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Evaluation of Cell-Specific Epigenetic Age Acceleration in People With Multiple Sclerosis
Vicki Maltby1, Alexandre Xavier1, Ewoud Ewing1
1From the School of Medicine and Public Health (V.M., R.L., J.L.-S.), University of Newcastle, University Drive, Callaghan; Immune Health Program (V.M., A.X., J.L.-S.), Hunter Medical Research Institute; Department of Neurology (V.M., J.L.-S.), John Hunter Hospital, New Lambton Heights; School of Biomedical Sciences and Pharmacy (A.X.), University of Newcastle, University Drive, Callaghan, Australia; Department of Clinical Neuroscience (E.E., L.K., M.J.), Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Neuroscience (M.-P.C., S.S., H.B., V.J.), Central Clinical School, Monash University, Victoria; Division of Molecular Genetics (R.J.S.), Pathology North, John Hunter Hospital, New Lambton Heights; MSBase Foundation (H.B.), Melbourne, Australia; Institute of Clinical Medicine (S.B.), University of Oslo,; Department of Neurology (S.B.), Oslo University Hospital, Norway; Flinders University (M.S.), Adelaide; Menzies Institute for Medical Research (I.A.M., B.V.T.), University of Tasmania, Hobart; Florey Institute of Neuroscience and Mental Health (A.-L.P.), The University of Melbourne; Centre of Epidemiology and Biostatistics (A.-L.P.), School of Population and Global Health, University of Melbourne; Murdoch Children's Research Institute (A.-L.P.), Royal Children's Hospital, Melbourne; and Centre for Genomics and Personalized Health (R.L.), School of Biomedical Science, Queensland University of Technology, Kelvin Grove, Australia.
Background And Objectives:
In multiple sclerosis (MS), accelerated aging of the immune system (immunosenescence) may be associated with disease onset or drive progression. DNA methylation (DNAm) is an epigenetic factor that varies among lymphocyte subtypes, and cell-specific DNAm is associated with MS. DNAm varies across the life span and can be used to accurately estimate biological age acceleration, which has been linked to a range of morbidities. The objective of this study was to test for cell-specific epigenetic age acceleration (EAA) in people with MS.
Methods:
This was a case-control study of EAA using existing DNAm data from several independent previously published studies. Data were included if .idat files from Illumina 450K or EPIC arrays were available for both a case with MS and an age-matched and sex-matched control, from the same study. Multifactor statistical modeling was performed to assess the primary outcome of EAA. We explored the relationship of EAA and MS, including interaction terms to identify immune cell-specific effects. Cell-sorted DNA methylation data from 3 independent datasets were used to validate findings.
Results:
We used whole blood DNA methylation data from 583 cases with MS and 643 non-MS controls to calculate EAA using the GrimAge algorithm. The MS group exhibited an increased EAA compared with controls (approximately 9 mths, 95% CI 3.6-14.4), p = 0.001). Statistical deconvolution showed that EAA is associated with MS in a B cell-dependent manner (β int = 1.7, 95% CI 0.3-2.8), p = 0.002), irrespective of B-cell proportions. Validation analysis using 3 independent datasets enriched for B cells showed an EAA increase of 5.1 years in cases with MS compared with that in controls (95% CI 2.8-7.4, p = 5.5 × 10-5). By comparison, there was no EAA difference in MS in a T cell-enriched dataset. We found that EAA was attributed to the DNAm surrogates for Beta-2-microglobulin (difference = 47,546, 95% CI 10,067-85,026; p = 7.2 × 10-5), and smoking pack-years (difference = 8.1, 95% CI 1.9-14.2, p = 0.002).
Discussion:
This study provides compelling evidence that B cells exhibit marked EAA in MS and supports the hypothesis that premature B-cell immune senescence plays a role in MS. Future MS studies should focus on age-related molecular mechanisms in B cells.
