Evaluation of Cell-Specific Epigenetic Age Acceleration in People With Multiple Sclerosis

Background: 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 lifespan and can be used to accurately estimate biological age acceleration which has been linked to a range of morbidities.

Objective: 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 was included if .idat files from Illumina 450K or EPIC arrays were available for both an MS case and an age and sex matched control, from the same study. Multifactor statistical modelling 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 three independent datasets was used to validate findings.

Results: We used whole blood DNA methylation data from 583 MS cases and 643 non-MS controls to calculate EAA using the GrimAge algorithm. The MS group exhibited an increased EAA compared to controls (∼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 three independent datasets enriched for B cells, showed an EAA increase of 5.1yrs in MS compared to 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).

Conclusion: 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.