CYBA C/C Mutation on Oxidative Genetics Testing
A CYBA C/C genotype (homozygous for the C allele at position 242) represents the wild-type or reference genotype for the C242T polymorphism in the p22phox subunit of NADPH oxidase, and is generally associated with higher oxidative stress potential and increased cardiovascular risk compared to T-allele carriers.
Understanding the CYBA Gene and C242T Polymorphism
The CYBA gene encodes p22phox (cytochrome b-245 alpha chain), which is a critical structural component of NADPH oxidase—the primary enzymatic source of reactive oxygen species (ROS) production in vascular and immune cells 1. The C242T polymorphism (rs4673) is a single nucleotide change that results in a histidine to tyrosine substitution at amino acid position 72 2.
Clinical Significance of the C/C Genotype
Oxidative Stress Profile
The C/C genotype is associated with lower levels of oxidative stress markers compared to other genotypes in some contexts. Specifically, patients with the CC genotype showed lower dimethylacetal (DMA) ratios (0.071 ± 0.003) compared to TT patients (0.089 ± 0.006), suggesting paradoxically lower oxidative stress in chronic kidney disease patients 2.
However, in breast cancer populations, the presence of the C allele (particularly in combination with other CYBA variants) correlates with elevated oxidative stress markers. The -930G/242C haplotype was associated with significantly higher malondialdehyde (MDA) levels, indicating increased lipid peroxidation and oxidative damage 3.
Cardiovascular Disease Risk
The C/C genotype has been linked to increased cardiovascular disease mortality in chronic kidney disease patients, with CC patients showing elevated CVD-related death rates compared to CT and TT genotypes 2.
In hypertensive populations, CYBA risk alleles (including the C allele) positively correlate with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and 8-isoPGF2α levels (an oxidative stress biomarker), while inversely correlating with protective catalase activity 4.
The T allele (242T) appears protective, with the T-allele carriers showing reduced cardiovascular disease prevalence and better antioxidant enzyme activity 4.
Disease Associations
Anthracycline-Induced Cardiotoxicity
- CYBA variants require additional validation (++/+ evidence level) for predicting anthracycline-induced cardiotoxicity risk, though genetic variations in CYBA have been associated with this complication in cancer patients receiving chemotherapy 1.
Chronic Granulomatous Disease (CGD)
- Biallelic pathogenic mutations in CYBA cause autosomal recessive chronic granulomatous disease, a primary immunodeficiency characterized by defective respiratory burst and recurrent severe bacterial and fungal infections 1. However, the C242T polymorphism is distinct from disease-causing CGD mutations.
Prematurity Complications
- The TT/CT genotype (T-allele carriers) shows protective associations with reduced risk of respiratory distress syndrome (OR 2.34 for CC vs TT/CT), retinopathy of prematurity (OR 1.72), and bronchopulmonary dysplasia (OR 1.60) in preterm infants 5.
Functional Implications
The C242T polymorphism affects NADPH oxidase activity and subsequent ROS production, though the exact functional consequences remain debated. The C allele may be associated with higher enzyme activity and greater oxidative capacity in certain cellular contexts 3, 4.
The polymorphism does not appear to significantly affect endothelium-dependent vasodilation in subjects with hypercholesterolemia, suggesting that its cardiovascular effects may operate through mechanisms other than direct nitric oxide bioavailability 6.
Clinical Interpretation
For a patient with C/C genotype:
Monitor cardiovascular risk factors more closely, particularly in the presence of chronic kidney disease, hypertension, or other oxidative stress-related conditions 2, 4
Consider enhanced antioxidant support or lifestyle modifications to mitigate oxidative stress, especially if other risk factors are present 4
In the context of anthracycline chemotherapy, the C/C genotype may warrant closer cardiac monitoring, though evidence is still emerging 1
The C/C genotype does NOT indicate chronic granulomatous disease, which requires biallelic loss-of-function mutations rather than this common polymorphism 1
Important Caveats
The clinical utility of C242T genotyping remains investigational for most conditions, as the polymorphism shows variable associations across different populations and disease contexts 2, 3, 6, 5, 4
Gene-environment interactions are critical—the impact of the C/C genotype may be modified by altitude, ethnicity, concurrent medications, and other genetic variants 4
This is a common polymorphism, not a disease-causing mutation—approximately 40-50% of most populations carry the C/C genotype, making it a risk modifier rather than a deterministic genetic factor 2, 4