Abstract
IntroductionA number of genetic-association studies have identified genes contributing to ankylosing spondylitis (AS) susceptibility but such approaches provide little information as to the gene activity changes occurring during the disease process. Transcriptional profiling generates a 'snapshot' of the sampled cells' activity and thus can provide insights into the molecular processes driving the disease process. We undertook a whole-genome microarray approach to identify candidate genes associated with AS and validated these gene-expression changes in a larger sample cohort.MethodsA total of 18 active AS patients, classified according to the New York criteria, and 18 gender- and age-matched controls were profiled using Illumina HT-12 whole-genome expression BeadChips which carry cDNAs for 48,000 genes and transcripts. Class comparison analysis identified a number of differentially expressed candidate genes. These candidate genes were then validated in a larger cohort using qPCR-based TaqMan low density arrays (TLDAs).ResultsA total of 239 probes corresponding to 221 genes were identified as being significantly different between patients and controls with a P-value <0.0005 (80% confidence level of false discovery rate). Forty-seven genes were then selected for validation studies, using the TLDAs. Thirteen of these genes were validated in the second patient cohort with 12 downregulated 1.3- to 2-fold and only 1 upregulated (1.6-fold). Among a number of identified genes with well-documented inflammatory roles we also validated genes that might be of great interest to the understanding of AS progression such as SPOCK2 (osteonectin) and EP300, which modulate cartilage and bone metabolism.ConclusionsWe have validated a gene expression signature for AS from whole blood and identified strong candidate genes that may play roles in both the inflammatory and joint destruction aspects of the disease.
Highlights
A number of genetic-association studies have identified genes contributing to ankylosing spondylitis (AS) susceptibility but such approaches provide little information as to the gene activity changes occurring during the disease process
Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease characterised by inflammation that leads to bone resorption and bone formation, resulting in progressive ankylosis [1]
In AS and spondyloarthritis (SpA) a number of recent studies have defined transcriptional profiles generated from peripheral blood mononuclear cells (PBMCs) isolation requiring immediate sample processing, which is not suitable for larger multicentre studies and limits the viability of such an approach [7]
Summary
A number of genetic-association studies have identified genes contributing to ankylosing spondylitis (AS) susceptibility but such approaches provide little information as to the gene activity changes occurring during the disease process. The mechanism by which HLA-B27 and other more recently identified genetic factors involved in AS susceptibility, lead to disease remains uncertain. Genetic studies provide little information as to the gene activity changes occurring during the disease process. Gene-expression profiling confers a “snapshot” of cellular activity providing information on mechanisms mediating disease changes, elucidating possible pathways involved and can generate diagnostic gene sets. In AS and spondyloarthritis (SpA) a number of recent studies have defined transcriptional profiles generated from peripheral blood mononuclear cells (PBMCs) isolation requiring immediate sample processing, which is not suitable for larger multicentre studies and limits the viability of such an approach [7]. An alternate approach is to use whole blood samples collected using PAXgene technology which preserves the integrity of the RNA even with limited storage at room temperature allowing delays in transport and handling to occur with minimal RNA degradation [7]
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