Background/Purpose: Ankylosing spondylitis is a chronic inflammatory disease characterized by inflammation of the sacroiliac joints and the spine leading to significant immobility. A subset of patients develops systemic organ involvement including uveitis, interstitial lung fibrosis, and cardiac manifestations. The etiology and pathogenesis of ankylosing spondylitis are incompletely understood, though most patients carry the HLA-B*27 allele. The objective of this study was to evaluate DNA methylation changes in ankylosing spondylitis with the goal of revealing novel mechanistic insights into this disease.

Methods: Genome-wide DNA methylation analysis was performed in whole blood DNA samples using the Infinium MethylationEPIC array in patients with ankylosing spondylitis compared to age, sex, and ethnicity matched controls with osteoarthritis as a non-inflammatory disease control. We studied 24 patients with ankylosing spondylitis, including 12 patients who carry HLA-B*27 and 12 patients who are HLA-B*27 negative. DNA methylation analysis was performed using ‘minfi’ and ‘betareg’ in R environment, and differential DNA methylation was conducted following extensive quality control steps using beta regression with adjusting for technical co-variates as well as blood cell composition in each sample.

Results: We identified a total of 68 differentially methylated sites between ankylosing spondylitis patients and osteoarthritis controls. Of these 31 were hypomethylated and 37 were hypermethylated, representing 21 and 30 genes respectively. Hypomethylated genes found included HCP5, which encodes a lncRNA within the MHC region, previously associated with genetic risk for psoriasis and toxic epidermal necrolysis, the transcription factor gene POU5F1, CHD5 which encodes a member of the chromodomain helicase DNA-binding protein family, PON1 which encodes a member of the paraoxonase enzyme family, and the RAS-signaling related gene RRAS2. Hypermethylated genes include GTPase-related genes such as ARHGAP6, RAB11FIP3, TBC1D3H, TBC1D1, and TBCD. Both HCP5 and POU5F1 were hypomethylated in HLA-B*27 positive compared to HLA-B*27 negative ankylosing spondylitis patients.

Conclusion: A genome-wide DNA methylation analysis in patients with ankylosing spondylitis found DNA methylation patterns that could provide potential novel insights into this disease. While most DNA methylation changes observed between patients and controls were not dependent upon HLA-B*27 status, two of the most hypomethylated loci in ankylosing spondylitis were directly linked to HLA-B*27 positivity. Our findings suggest HLA-B*27 might play a role in ankylosing spondylitis in part through ‘epigenetic linkage disequilibrium’ inducing epigenetic dysregulation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-dna-methylation-analysis-in-ankylosing-spondylitis/