Global study finds genetic signature in blood that identifies NMOSD
Specific immune-related molecules may help doctors diagnose the disease faster
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A specific set of immune-related genes is significantly more active in the blood of people with neuromyelitis optica spectrum disorder (NMOSD), potentially offering a new diagnostic approach for the rare disease.
A study in Iran found that seven genes involved in a major inflammatory pathway, called nuclear factor kappa B (NF-κB), were 4-16 times more active in NMOSD patients than in healthy adults, with some markers identifying the disease with 100% accuracy.
These genes included four that code for long non-coding RNAs (lncRNAs), a type of molecule that regulates gene activity and that has been previously implicated in NMOSD. Activity levels of two of these lncRNA genes — DICER-AS and ADINR — allowed researchers to accurately distinguish adults with NMOSD from healthy adults, data showed.
These molecules might be used in “future biomarker discovery attempts” for NMOSD in larger groups of patients and controls, researchers wrote.
The study, “A blood-based co-expression signature of LncRNAs and transcription factors in neuromyelitis optica with diagnostic and mechanistic implications,” was published in Scientific Reports.
Role of the NF-κB pathway in inflammation
NMOSD is a rare autoimmune disease that mainly causes inflammation and damage to the spinal cord and optic nerves (which relay signals between the eye and the brain). This can lead to symptoms such as vision problems, nerve pain, weakness, or paralysis in the arms or legs.
Research has found that the overactivation of the NF-κB signaling pathway, which normally helps control immune responses and inflammation, drives the release of pro-inflammatory signaling proteins that damage nerve cells in NMOSD.
Long non-coding RNAs are molecules that help regulate gene activity, thereby influencing protein production. Some NF-κB-related lncRNAs have been found at abnormal levels in the blood of people with multiple sclerosis, an NMOSD-related autoimmune condition.
In the study, scientists in Iran measured gene expression in the NF-κB pathway, including lncRNAs, in the blood of NMOSD patients to better understand their possible roles in the disease.
The study included 40 adults with NMOSD, mostly women (80%), and 40 age- and sex-matched healthy individuals, who served as controls. All patients tested positive for self-directed antibodies against aquaporin-4, the most common type of NMOSD-driving antibody.
Blood samples were analyzed for the activity of four lncRNA genes (ADINR, ANRIL, NKILA, and DICER-AS) and three protein-coding genes (DILC, CEBPA, and PACER). Results showed that the activity of all seven genes was significantly elevated in NMOSD patients compared with controls, ranging from four- to 16-fold higher.
Among them, only one lncRNA gene (ADINR) and one protein-coding gene (CEBPA) showed differences between male and female patients, indicating that NMOSD itself, not sex differences, primarily drove higher NF-κB-related gene activity.
“Nevertheless, interpretation of the sex terms is limited by the pronounced female predominance in our cohort (32/40 females), which reduces power to detect or precisely estimate sex-specific effects and may inflate uncertainty for those comparisons,” the team wrote.
The elevated activity of several lncRNAs in patients also correlated with one another: higher activity of the ADINR gene was significantly associated with higher activity of the ANRIL, NKILA, and DICER-AS genes, while NKILA’s higher activity correlated with DICER-AS’s higher activity.
Increased activity of these genes “in patients versus controls, and strong … correlations across the panel were consistent with a tightly co-regulated module in blood samples of patients,” the researchers wrote. “Such coordinated [lncRNAs] are increasingly recognized as drivers of immune cell state and inflammatory [profiles].”
Activity-level differences in most of the evaluated lncRNAs and protein-coding genes effectively distinguished people with NMOSD from healthy controls, with sensitivities ranging from 88% to 100%. Sensitivity refers to a test’s ability to correctly identify people who have the disease (true positives).
The lncRNA gene DICER-AS showed 100% sensitivity and specificity, indicating that it correctly discriminated all NMOSD patients from healthy controls. Specificity refers to a test’s ability to correctly rule out people who don’t have the disease (true negatives). ADINR activity levels achieved a sensitivity and specificity of 87.5%.
The lncRNA genes ANRIL and NKILA, and the protein-coding PACER gene, each achieved 100% sensitivity, correctly identifying all NMOSD patients, but showed lower specificities (67.5%-70%). Similarly, the DILC and CEBPA genes had sensitivities of 95% and 97.5%, respectively, but both showed low specificities (around 67.5%).
Linking gene activity to patient age
The researchers then looked at potential links between gene activity and patients’ demographic and clinical features.
They found that higher activity of the ADINR, ANRIL, and DILC genes was each significantly associated with older age at the time of the study and at disease onset. However, none of the seven genes showed significant associations with disability severity, as assessed with the validated Expanded Disability Status Scale.
“Future studies are needed to confirm the results of current study using cell sorting for separation of cell populations within whole blood, in addition to evaluation of NF-κB activity [and gene suppression tests] to confirm the function of mentioned genes,” the researchers wrote.
