Faster progression to multiple sclerosis disability is linked to neuronal pathways associated with neurodegeneration: An ethnicity study

Abstract

Although the causes of multiple sclerosis are largely unknown, genetic and environmental components play an important role. Geographic distribution, varying with latitude, reflects both genetic and environmental influences. We conducted a retrospective exploratory observational study to characterize the disability progression of 2396 Jewish patients with relapsing-remitting multiple sclerosis, followed at the Sheba Multiple Sclerosis Center, Tel-Aviv, Israel; 188 patients who originated in Iraq and 2207 patients who originated in northern Europe. Peripheral blood microarray gene expression analysis was performed in a subgroup of patients to identify molecular pathways associated with faster disability progression. During a follow-up period of 18.8 and 19.8 years, respectively, 51.6% of patients with an Iraqi origin progressed to moderate disability defined as expanded disability status scale (EDSS) score of 3.0 to 5.5, compared to 44.2% of patients with a northern European origin (odds ratio 1.347, 95% CI 1.0–1.815, p = 0.049). An Iraqi origin was associated with increased risk of progression to moderate disability adjusted for sex, disease duration, age at onset, and treatment with immunomodulatory drugs (hazard ratio 1.323; 95% CI, 1.049–1.668, p = 0.02), but not to severe disability defined as EDSS score > = 6.0 (i.e., walking aids are required for a distance of 100 meters, (hazard ratio 1.311; 95% CI, 0.918–1.874, p = 0.136). Gene expression analysis disclosed 98 differentially expressed genes (79 over-expressed and 19 under-expressed) between relapsing-remitting multiple sclerosis patients of Iraqi origin (N = 17) and northern European (N = 34) origin. Interestingly, this gene expression was enriched with genes related to neuronal pathways associated with morphology of axons, branching of neurites, proliferation of neocortical neurons, and formation of myelin sheath, suggesting an augmented process of neurodegeneration in relapsing-remitting multiple sclerosis patients with an Iraqi origin. The study results suggest that relapsing-remitting multiple sclerosis patients with an Iraqi origin progress faster to disability possibly due to an enhanced process of neurodegeneration.

Long-Term Disability Outcomes in Relapsing–Remitting Multiple Sclerosis Patients: Impact of Clinical and Demographic Factors on Disease Progression

“…Harari et al, in an epidemiogenetical study that spanned over 18 years and involved a cohort of 2396 Jewish PwMS (Iraqi-born Jewish patients or Israeli-born Jewish patients with both parents born in Iraq vs. those of Northern European origin, who were partially treated with DMTs), concluded that patients of Iraqi origin tended to progress faster to an EDSS of 3.0 compared to those of Northern European origin. This emphasizes ethnic disparities in RRMS progression, although approximately half of the subjects from both cohorts reached an EDSS of at least 3.0—findings and methodology consistent with our study [ 56 ]. This variability depends on the heterogeneity of PwMS, accessibility to medical services, as well as genetic, socio-economic, and environmental factors.…”

Pilot Study of the Total and Phosphorylated Tau Proteins in Early-Stage Multiple Sclerosis

“…However, these characteristics predominantly represent an ongoing neuroinflammation. Meanwhile, neurodegeneration has been considered the driving force of disability progression [ 3 , 4 ].…”