TY - JOUR
T1 - Evaluation of Cell-Specific Epigenetic Age Acceleration in People with Multiple Sclerosis
AU - Maltby, Vicki
AU - Xavier, Alexandre
AU - Ewing, Ewoud
AU - Campagna, Maria Pia
AU - Sampangi, Sandeep
AU - Scott, Rodney J.
AU - Butzkueven, Helmut
AU - Jokubaitis, Vilija
AU - Kular, Lara
AU - Bos, Steffan
AU - Slee, Mark
AU - Van Der Mei, Ingrid A.
AU - Taylor, Bruce V.
AU - Ponsonby, Anne Louise
AU - Jagodic, Maja
AU - Lea, Rodney
AU - Lechner-Scott, Jeannette
PY - 2023/8/15
Y1 - 2023/8/15
N2 - Background and ObjectivesIn 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.MethodsThis 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.ResultsWe 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 (βint = 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).DiscussionThis 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.
AB - Background and ObjectivesIn 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.MethodsThis 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.ResultsWe 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 (βint = 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).DiscussionThis 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.
KW - Multiple Sclerosis
KW - age-associated B cells
KW - DNA methylation
KW - epigenetic age acceleration
UR - http://www.scopus.com/inward/record.url?scp=85168221592&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000207489
DO - 10.1212/WNL.0000000000207489
M3 - Article
C2 - 37541839
AN - SCOPUS:85168221592
SN - 0028-3878
VL - 101
SP - E679-E689
JO - Neurology
JF - Neurology
IS - 7
ER -