New study identifies genetic variants tied to AQP4-positive NMOSD
Findings suggest disease shares risk factors with autoimmune disorders
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An international team of researchers has identified three genetic variants significantly associated with higher odds of developing neuromyelitis optica spectrum disorder (NMOSD) with self-reactive antibodies against the AQP4 protein.
The data also suggest that, in terms of genetic risk factors, AQP4-positive NMOSD is more similar to systemic autoimmune diseases than to multiple sclerosis (MS), despite sharing overlapping neurological features.
Because the study showed shared genetic risk factors between AQP4-positive NMOSD and other autoimmune diseases in which TYK2 inhibitors have shown benefit, the results suggest the TYK2-STAT4 pathway as a possible target for future NMOSD treatments.
Study explored genetics of AQP4-positive NMOSD
The findings were described in the study “Identification of genetic risk loci associated with aquaporin 4-positive neuromyelitis optica spectrum disorder: a genome-wide association study,” which was published in The Lancet Neurology.
NMOSD is a rare autoimmune disease that mainly affects the spinal cord and optic nerves, causing symptoms such as pain, muscle weakness, and vision problems. More than 70% of those with NMOSD have self-reactive antibodies targeting the AQP4 protein.
At the time of first symptoms, AQP4-positive NMOSD can resemble other autoimmune diseases affecting the brain and spinal cord, including MS, making accurate diagnosis challenging and dependent on specific antibody tests and MRI results.
Compared with MS, the genetics of AQP4-positive NMOSD have been poorly studied, largely because the disease is uncommon and diagnostic testing is not widely accessible.
To address this gap, neurologists and immunologists formed the International NMOSD Genetics Consortium and conducted multi-ancestry genome-wide association studies (GWAS) of AQP4-positive NMOSD. GWAS is a type of study that scans the entire genome — a person’s full set of genetic material — to identify small genetic variants, called SNPs, linked to a particular trait or disease.
“We aimed to provide the first pan-ancestry [multi-ancestry] GWAS of individuals with clinically confirmed AQP4-positive NMOSD, and to explore the hypothesis of shared heritability of AQP4-positive NMOSD with other autoimmune diseases,” the team wrote.
The pan-ancestry GWAS analyzed data from 1,573 AQP4-positive NMOSD patients and 1,260 controls, comprising non-affected relatives, healthy non-relatives, and those with other autoimmune diseases.
Three variants tied to higher NMOSD odds
This analysis identified three SNPs (rs1150753, rs607929, and rs35593987) that were significantly and independently associated with AQP4-positive NMOSD.
rs1150753 and rs607929 were located in the major histocompatibility complex (MHC), a region well known for regulating immune function. The rs607929 variant was associated with nearly two times higher odds of AQP4-positive NMOSD, while rs1150753 was associated with nearly three times higher odds.
The third SNP, rs35593987, was in a gene called STAT4, which helps regulate immune signaling and gene activity, and was associated with 1.75 times higher odds of AQP4-positive NMOSD.
A separate GWAS involving 803 AQP4-positive NMOSD patients and 1,054 controls of European ancestry also identified rs607929 as significantly associated with the disease, along with two other SNPs. Notably, these other SNPs, rs1270942 and rs3821236, were closely linked to the rs1150753 and rs35593987 SNPs of the pan-ancestry GWAS, respectively.
Similar to the pan-ancestry study, carrying rs1270942, rs3821236, or rs607929 was significantly associated with more than 1.5 to nearly three times higher odds of AQP4-positive NMOSD.
The team also found that rs1270942 was in linkage disequilibrium with rs1150753, meaning the two variants are often inherited together. rs1270942 was also in linkage disequilibrium with two variants in specific HLA genes, which encode immune-recognition proteins in the MHC region, that were each significantly linked to more than 2.5 times higher odds of AQP4-positive NMOSD.
The MHC variants rs1150753 and rs607929 were also linked to the activity or protein levels of immune-related genes, including C4A and C4B, which are part of the immune complement cascade that contributes to immune-mediated damage in NMOSD.
TYK2 pathway may be future treatment target
The researchers also evaluated the effects of a specific variant, P1104A (rs34536443), in the TYK2 gene that reduces the gene’s activity and mirrors the effects of TYK2 inhibitors that have shown benefit in some autoimmune conditions. Of note, TYK2 works upstream of the STAT4 gene in the same biological pathway.
This variant was found to be protective against AQP4-positive NMOSD in both pan-ancestry and European GWAS, being linked to nearly 50% lower odds of the disease.
“Having demonstrated that the TYK2-STAT4 pathway is associated with such shared vulnerability, this could be a promising therapeutic target for treating patients with AQP4-positive NMOSD,” the team wrote.
An analysis of genetic risk sharing among autoimmune diseases in Europeans found that AQP4-positive NMOSD was most similar to myositis, systemic lupus erythematosus (SLE, the most common form of lupus), and idiopathic membranous nephropathy (a kidney disease).
Further genetic analyses found that AQP4-positive NMOSD was genetically correlated with SLE and sarcoidosis. No significant genetic correlation was found between AQP4-positive NMOSD and rheumatoid arthritis, collagenous colitis, microscopic colitis, or MS.
“AQP4-positive NMOSD is more genetically similar to [body-wide] autoimmune diseases than to multiple sclerosis, despite sharing overlapping clinical [characteristics],” the researchers wrote.
