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Impact of CYBA genotypes on severity and progression of multiple sclerosis
Andreas Törnell1, Roberta Kiffin1, Sara Haghighi2,3
1Sahlgrenska Center for Cancer Research, Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Background And Purpose:
The NOX2 enzyme of myeloid cells generates reactive oxygen species (ROS) that have been implicated in the pathology of multiple sclerosis (MS). We aimed to determine the impact of genetic variation within CYBA, which encodes the functional CYBA/p22phox subunit of NOX2, on MS severity and progression.
Methods:
One hundred three MS patients with up to 49 (median = 17) years follow-up time from first MS diagnosis were genotyped at the single nucleotide polymorphisms rs1049254 and rs4673 within CYBA. Results were matched with disease severity and time to diagnosis of secondary progressive MS (SPMS). NOX2-mediated formation of ROS was measured by chemiluminescence in blood myeloid cells from healthy donors (n = 55) with defined genotypes at rs1049254 and rs4673.
Results:
The rs1049254/G and rs4673/A CYBA alleles were associated with reduced formation of ROS and were thus defined as low-ROS alleles. Patients carrying low-ROS alleles showed reduced multiple sclerosis severity score (p = 0.02, N = 103, linear regression) and delayed onset of SPMS (p = 0.02, hazard ratio [HR] = 0.46, n = 100, log-rank test). In a cohort examined after 2005, patients carrying low-ROS CYBA alleles showed >20 years longer time to secondary progression (p = 0.003, HR = 0.29, n = 59, log-rank test).
Conclusions:
These results implicate NOX2 in MS, in particular for the development of secondary progressive disease, and point toward NOX2-reductive therapy aiming to delay secondary progression.
Insights
Genetic variations in the CYBA gene, encoding a subunit of the NOX2 enzyme, are linked to reduced reactive oxygen species (ROS) production. This finding suggests a potential therapeutic target for mitigating multiple sclerosis (MS) progression.
Area of Science:
- Neuroimmunology
- Genetics of Neurological Disorders
- Oxidative Stress in Disease
Background:
- The NOX2 enzyme in myeloid cells generates reactive oxygen species (ROS), implicated in multiple sclerosis (MS) pathology.
- Genetic variations in CYBA, encoding the NOX2 functional subunit p22phox, may influence MS severity and progression.
Purpose of the Study:
- To investigate the impact of specific CYBA gene single nucleotide polymorphisms (SNPs) on MS severity and disease progression.
- To correlate CYBA genotypes with NOX2-mediated ROS production in myeloid cells.
Main Methods:
- Genotyping of 103 MS patients for CYBA SNPs rs1049254 and rs4673.
- Correlation of genotypes with clinical data including disease severity and time to secondary progressive MS (SPMS).
- Measurement of NOX2-mediated ROS by chemiluminescence in myeloid cells from 55 healthy donors with defined genotypes.
Main Results:
- CYBA alleles rs1049254/G and rs4673/A were associated with reduced ROS production ('low-ROS alleles').
- Patients with low-ROS alleles exhibited a reduced Multiple Sclerosis Severity Score (p=0.02).
- Low-ROS alleles were linked to a delayed onset of SPMS (p=0.02, HR=0.46) and significantly longer time to secondary progression (>20 years, p=0.003, HR=0.29) in a recent cohort.
Conclusions:
- NOX2 activity, influenced by CYBA genetics, plays a significant role in MS pathogenesis, particularly in the development of secondary progressive disease.
- Targeting NOX2 to reduce ROS production represents a potential therapeutic strategy to delay MS progression.
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