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The first genetic variant associated with faster disease progression in multiple sclerosis (MS) has been identified.

In a genome-wide association study (GWAS) of 22,000 people with MS, a significant association between age-related disease severity scores and rs10191329 in the DYSF–ZNF638 locus emerged, reported Sergio Baranzini, PhD, of the University of California San Francisco, and co-authors.

Homozygous carriers of the variant needed a walking aid a median of 3.7 years earlier than non-carriers, the researchers reported in . These MS patients also showed increased brainstem and cortical pathology in brain tissue.

The findings mark a significant breakthrough in understanding how MS progresses and suggest central nervous system resilience and reserve may determine the course of the disease.

Though many treatments have been approved for MS relapses, none reliably prevent disability from accumulating. Smoldering inflammation can develop over time, even in patients treated with effective disease-modifying therapies.

"We have known for some time that the damage in MS is caused by the immune system, but that immune system genes and profiles do not necessarily predict disease severity," said Robert Bermel, MD, of the Cleveland Clinic in Ohio, who wasn't involved with the research.

"This study identifies that pathways and mechanisms in the central nervous system are more closely linked to disease severity and outcome in MS," Bermel told 番茄社区. "In particular, the resilience of the nervous system and ability to recover from damage may be explained by gene variants within the nervous system itself."

The variant sits between DYSF and ZNF638, two genes with no prior connection to MS. DYSF is involved in repairing damaged cells and ZNF638 helps control viral infections. The variant's proximity to these genes suggests they may be involved in disease progression.

"The observation, via a GWAS study, of a significant association between two single nucleotide polymorphisms and MS severity unrelated to disease susceptibility is unsurprising," noted Gavin Giovannoni, MBBCh, PhD, of Queen Mary University of London in England, who also wasn't involved with the research. "Why wouldn't MS severity be affected by genetic factors?"

ZNF638 encodes a DNA-binding zinc-finger protein, Giovannoni pointed out. "ZNF638 mediates transcriptional repression of retroviral DNA using chromatin repressors involved in the epigenetic silencing of human endogenous retroviruses," he told 番茄社区. "Could this tell us something about one of the mechanisms driving smoldering MS?"

"Importantly, ZNF638 is expressed in the brain, particularly in oligodendrocytes and their precursor cells, and is implicated in cognitive ability," Giovannoni added. "This work has opened up several new lines of research that will hopefully lead to new therapeutic targets to tackle the major unmet need in MS, smoldering-associated worsening independent of focal inflammatory disease activity."

Baranzini and colleagues studied 12,584 cases and replicated their findings in an additional 9,805 cases. Data came from two large MS research groups, the International Multiple Sclerosis Genetics Consortium () and the consortium. Disease worsening was based on Expanded Disability Status Scale () scores, with individual measures adjusted for age.

Among 8,325 individuals who had EDSS scores documented at three or more timepoints (5,565 from the discovery cohort and 2,760 from the replication cohort), a generalized linear mixed model analysis across all visits showed that DYSF–ZNF638 risk allele carriers had faster disability progression (P=0.002).

An independent MS autopsy cohort of 290 individuals showed that homozygous DYSF–ZNF638 risk allele carriers had a 1.83-fold higher number of lesions in the brainstem and a 1.76-fold higher rate of cortical lesions.

The researchers also used Mendelian randomization to evaluate environmental effects and found that years of education reduced the severity of MS while smoking worsened it, further supporting the role of resilience.

"Factors associated with enhanced cerebral reserve capacity, including years of education, track with better patient outcomes," Bermel noted.

The study had several limitations, the researchers noted. The EDSS has shortcomings, including its nonlinear nature, they acknowledged, and factors like education and smoking are traits influenced by both genes and environment.

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