Whole blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that might contribute to the inflammatory and tissue-destructive disease aspects

Pimentel-Santos, Fernando; Ligeiro, Dário; Matos, Maria Margarida Nunes Gaspar de; Mourão, Ana Filipa; Costa, José António; Santos, Helena; Barcelos, Anabela; Godinho, Fátima; Pinto, Patrícia; Cruz, Margarida; Fonseca, João Eurico; Guedes-Pinto, Henrique; Branco, Jaime; Brown, Matthew A.; Thomas, Gethin

doi:10.1186/ar3309

Cited by 69 publications

(68 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous microarray studies in AS have generally not included sex-matched patients and controls, while those that balanced the sex of patients and controls did not independently analyze males and females (26)(27)(28)(29). These studies demonstrate mild hierarchal clustering of AS patients and controls, as in the current study, supporting the heterogeneity of the disease at the transcription level.…”

Section: Discussionsupporting

confidence: 68%

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Gracey

Yao

Green

et al. 2016

Arthritis & Rheumatology

139

101

View full text Add to dashboard Cite

ObjectiveTo identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS).MethodsCohorts of male and female patients with AS and age‐ and sex‐matched healthy control subjects were selected, and the levels of serum cytokines (interferon‐γ [IFNγ], tumor necrosis factor α, interleukin‐17A [IL‐17A], and IL‐6) were examined by enzyme‐linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches.ResultsThe frequency of IL‐17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS. In contrast, AS‐associated alterations in the Th1 axis, such as the frequency of IFNγ and Th1 cells in serum, were independent of a patient's sex. Results of microarray analysis supported an altered Th17 axis in male patients, with a specific increase in IL17RA. In addition, male and female patients with AS displayed shared gene expression patterns, while male patients with AS had additional alterations in gene expression that were not seen in female patients with AS. The differential sex‐related immune profiles were independent of HLA–B27 status, clinical disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index), or treatment (with nonsteroidal antiinflammatory drugs or biologic agents), implicating intrinsic sexual dimorphism in AS.ConclusionThe results of this study demonstrate distinct sexual dimorphism in the activation status of the immune system in patients with AS, particularly in the Th17 axis. This dimorphism could underlie sex‐related differences in the clinical features of AS and could provide a rationale for sex‐specific treatment of AS.

show abstract

Section: Discussionsupporting

confidence: 68%

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Gracey

Yao

Green

et al. 2016

Arthritis & Rheumatology

139

101

View full text Add to dashboard Cite

show abstract

“…139 A role for the innate system in AS has long been postulated due to the proposed link between an as yet unknown pathogen and disease onset. 140 SPARC, a bone matrix protein, was also upregulated in two of the studies 136,137 which suggests dysregulation of the bone matrix which might contribute to the joint ankylosis.…”

Section: Circulating Cell Studiesmentioning

confidence: 99%

“…Two kits have been specifically developed for transcriptomic studies in whole blood with the blood collected into an RNA preservative which stabilises the RNA allowing shipping/initial storage at room temperature with minimal degradation (PAXgene from Qiagen Three whole genome expression profiling studies have been published using whole blood in spondylarthropy all using the PAXgene technology. [135][136][137] Sharma et al compared healthy controls and spondyloarthropy patients but used a slightly unusual approach. Rather than analysing a main sample group by microarray then confirming candidate genes by qPCR in a second cohort, they split the sample groups into a discovery and a validation set and microarrayed both groups and compared differentially expressed genesets.…”

Section: Circulating Cell Studiesmentioning

confidence: 99%

“…Both Assassi et al and Pimental-Santos et al focussed on AS, using patients with confirmed AS according to the Modified New York Criteria, with Assassi also comparing their datasets with those from systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) patients. 135,136 Both these studies undertook an initial microarray study and confirmed candidate genes by qPCR in a larger 2nd cohort. The Pimentel-Santos study was the largest study with 18 patients and 18 controls in the initial microarray cohort and validated in 156 patients and controls using Taqman Low Density Arrays (TLDAs).…”

Section: Circulating Cell Studiesmentioning

confidence: 99%

See 1 more Smart Citation

The genomics and genetics of ankylosing spondylitis

Kenna¹,

Davidson²,

Thomas³

2011

AGG

View full text Add to dashboard Cite

Abstract:The spondyloarthropathies are a group of arthritides which specifically target the spine and pelvis with ankylosing spondylitis (AS) being the most prevalent and debilitating of these conditions. Unique to AS is the progression to excessive uncontrolled bone formation following an initial inflammatory phase that can result in joint fusion and significant disability. Spondyloarthritis is estimated to affect 1%-2% of the population, twice as many as rheumatoid arthritis and thus constitutes a significant health problem. Currently AS pathogenesis is very poorly understood but recent large-scale genetics and gene expression profiling studies have identified some of the underlying mechanisms and pathways contributing to the disease. Genome-wide association studies have identified a number of candidate genes associated with AS sharing the same pathways which are now being targeted for therapeutic intervention. However, although such approaches can identify genes contributing to the disease process and are very informative as to disease aetiopathogenesis, they cannot profile the actual changes in gene/cell activity at any point in the disease process or possibly more importantly at specific sites. Such information is generated using expression profiling. A number of expression profiling studies have been undertaken in AS, looking at both circulating cells and tissues from affected joints. Although some common genes/pathways have been identified, overall the results to date have been somewhat disappointing due to differences in experimental design and tissue source as well as the low power of the studies. More recent better powered studies have shown some potential in developing gene expression profiling as a diagnostic tool in AS. True future success will rely on larger genetic and genomic studies and the combination of these datasets in eQTL studies requiring significant collaborative efforts. Such larger-scale approaches will also generate sufficient power to target specific disease stages and sites.

show abstract

“…This technology has been widely used to screen for potential gene candidates underlying the pathogenesis of numerous diseases, including ankylosing spondylitis, which is also an autoimmune disease (16). To date, a limited number of transcriptomic studies of KD have been conducted.…”

Section: Introductionmentioning

confidence: 99%

Screening of differentially expressed genes associated with Kawasaki disease by microarray analysis

Jiang

Cai

et al. 2017

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. Kawasaki disease (KD) is an autoimmune disorder that can induce coronary artery aneurysms, particularly in the case of delayed diagnosis and/or treatment. Early diagnosis is important for treatment and reduces the risk of heart injury. The aim of the present study was to identify differentially expressed genes by comparing the levels of gene expression in human umbilical vein endothelial cells following treatment with plasma from healthy individuals and patients with acute or convalescent KD. Following comparison of the control and acute KD groups, 385 up-regulated and 537 down-regulated genes were identified in the acute KD group. In the convalescent group, 505 and 879 genes were up-regulated and down-regulated, respectively, relative to the control group. Genes involved in the immune system and cell growth factors were up-regulated, while genes functioning in methylation were down-regulated, following treatment with KD plasma. In addition, five potential candidate molecular markers of KD, C-X-C motif chemokine ligand 2 (CXCL2), interleukin (IL) 8, tripartite motif containing 58 (TRIM58), immunoglobulin superfamily member 3 (IGSF3) and runt related transcription factor 1 (RUNX1) were identified by microarray analysis and verified using quantitative polymerase chain reaction. A significant positive correlation was identified between the neutrophil polys and expression levels of four of these candidate genes, including CXCL2, IL8, TRIM58, and IGSF3 (all P<0.01; R 2 ≥0.64). However, only CXCL2 expression was significantly positively correlated with neutrophil polys (P=0.01; R 2 =0.64) and neutrophil bands (P<0.001; R 2 =0.73).These results indicate that CXCL2 serves a crucial role in the injury of endothelial cells by KD plasma.

show abstract

Whole blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that might contribute to the inflammatory and tissue-destructive disease aspects

Cited by 69 publications

References 47 publications

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

The genomics and genetics of ankylosing spondylitis

Screening of differentially expressed genes associated with Kawasaki disease by microarray analysis

Contact Info

Product

Resources

About