Reduced cyclin D3 expression in erythroid cells protects against malaria

Area of Science:

• Genetics
• Hematology
• Infectious Diseases

Background:

• Malaria severity varies, but underlying mechanisms are unclear.
• Erythrocytes (red blood cells) are crucial in malaria.
• Genetic variants influencing erythrocyte development may determine disease severity.

Purpose of the Study:

• Investigate the rs112233623-T variant's effect on erythrocyte properties.
• Examine the variant's role in modulating malaria severity.
• Elucidate the mechanistic basis of malaria resistance.

Main Methods:

• Analyzed the rs112233623-T variant's association with erythrocyte traits.
• Studied the variant's impact on CCND3 expression and cell cycle progression in erythroblasts.
• Employed population genetic methods to detect selection signatures.
• Assessed Plasmodium falciparum growth in infected erythrocytes from variant carriers.

Main Results:

• rs112233623-T increases hemoglobin A2, erythrocyte size, and decreases erythrocyte number.
• The variant disrupts SMAD3 binding, reduces CCND3 expression, and inhibits erythroblast cell cycle.
• Positive selection for rs112233623-T observed in Sardinian population.
• Parasite growth is impaired in rs112233623-T carrier erythrocytes, linked to reactive oxygen species (ROS).

Conclusions:

• Reduced CCND3 expression in erythroblasts is a novel malaria resistance mechanism.
• The variant's effect on ROS levels contributes to malaria protection.
• This finding may inform new therapeutic interventions for malaria.