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Potential anti-TNF response biomarker identified
Date:6/12/2014

le to maintain a full-time job.3 1In this study, patients were selected from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) longitudinal cohort based on having an extreme response phenotype after three months of treatment with etanercept or adalimumab. Of the patients in the study, 36 patients were good responders to etanercept and 45 to adalimumab as defined by having an endpoint of DAS28<2.6. Poor responders to etanercept (35) and adalimumab (27) were defined by having an improvement of <0.6 or between 0.6-1.2 with an endpoint DAS28 of >5.1.

DNA from each patient was sampled before therapy was initiated. Following bisulfite conversion of the DNA, an epigenome-wide association study was conducted using the HumanMethylation450 BeadChip (Illumina) to determine unmethylated versus methylated cytosines within the DNA. The results from each drug were analysed separately and together using the minfi package in R and probes with a detection-p value > 0.01 were removed. Differentially methylated positions between responders and non-responders were identified using the F-test following quantile normalisation.

In the etanercept study, four CpG* sites showed differential DNA methylation that passed a false discovery rate of 0.05, while in the adalimumab study less significant results were observed. The most differentially methylated position in etanercept patients mapped to the LRPAP1 gene (p=1.46x10-8). This gene encodes a chaperone of low density lipoprotein receptor-related protein 1 (LRP1) which is known to influence TGF-β activity. Technical validation of methylation at this site by pyrosequencing showed very good correlation (Spearmans r=0.8). In the adalimumab patients, the most differentially methylated position maps to the PDZD8 gene. Joint analysis of the two drugs together identified a differentially methylated region overlapping the CRYZ and TYW3 genes, which have previously been associated with inflammatio
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Contact: EULAR Press Office
eularpressoffice@cohnwolfe.com
44-078-801-73209
European League Against Rheumatism
Source:Eurekalert

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