title: Fy(a)/Fy(b) antigen polymorphism in human erythrocyte Duffy antigen affects susceptibility to Plasmodium vivax malaria.
abstract: Plasmodium vivax (Pv) is a major cause of human malaria and is increasing in public health importance compared with falciparum malaria. Pv is unique among human malarias in that invasion of erythrocytes is almost solely dependent on the red cell's surface receptor, known as the Duffy blood-group antigen (Fy). Fy is an important minor blood-group antigen that has two immunologically distinct alleles, referred to as Fy(a) or Fy(b), resulting from a single-point mutation. This mutation occurs within the binding domain of the parasite's red cell invasion ligand. Whether this polymorphism affects susceptibility to clinical vivax malaria is unknown. Here we show that Fy(a), compared with Fy(b), significantly diminishes binding of Pv Duffy binding protein (PvDBP) at the erythrocyte surface, and is associated with a reduced risk of clinical Pv in humans. Erythrocytes expressing Fy(a) had 41-50% lower binding compared with Fy(b) cells and showed an increased ability of naturally occurring or artificially induced antibodies to block binding of PvDBP to their surface. Individuals with the Fy(a+b-) phenotype demonstrated a 30-80% reduced risk of clinical vivax, but not falciparum malaria in a prospective cohort study in the Brazilian Amazon. The Fy(a+b-) phenotype, predominant in Southeast Asian and many American populations, would confer a selective advantage against vivax malaria. Our results also suggest that efficacy of a PvDBP-based vaccine may differ among populations with different Fy phenotypes.
authors: Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 44106, USA. cxk21@case.edu
authors: Christopher L
authors: CL
authors: King
authors: John H
authors: JH
authors: Adams
authors: Jia
authors: J
authors: Xianli
authors: Brian T
authors: BT
authors: Grimberg
authors: Amy M
authors: AM
authors: McHenry
authors: Lior J
authors: LJ
authors: Greenberg
authors: Asim
authors: A
authors: Siddiqui
authors: Rosalind E
authors: RE
authors: Howes
authors: Monica
authors: M
authors: da Silva-Nunes
authors: Marcelo U
authors: MU
authors: Ferreira
authors: Peter A
authors: PA
authors: Zimmerman
mesh_terms: D019138:Antibodies, Blocking / Q000276:immunology; D000913:Antibodies, Protozoan / Q000276:immunology; D000953:Antigens, Protozoan / Q000378:metabolism; D001192:Arylsulfatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004375:Duffy Blood-Group System / Q000235:genetics* / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005843:Geography; D006801:Humans; D016780:Malaria, Vivax / Q000235:genetics* / Q000469:parasitology*; D010966:Plasmodium vivax / Q000502:physiology*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D015800:Protozoan Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
chemical_list: C473745:ACKR1 protein, human; D019138:Antibodies, Blocking; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D004375:Duffy Blood-Group System; C066001:Duffy antigen binding protein, Plasmodium; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D001192:Arylsulfatases