PCSK9 single nucleotide variants might affect susceptibility to malaria through regulation of CD36

• Published in: Medical hypotheses Vol. 184; p. 111294
• Main Author: Fan, Frank S.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.03.2024
• Subjects: Cancer; Cluster of differentiation 36; Malaria; Proprotein convertase subtilisin/kexin type 9; Single nucleotide variant; Proprotein convertase subtilisin/kexin type 9; Malaria; Cluster of differentiation 36; Single nucleotide variant; Cancer
• ISSN: 0306-9877; 1532-2777
• DOI: 10.1016/j.mehy.2024.111294

•Clearance of Plasmodium-infected erythrocytes depends on phagocytosis by macrophages with CD36 as the adhesion molecule.•Certain single nucleotide variants of PCSK9 presumably affect its capability of regulating CD36 degradation and expression.•Malaria is hence hypothesized to be the pathogen-driven selective pressure for the designated PCSK9 variants.•These PCSK9 polymorphisms might also influence the prognosis of cancer patients on account of the tumor-promoting role of CD36. Genetic polymorphism of proprotein convertase subtilisin/kexin type 9 (PCSK9), identified as single nucleotide variant (SNV), when locating at the Cys-His rich domain (CHRD), for example, E670G and I474V, is herein hypothesized to affect the domain’s binding affinity to cluster of differentiation 36 (CD36), which plays a major role in the phagocytosis of Plasmodium parasitized erythrocytes, and thus bringing on divergent susceptibility to malaria, with supporting evidence coming from epidemiologic studies of Malian children infected by malaria and population genetic comparison of European-Americans and African-Americans whose ancestors originated in the land ravaged by malaria. Starting from this proposal, the hypothesis extends further to the possible influence of PCSK9 CHRD SNVs on the development, therapeutic effects, and prognosis of cancer based on recently discovered roles of CD36 in tumour biology. It is hoped that more laboratory, epidemiology, and computation analyses in the near future can prove the whole speculation and broaden our knowledge about the physiology of PCSK9.