Leukocyte telomere length in patients with multiple sclerosis and its association with clinical phenotypes

Abstract

Aging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS.We measured the average leukocyte telomere length (LTL) in biobanked DNA samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS) and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Changes in LTL over a period of >10 years were evaluated in a subset of 10 patients. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistical tests and regression models adjusted for age and sex.The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up. The LTL decrease over time was similar in RRMS patients and PPMS patients in the longitudinal analysis.Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between disease-related immune system alterations, immunosenescence and telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained, e.g., by exploring the distribution of telomere lengths in specific blood cell populations.Research in contextEvidence before this studyThere is a growing research interest in the relationship between age and the pathophysiology and clinical presentation of multiple sclerosis (MS). Telomere shortening is a hallmark of biological aging. However, the role of telomeres in this chronic immune-mediated neurodegenerative disease has not yet been widely studied. Two research groups provided evidence that the telomeres of immune cells in the peripheral blood are shorter in patients with MS than in healthy subjects.Added value of this studyWe found that leukocytes from patients with relapsing-remitting MS (RRMS) are characterized by relatively short telomere lengths (TL). On average, we observed 18% shorter TL in the RRMS patient cohort (n=40) than in the age- and sex-matched healthy control cohort (n=60). We further analyzed the association of TL and long-term clinical outcomes. RRMS patients with shorter TL had a higher rate of converting to secondary progressive MS over a 10-year follow-up period.Implications of all the available evidenceAs we and others have shown, TL are generally shorter in MS patients and associated with disease progression, independent of age. These findings suggest a link between biological aging and the heterogeneous clinical course of MS patients. It currently remains unclear whether shortened telomeres in MS are a cause or a consequence of the pathophysiological processes. Further studies with larger patient cohorts and different cell populations will be needed to expand our knowledge of age-related disease mechanisms and the use of TL as a biomarker in MS.

Systematic Review of Studies on Telomere Lengths in Patients with Multiple Sclerosis

“…In the studies by Guan et al, the measured TL were on average 26% and 24% shorter in the PPMS subgroup [51] and in the general MS group [52], respectively, as compared to the controls. In line with this, Habib et al found significantly shorter telomeres in each MS subgroup (RRMS: 19%, SPMS: 29% and PPMS: 29% shorter) [55], and, finally, Hecker et al observed 18% shorter LTL in the RRMS patient cohort than in the control cohort [56]. A meta-analysis of these 4 studies substantiated that LTL are significantly shorter in MS patients as compared to healthy controls (overall SMD=−0.66, p=0.003).…”

“…Subsequently, 18 studies were discarded because they did not contain an analysis of MS patient samples (III), and finally, 21 studies were rejected because they were not concerned with measuring TL (IV). In consequence, we included 7 studies in our systematic review [50][51][52][53][54][55][56] (Supplemental Table 1). Four of these studies also provided sufficient data to be pooled into a meta-analysis [51,52,55,56].…”

“…In consequence, we included 7 studies in our systematic review [50][51][52][53][54][55][56] (Supplemental Table 1). Four of these studies also provided sufficient data to be pooled into a meta-analysis [51,52,55,56]. We then gathered diverse information from the selected articles, e.g., study design, sample size, patient characteristics, TL measurement method and cell population under scrutiny.…”

“…Shorter TL also correlated with higher EDSS scores (p = 0.001), but this association was again driven by age. The most recent study by Hecker et al [56] comprised 40 RRMS patients, 20 PPMS patients and 60 healthy controls. Those three groups were well matched for age (with an average of 48.0 years and 48.1 years for patients and controls, respectively) and sex (female:male ratio always 1:1).…”

“…In 5 out of the 7 reviewed studies, whole blood samples were used for TL analysis (Table 2) [50][51][52][53], TL were determined by non-radioactive TRF analysis, with only minor differences in the applied protocol: Following electrophoretic separation of digested DNA and Southern blotting, DNA fragments were hybridized to digoxigenin-labeled telomere-specific probes, incubated with anti-digoxigenin antibodies conjugated to alkaline phosphatase, and detected on the blot using chemiluminescent enzyme substrates. In the other 3 studies, qPCR assays were employed: Krysko et al [54] used the qPCR method by Cawthon from 2002 [37], while Habib et al [55] and Hecker et al [56] used the adapted mmqPCR assay by Cawthon from 2009 [38]. In both qPCR-based approaches, relative TL are measured as T/S ratios.…”