Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most prevalent enzymatic disorder on the global scale, affecting over 400 million individuals. The genetic variants c.292G>A and c.376A>G in the G6PD have been identified as significant contributors to the most prevalent forms of enzymatic deficiency observed among populations of African descent. In patients diagnosed with autoimmune hemolytic anemia (AIHA), the presence of these variants has been observed to potentially exacerbate oxidative damage and intensify hemolysis. This observation signifies a clinically modifying factor that remains to be extensively explored.

The following exposition shall present recent research findings on the c.292G>A and c.376A>G variants in the G6PD gene that may modulate the clinical presentation of AIHA.

This study was based on an integrative literature review conducted between January 2019 and January 2025, using PubMed, SciELO, and LILACS databases. The following keywords were included: “G6PD deficiency,” “oxidative stress,” and “autoimmune hemolytic anemia.” Original research articles, systematic reviews, and case reports.

The c.292A and c.376G variants are primary contributors to reduced G6PD enzymatic activity, resulting in diminished capacity of red blood cells to counteract oxidative stress. The c.292A variant is associated with more severe clinical manifestations, while c.376G is usually asymptomatic when in isolation. Their presence increases erythrocyte vulnerability to hemolysis, especially in contexts involving inflammation, infections, or oxidative drugs. Research indicates these variants in AIHA patients are linked to elevated hemolysis rates, severe clinical presentations, and increased transfusion requirements during acute hemolytic crises. Genetic data from African and Latin American cohorts show these variants in over 10% of individuals of African descent worldwide, including some regions of Brazil. This underscores the importance of systematic screening in patients with suspected or confirmed AIHA, particularly in areas with high prevalence.

This analysis underscores that the c.292A and c.376G SNVs do not have a direct association with AIHA. However, they act as pathophysiological cofactors, intensifying hemolysis initiated by various mechanisms, particularly inflammatory and immunological processes. Impairment in NADPH regeneration and reduction in glutathione, both essential for protecting erythrocytes against oxidative stress, contribute to the intensification of acute and chronic hemolytic episodes in AIHA patients. Conclusion: Genetic variants in the G6PD gene have significant clinical implications in the pathophysiology of autoimmune hemolytic anemia, particularly by intensifying oxidative stress and exacerbating hemolytic episodes. Timely identification of single nucleotide variants can enhance risk stratification, facilitating immediate, safe, and customized therapeutic interventions. This approach may minimize adverse outcomes by ensuring appropriate and timely treatment.