New study links alternative splicing patterns to Sjögren’s severity
Differences in select genes tied to disease activity markers
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People with primary Sjögren’s disease, particularly those with more severe illness, show significantly different patterns of alternative splicing — a process in which cells mix and match gene instructions to create different versions of a protein — in 10 genes compared with healthy people, according to a study in China.
Data also showed that alternative splicing in several of these genes was significantly associated with measures of Sjögren’s severity, highlighting potential avenues for future research into the disease’s underlying biology.
The study, “Alternative splicing signatures correlate with disease severity and clinical subtypes in primary Sjögren’s syndrome,” was published in Genomics.
How alternative splicing works
Each protein-coding gene contains exons, sections that carry instructions for building parts of a protein, along with introns, which are non-coding regions in between.
When a cell needs to make a protein, the instructions in DNA are copied into a template molecule called messenger RNA (mRNA). Mature mRNA is generated when sections corresponding to introns are removed, or spliced out, and those corresponding to exons are joined together.
Alternative splicing occurs when certain exons, and sometimes parts of introns, are included or excluded from the mature mRNA, allowing cells to make different versions of the same protein from a single gene. It’s like having a set number of Lego pieces in a box but choosing only certain ones to build a particular model.
A growing body of research suggests that alternative splicing may play a role in several autoimmune diseases, but it has not been extensively studied in Sjögren’s.
Sjögren’s is an autoimmune disease in which the immune system mistakenly attacks the body’s moisture-producing glands, leading to hallmark symptoms such as dry eyes and dry mouth. However, it can also affect many other tissues and organs.
Study examines gene activity in Sjögren’s patients
Here, scientists in China analyzed alternative splicing in blood samples from 119 women (median age 56) with primary Sjögren’s, a form of the disorder that develops on its own, rather than secondary to another condition. Blood samples from 45 age- and sex-matched healthy people were used for comparison.
Based on gene activity data from these blood samples, the researchers found that the Sjögren’s patients could be broadly divided into two groups.
In the first group, gene activity showed no significant differences from those seen in healthy people. Patients in this group tended to have less severe Sjögren’s, as reflected by lower scores on the standard European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (ESSDAI).
The second group of patients showed significantly different gene activity patterns compared with both healthy volunteers and the first group. These patients also had significantly higher ESSDAI scores, indicating more severe disease.
Further analyses showed that patients in the second group had significantly different alternative splicing patterns in 10 genes compared with healthy controls. Only three of these genes showed significant differences in alternative splicing between the two patient groups.
“Most of these genes showed significantly elevated [activity] in the [second] subgroup,” the team wrote, adding that these alternative splicing events may have different effects on the resulting proteins.
Findings point to potential biomarkers, future research
The researchers noted that many of the identified genes are involved in immune responses, and some have been linked to Sjögren’s in prior studies.
“The enrichment of identified genes in [immune-regulating] pathways aligns with established knowledge of [primary Sjögren’s development], and the involvement of individual genes has been previously validated in [primary Sjögren’s], indicating the profound significance of our study in exploring disease mechanisms,” the scientists wrote.
Further statistical analyses showed significant associations between alternative splicing patterns in these genes and measures of Sjögren’s severity. For example, specific alternative splicing of the WARS1, DDX60, and MYO7B genes was significantly linked to variations in immune cell counts and ESSDAI scores.
“These [alternative splicing] events are not merely markers of molecular subgroups but also significantly correlate with disease activity and multi-dimensional laboratory indicators,” the researchers wrote.
The scientists noted that this study was limited to patients at a single center, highlighting the need for additional research to validate and expand on the findings. They said that a better understanding of the role of alternative splicing in primary Sjögren’s may help identify potential disease biomarkers and treatment targets.
