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Genome-wide DNA methylation analysis of peripheral blood samples of moderate-to-severe psoriasis patients treated with anti-TNF drugs

ABSTRACT: Genome wide DNA methylation profiling of peripheral blood samples of moderate-to-severe psoriasis patients treated with anti-TNF drugs. Patients were distributed on Excellent Responders (ER) if they achieved PASI90 (a 90% reduction with respect to baseline PASI) at 3 and 6 months of treatment with anti-TNF drugs and Partial responders if they did not achieve a PASI75 (a 75% reduction with respect to baseline PASI) at 3 and 6 months of treatment. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 485,000 CpGs in 49 ER and 21 PR which were obtained from peripheral blood samples of anti-TNF drug treated patients. We have searched for pharmaoepigenetic biomarkers of anti-TNF response in moderate-to-severe psoriasis patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151278 | GEO | 2020/05/28

REPOSITORIES: GEO

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Project description:The success of TNF inhibitors for treatment of psoriasis and other inflammatory diseases was previously attributed to blockade of innate immunity. In a clinical trial using etanercept TNF blocking agent to treat psoriasis vulgaris, we used affymetrix gene arrays to analyze broad gene profiles in lesional skin at multiple timepoints during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. This analysis created a temporal model of TNF-dependent gene regulation that informs molecular mechanisms of TNF-mediated inflammation. We identified four gene clusters that were differentially down-modulated during etanercept treatment: the cluster down-regulated most rapidly contained mostly dendritic cell activation genes. Culturing human keratinocytes with TNF, IFNg and IL-17 generated a list of keratinocyte genes regulated by each cytokine. The IL-17 pathway genes were strongly down-modulated early, whereas IFNg pathway genes were not down-modulated until final disease resolution at week 12. Finally, we show that TNF blockade rapidly inhibits IL-12/IL-23 p40 subunit expression, and that p40 neutralization inhibits psoriatic dermal emigre-mediated Th17 polarization. We hypothesize that etanercept inhibits myeloid dendritic cell production of IL-23, a Th17 survival cytokine, resulting in rapid downregulation of IL-17 pathway genes. This data links effects of TNF blockade on the innate immune system with the adaptive immune system. Experiment Overall Design: In this study 15 patients with moderate-to-severe psoriasis were given 50mg of etanercept (Amgen) biweekly for 12 weeks. And analyzed using gene array on mRNA extracted from tissue collected at each biopsy time point (non-lesional Time: 0; lesional Time: 0, weeks 1, 2, 4, and 12). Patients were stratified as 'responders' or 'non-responders' based on whether or not they achieved histologic disease resolution by week 12 of etanercept treatment (decreased epidermal thickening, normalization of proliferation marker Ki67, and loss of differentiation marker K16).

Project description:Objective: use comprehensive molecular profiling to understand the molecular mechanisms that affect clinical response to anti-TNF therapy in rheumatoid arthritis (RA) and to identify predictive markers to differentiate good responders and non-responders. Methods: two independent cohorts of 40 and 36 biologic-naïve RA patients were selected from the Corrona (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) CERTAIN registry and categorized by EULAR response criteria. Whole-blood RNA and plasma samples from baseline and after 3 months of anti-TNF treatment were profiled using RNA-seq, shotgun proteomics and glycopeptide analysis. A cell type-specific transcriptional data analysis was applied to RNA-seq data to evaluate the impact of the most common immune cell sub-populations. Results: a treatment-related molecular signature was identified that showed a high level of correlation (ρ=0.62; permutation p<0.01) between cohorts. Treatment led to a reduction of neutrophils, independent of the status of response. Gene expression differences between good responders and non-responders at baseline did not manifest statistically significant concordance genome-wide between the two cohorts. However, a cell type-specific analysis indicated increased representation of innate cell type signatures in good responders and, conversely, increased expression of adaptive cell type signatures in non-responders at baseline in both cohorts. This result was confirmed by applying the cell-type specific analysis to other publicly available RA datasets. Evaluation of the neutrophil to lymphocyte ratio (NLR) at baseline in the remaining patients (n=1962) from the CERTAIN database using a logistic regression model further confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03 – 1.41; p = 0.02]). Conclusion: differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.

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Genome-wide DNA methylation analysis of peripheral blood samples of moderate-to-severe psoriasis patients treated with anti-TNF drugs

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