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Updated: Jan 31, 2026
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Genetic Association and Altered Gene Expression of CYBB in Multiple Sclerosis Patients
Giulia Cardamone1, Elvezia Maria Paraboschi2, Giulia Soldà3,4
1Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy. giulia.cardamone@st.hunimed.eu.
Abstract:
Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation, demyelination, and axonal damage. Increased levels of reactive oxygen species (ROS), produced by macrophages and leading to oxidative stress, have been implicated as mediators of demyelination and axonal injury in both MS and experimental autoimmune encephalomyelitis, the murine model of the disease. On the other hand, reduced ROS levels can increase susceptibility to autoimmunity. In this work, we screened for association with MS 11 single nucleotide polymorphisms (SNPs) and two microsatellite markers in the five genes (NCF1, NCF2, NCF4, CYBA, and CYBB) of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) system, the enzymatic pathway producing ROS in the brain and neural tissues, in 347 Finnish patients with MS and 714 unaffected family members. This analysis showed suggestive association signals for NCF1 and CYBB (lowest p = 0.038 and p = 0.013, respectively). Functional relevance for disease predisposition was further supported for the CYBB gene, by microarray analysis in CD4+/- mononuclear cells of 21 individuals from five Finnish multiplex MS families, as well as by real-time RT-PCRs performed on RNA extracted from peripheral blood mononuclear cells of an Italian replication cohort of 21 MS cases and 21 controls. Our results showed a sex-specific differential expression of CYBB, suggesting that this gene, and more in general the NOX2 system, deserve to be further investigated for their possible role in MS.
Insights
Investigating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) system in multiple sclerosis (MS) revealed suggestive associations with the NCF1 and CYBB genes. Further research into CYBB showed sex-specific differential expression, indicating its potential role in MS pathogenesis.
Area of Science:
- Neuroimmunology
- Genetics of Neurological Disorders
- Oxidative Stress Research
Background:
- Multiple sclerosis (MS) is a chronic neurological disorder involving inflammation, demyelination, and axonal damage.
- Reactive oxygen species (ROS), produced by the NOX2 system, are implicated in MS pathogenesis, with both increased and decreased levels potentially contributing to disease.
- Genetic variations in NOX2 system genes may influence MS susceptibility and progression.
Purpose of the Study:
- To investigate the association of single nucleotide polymorphisms (SNPs) and microsatellite markers in five NOX2 system genes (NCF1, NCF2, NCF4, CYBA, CYBB) with MS.
- To explore the functional relevance of the CYBB gene in MS predisposition.
- To examine the expression patterns of CYBB in relation to MS.
Main Methods:
- Genetic association study screening 11 SNPs and 2 microsatellite markers in 347 Finnish MS patients and 714 controls.
- Microarray analysis of CD4+/- mononuclear cells from 21 individuals in Finnish multiplex MS families.
- Real-time RT-PCR on peripheral blood mononuclear cells from an Italian cohort of 21 MS cases and 21 controls.
Main Results:
- Suggestive association signals for MS were found for NCF1 (p=0.038) and CYBB (p=0.013).
- Microarray and RT-PCR analyses supported the functional relevance of CYBB in disease predisposition.
- A sex-specific differential expression of CYBB was observed in MS patients.
Conclusions:
- The NOX2 system, particularly the CYBB gene, warrants further investigation for its role in multiple sclerosis.
- Genetic variations and differential expression of CYBB may contribute to MS pathogenesis.
- Findings suggest a potential sex-specific influence of CYBB in MS.
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