POS0556 DNA METHYLATION ESTIMATES OF HYPER-AGING IN SYSTEMIC SCLEROSIS AND IDIOPATHIC PULMONARY FIBROSIS
Authors: K. Keen, B. Zhuang, M. Fritzler, C. Ryerson, P. Wilcox, M. Jude, K. Dever, J. Macissac, M. Kobor, B. Whalen, B. Sahin, J. Dunne
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology characterized by microvascular injury and increasing fibrosis of multiple organs. Interstitial lung disease (ILD) is a frequent comorbidity. SSc and idiopathic pulmonary fibrosis (IPF) are both considered to be diseases of early aging. As well, disorders of epigenetic processes are implicated in SSc-ILD, which is predominantly female, and IPF, which is predominantly male. DNA methylation is one mechanism of epigenetic disorder that predicts all-cause mortality. Epigenetic clocks are widely used biomarkers that are DNA-methylation based and trained to predict either chronological age or age-related processes. One such biomarker of aging is DunedinPACE, which is a second-generation clock trained on longitudinal changes of multi-organ system biomarkers and is used to predict associations with increased risk of disease and death. The DunedinPACE measure goes one step further than static epigenetic clocks to measure the pace of aging. <h3>Objectives:</h3> The objectives were to explore, to compare and to contrast the pace of epigenetic aging for the diffuse cutaneous (dc) and limited cutaneous (lc) forms of SSc, with or without ILD, compared to the broad spectrum of healthy controls and patients with IPF who did not have overt autoimmune features. <h3>Methods:</h3> Written consent was obtained from 76 voluntary participants, including 12 healthy controls, in accordance with the Declaration of Helsinki and a harmonized research-ethics-board. ILD was confirmed by radiologist-interpretation of high-resolution computed tomography scans. Diagnosis of dcSSc and lcSSc subtypes was performed by SSc-specialist rheumatologists. DNA methylation profiles of participants were assessed using the Infinium MethylationEPIC BeadChip and were subsequently used for DunedinPACE estimation (Belsky <i>et al</i>., 2022. DOI: doi.org/10.7554/eLife.73420) and estimation of leukocyte-subtype proportions (Salas <i>et al</i>., 2022, DOI: doi.org/10.1038/s41467-021-27864-7). Custom panels with peripheral blood were done for 73 cytokines and 50 autoantibodies by Eve Technologies and Mitogen Diagnostics. <h3>Results:</h3> Table 1 presents the results of a curated multiple linear regression model with only statistically significant (p-value &lt; 0.05) explanatory variables, save for IL-6 (p = 0.0586), which is also included. The multiple R-squared for this model is 0.5271 (p &lt; 0.0000`. Figure 1 presents the fitted values of DunedinPACE as a function of age for each of the 6 participant categories. A DunedinPACE point estimate of 1.2, for example, represents 1.2 years of accelerated biological aging for each year of chronological age because of DNA methylation. The lowest aging and slowest pace of increase of age was observed for healthy controls, which was below 1. All forms of ILD had fitted values greater than 1 with the pace of increase steepest for IPF. The ordering of level and pace of aging was consistent with conventional wisdom based upon overall disease severity and greater than that of healthy controls. The imputed basophil (p = 0.0067) and neutrophil (p = 0.0022) were the only leucocytes found to be statistically significantly associated with DunedinPACE and both are harbingers of inflammation. Among therapeutic variables, only nintedanib administration was found to be statistically significant (p = 0.0244). <h3>Conclusion:</h3> The DunedinPACE measure of the pace of aging based upon DNA methylation in a small sample indicates the pace of aging was greater than 1 year for patients with ILD and the rate of increase of the pace of aging was greater for patients with SSc or ILD compared to controls. 150 more samples are available in the Scleroderma (Association of British Columbia) Biobank to develop a firm clinical indication in this regard. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> Research funding provided by the Scleroderma Association of British Columbia. <h3>Disclosure of Interests:</h3> Kevin Keen Hoffman-La Roche Ltd., Merck Canada Inc., Pfizer Canada, Beryl Zhuang: None declared, Marvin Fritzler Medical Director of Mitogen Diagnostics Corporation (Calgary, Canada), Werfen (San Diego, USA and Barcelona, Spain), Christopher Ryerson Boehringer Ingelheim, Pearce Wilcox: None declared, Marcia Jude: None declared, Kristy Dever: None declared, Julie MacIssac: None declared, Michael Kobor: None declared, Beth Whalen: None declared, Basak Sahin: None declared, James Dunne Boehringer Ingelheim.