A study led by Prof. Francesco Cucca, has revealed a new genetic mechanism that protects against malaria. Conducted by a team primarily consisting of researchers from the Institute for Genetic and Biomedical Research of the National Research Council (CNR-IRGB) and the University of Sassari, the study of Marini, Mingoia, Steri et al. entitled “Reduced cyclin D3 expression in erythroid cells protects against malaria” shows how a naturally occurring variant in the Sardinian population causally affects the biology of red blood cells and disrupts the growth of the malaria parasite, opening up new avenues for future therapeutic strategies.
The research focuses on the rs112233623-T genetic variant, which is located in an erythroid enhancer that controls the expression of the CCND3 gene in red blood cell precursors. CCND3 encodes Cyclin-D3, which activates cell division and enhances the pentose-phosphate pathway (PPP), thereby counteracting reactive oxygen species (ROS). Previous genome-wide association analyses of approximately 7,000 volunteers from the SardiNIA general population cohort study in the Lanusei valley in Sardinia have shown that the rs112233623-T variant is associated with higher levels of haemoglobin A2, increased erythrocyte size, and reduced erythrocyte number.
The study shows that rs112233623-T, by disrupting a SMAD3 transcription factor binding site, weakens enhancer activity, resulting in reduced CCND3 expression. This lowers cyclin-D3 levels, thereby slowing the transition from the G1 to S phase of the cell cycle during erythropoiesis, which is consistent with the observed decrease in the number of larger erythrocytes.
The rs112233623-T variant is only present in Europe, suggesting that it originated after the out-of-Africa migration of modern humans, and within Europe, it shows a south-to-north gradient, with the highest frequency found in Sardinia. Using population genetic methods, the study further revealed consistent signatures of positive selection for this variant in Sardinia, accounting for its high frequency on this island. Given the critical role of cyclin-D3 in red blood cell precursors, the authors hypothesised that past endemic malaria in Sardinia was the main driver of such positive selection. Through functional experimentation, the authors then demonstrated that Plasmodium falciparum grows less efficiently in red blood cells carrying this genetic variant, which correlated with increased levels of reactive oxygen species. Similar observations were made in erythrocytes from individuals in the cohort who were deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD). This genetic trait has been reported to be associated with malaria resistance, suggesting a shared mechanism of parasite inhibition.
Together, these findings identify reduced CCND3 expression as a previously unrecognised factor of resistance to malaria and highlight this pathway as a potential target for future antimalarial therapies.
Link to:
Original Investigation: https://www.nature.com/articles/s41586-026-10110-9
Editorial Comment:
https://www.nature.com/articles/d41586-026-00289-2
https://www.nature.com/articles/s41588-026-02558-2
Plain Language Summary:
https://www.clearskyscience.com/en/10.1038/s41586-026-10110-9/