Session Type: Abstract Submissions (ACR)
Arthritis mutilans is a severe form of psoriatic arthritis (PsA). Why some patients develop this rapidly progressive destructive disease remains unclear. We hypothesized that the epigenetic signature may be different between PsA patients with and without arthritis mutilans. The aim of this study was to investigate DNA methylation in PsA patients with and without arthritis mutilans.
Arthritis mutilans was defined using the modified Steinbrocker scoring (mSS) method which classifies each of a total of 42 joints on a 0-4 scale where grade 0=normal, 1= juxta-articular osteopenia or soft tissue swelling, 2=erosion, 3=erosion and joint space narrowing and 4=total destruction (severe osteolysis, subluxation, ankylosis, pencil-in-cup change). Patients with at least 1 joint with grade 4 damage were classified as having arthritis mutilans and those with no damage following similar duration of follow up were classified as PsA patients without mutilans. All patients were Caucasians of Northern European Ancestry. Genome-wide DNA methylation profiling was performed on the blood DNA samples from 24 PsA patients with mutilans and 24 patients without arthritis mutilans. The methylation profiling was performed using Illumina HumanMethylation450k Beadchips, which measures up ~480,000 different CpG sites per sample and covers 96% of RefSeq genes. The methylation level at each CpG site was measured by β values varying from 0 (no methylation) to 1 (100% methylation).
PsA patients with arthritis mutilans (50% males) had mean of disease onset at age 31.8 (10.7) years and age at time of assessment was 42.8 (11.4) years Meanwhile, PsA patients with no evidence of arthritis mutilans (50% males) had mean of disease onset at age 32.7 (16.1) years and age at time of assessment was 41.8 (15.1) years. Methylation data were normalized using BMIQ method and no batch effects were detected by PCA analysis. Methylation analysis was performed on 332,530 autosomal CpG sites after applying quality control filtering. Two outliers were identified and excluded in the subsequent analysis. Methylation profiling analysis revealed 37 CpG locations where there was at least 10% difference in β values between patients with and without arthritis mutilans. The three locations that differentiated the most after correction for multiple testing included CpG sites in WNT3A (hypermethylated; p=3.74×10-5); NRXN2 (hypomethylated; p=6.02×10-5) and an agenic region (hypomethylated; p=4.53×10-5). Based on functional relevance to PsA pathology, particularly antigen presentation, cytokine signalling, and bone remodeling, 5 candidate genes (2 hypomethylated; 3 hypermethylated) emerged: PELI2 (β diff=-0.1249; p=0.001), SEEK1 (β diff=0.1834; p=0.002), COL11A1 (β diff=0.1085; p=0.006), ADAMTS1 (β diff=-0.1030; p=0.005), and WNT3A (β diff=0.0752; 3.74×10-5).
These preliminary results demonstrate that the DNA methylation signature in PsA patients with arthritis mutilans is distinct compared with PsA patients without mutilans. High priority candidate genes identified in this study warrants further validation.
D. D. Gladman,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-methylome-investigation-reveals-new-candidate-genes-associated-with-arthritis-mutilans/