mRNA quantification results from the assay were similar to those obtained by quantitative reverse transcription-PCR. Both single- and multiplex assay formats were compatible with common anticoagulants and PAXgene-treated samples; however, PAXgene preparations induced expression of known antiapoptotic genes in whole blood. Conclusions: Both the singleplex and the multiplex branched DNA assays can quantitatively measure mRNA expression directly from small volumes of whole blood. The assay offers an alternative to current technologies that depend on RNA isolation and is amenable to high-throughput gene expression analysis of whole blood.

Differential Gene Expression Analysis Predicts For Response To Bortezomib In The Treatment Of Steroid Refractory Chronic Graft-Versus-Host Disease (cGVHD)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4587-4587 ◽  
Author(s):  
Alan M Miller ◽  
Reva Schneider ◽  
Estil A. Vance ◽  
Edward Agura ◽  
Sheila Powell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Poor Responders ◽  
Healthy Controls ◽  
Refractory Disease ◽  
Early Improvement ◽  
Differential Gene Expression Analysis ◽  
Differential Gene ◽  
Steroid Refractory

We conducted a trial of bortezomib in patients with steroid-refractory cGVHD. Patients received 1.6 mg/m2 q wk x 4 followed by one week of rest, for up to six cycles, with some going on to a maintenance phase of treatment every other week for an additional 6 months. Twenty-one patients were registered on trial two patients withdrew before beginning treatment. Nineteen patients received between two and twelve months of treatment. The treatment was well tolerated with no grade 3 or higher adverse events (AE). Six patients had either CR or near CR. Average Rodnan scores on the 8 patients with sclerosis completing 2 or more cycles of therapy decreased from 22.6 ± 12.8 to 5.9 ± 6.2, p<0.005. One patient with non-healing suppurating lesions of his lower extremities had marked healing, another had significant decrease in chronic diarrhea. Weekly bortezomib for cGVHD was well tolerated and resulted in early improvement in a subset of patients with long standing refractory disease. Differential gene expression analysis was performed on the blood of patients prior to starting therapy, after two cycles and after their final cycle of therapy. All samples were run simultaneously at the end of the trial. Patients were classified as High (CR or near CR), intermediate (PR or stable disease), or poor responders (progression or not evaluable) based on clinical response. At baseline cGVHD patients express an overall decrease in T cell markers such as lineage (CD4), chemokine receptors (CCR6, CXCR3 and CCR7), and co-stimulatory molecules (CD40L, ICOS, CD28, and CD27), as well as decreases in IL23 and Granzyme K message compared to healthy controls. Increases were seen in myeloid/macrophage markers (CD163 and OSCAR). Baseline profiles of good responders were closer to those of healthy controls as compared to poor responders (figure below). Inflammation, cell death and apoptosis modules are up regulated and immune response modules are down-regulated in low and medium responders HC – Healthy Control; DC – Disease Control (allogeneic BMT recipients without cGVHD) Weekly bortezomib for cGVHD appears to be well tolerated and results in early improvement in long standing refractory disease in a subset of patients. Gene expression profiles at the initiation of treatment correlated with response and may be useful in predicting which patients will respond to bortezomib. Disclosures: Miller: Millennium Pharmaceuticals: Research Funding. Off Label Use: Bortezomib for chronic graft vs. host disease.

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