GAL Gene Variant May Put MS Patients at Risk for Rapidly Progressive Disease, Study Suggests

Although MS is not an inherited disease, about 200 genes, most of them related to the immune response, have been identified as contributing to the overall risk of developing MS.

Research is ongoing to better understand genetic risk and other factors that may contribute to MS development. This may be a promising new approach to help predict disease severity, and provide a better understanding of the mechanisms underlying disease progression.

The gene coding for galanin (GAL) is an example of a non-immune gene that may affect how MS progresses. Galanin is a small protein widely produced in the brain and spinal cord (central nervous system or CNS), and gut, with neuroprotective effects in response to CNS damage.

In the brains of MS patients, galanin was associated with the body’s response to demyelination (loss of myelin, a hallmark of MS), and in animal models, it was linked with lower disease severity.

Earlier research suggested that small variations in a specific region of the human GAL gene — called the rs948854 polymorphism — affects the MS risk in a gender-specific way. The presence of a minor, less common variation increased the risk of MS in men, but not in women, with male carriers who developed the disease later (after age 30) at particular risk. Moreover, regardless of sex, this variant was associated with faster-progressing disease.

Based on these results, and given that this genetic variation is relatively common, the researchers involved in this prior study proposed that it may be “considered as one of the potential genetic markers for the risk stratification in patients.”

To further characterize the variant’s role, the team performed another study to confirm these results, including its association with disease progression and severity.

Using a group of 110 MS patients (66 women and 44 men; mean age of 40.9 years), the researchers confirmed a significant association of the minor ‘G’ variation in rs948854 in patients and disease severity, which supported their earlier findings.

A greater proportion of minor variant carriers were rapidly progressing patients (55.6%) — with a score above 5 in the Multiple Sclerosis Severity Score (MSSS) — compared to patients with the most frequent ‘A’ variant (28.6%).

According to the analysis, the presence of the ‘G’ variant nearly doubled the risk of rapid MS progression.

Similar findings were supported by an alternative measure of disease progression based on the Expanded Disability Status Scale. Patient carriers of the minor variant had worse progression indexes.

No differences in the patients’ disease progression (assessed by MSSS) or the genetic variants they carried were associated with the type of disease-modifying therapy they were taking.

The analysis also revealed a significant correlation between age at disease onset and MS severity (as measured by MSSS), but only in the group of minor variant carriers — the older they developed MS, the more likely their disease progressed rapidly.

After stratifying patients by age, the researchers noted that the effect of the minor variant in MS severity was only significant in patients with later disease onset, who developed MS when they were older than 30.

In addition, no correlations were found between GAL variants and serum levels of TNF-α (a marker of inflammation) and pNF-H (a marker of nerve cell loss).

Overall, applying different approaches, the researchers “demonstrated the association of rs948854 polymorphism with the severity of MS,” and replicated earlier findings.

“In addition, the current study demonstrated that minor rs948854 allele [variant] carriers with later onset of MS, have the highest risk of adverse course of the disease,” they said.