Gene expression patterns in peripheral blood cells associated with radiographic severity in African Americans with early rheumatoid arthritis

Abstract

Gene expression profiling may be used to stratify patients by disease severity to test the hypothesis that variable disease outcome has a genetic component. In order to define unique expression signatures in African American rheumatoid arthritis (RA) patients with severe erosive disease, we undertook a gene expression study using samples of RNA from peripheral blood mononuclear cells (PBMCs). RNA from baseline PBMC samples of 96 African American RA patients with early RA (<2 years disease duration) was hybridized to cDNA probes of the Illumina Human HT-V3 expression array. Expression analyses were performed using the ca. 25,000 cDNA probes, and then expression levels were compared to the total number of erosions in radiographs of the hands and feet at baseline and 36 months. Using a false discovery rate cutoff of Q = 0.30, 1,138 genes at baseline and 680 genes at 36 months significantly correlated with total erosions. No evidence of a signal differentiating disease progression, or change in erosion scores between baseline and 36 months, was found. Further analyses demonstrated that the differential gene expression signature was localized to the patients with the most erosive disease (>10 erosions). Ingenuity Pathway Analysis demonstrated that genes with fold change greater than 1.5 implicated immune pathways such as CTLA signaling in cytotoxic T lymphocytes. These results demonstrate that CLEAR patients with early RA having the most severe erosive disease, as compared to more mild cases (<10 erosions), may be characterized by a set of differentially expressed genes that represent biological pathways with relevance to autoimmune disease.

Brief Report: Expression of Interferon‐γ Receptor Genes in Peripheral Blood Mononuclear Cells Is Associated With Rheumatoid Arthritis and Its Radiographic Severity in African Americans

“…The 10 patients categorized as having early disease/high damage had a disease duration of <2 years and the highest damage scores; the 10 patients with early disease/low damage were chosen from among those with normal radiographs who were anti–cyclic citrullinated peptide (anti‐CCP) antibody positive; the 10 patients with late disease/high damage were those with the highest damage scores (most severe) and a disease duration of >2 years; and the 10 patients categorized as having late disease/low damage were randomly chosen from among those with normal radiographs who were anti‐CCP antibody positive. We chose 182 genes for analysis (additional information is available from the corresponding author) based on our previous findings , literature review, and available panels of low‐density arrays focused on pathways relevant to RA. The aim of the second (replication) phase was to validate these findings in a previously unstudied sample of 576 African American patients with RA and 51 African American control subjects.…”

“…The criteria for candidate genes were the strength of association with RA, the biologic relevance or known role of the gene in RA and its severity, and the availability of assays. Genes in the SABiosciences Human Innate and Adaptive Immune Responses RT 2 Profiler PCR Array (SAB array) and the Applied Biosystems Human Immune Array (ABI) were analyzed, as were 17 genes identified from our preliminary analysis of early erosive disease using a global gene expression approach (additional information is available from the corresponding author). The SAB array (http://www.sabiosciences.com/rt_pcr_product/HTML/PAHS-052A.html) includes 84 genes that are involved in the host response to bacterial infection and sepsis and 5 housekeeping genes.…”

Upcoming value of gene expression analysis in rheumatology

“…Радиографическая тяжесть заболевания, основанная на оценке числа эрозий у больных РА, ассоциировалась с повышением экспрессии сигнальных путей IFN и TGFb, апоптозной активности и со снижением окислительного фосфорилирования в митохондриях как в начале заболевания, так и после трёх лет наблюдения [141]. В другом исследовании было идентифицировано 14 генов, кодирующих провоспалительные цитокины и ингибиторы роста, экспрессия которых в крови была повышена и ассоциировалась с негативным прогнозом в отношении тяжести заболевания [142].…”

Patient stratification and choice of therapy based on blood gene expression profiles in rheumatoid arthritis

“…Кроме того, анализ уровня генов в крови показал, что выраженность рентгенологических проявлений РА (число эрозий) связана с повышением активности ИФН-и ТРФβсигнальных путей и апоптоза, а также снижением активности окислительного фосфорилирования и функций митохондрий как в начале исследования, так и через 3 года наблюдения [92]. В другом исследовании в крови больных РА было идентифицировано 14 генов с повышенной экспрессией, включая провоспалительные гены и гены, связанные с прекращением роста, которые способны прогнозировать тяжесть заболевания [93].…”