**5.4 FY gene polymorphisms and malaria**

In addition to the role it plays in transfusion incompatibility and hemolytic disease of newborns, Duffy Blood Group System is important in medicine due to its association with the invasion of RBCs by the parasite *P. vivax*. Outside Africa, *P. vivax* is the most widespread malaria parasite species, with 40% of cases in the Eastern Mediterranean [167]. Without Duffy antigens on their surface, RBCs are relatively resistant to *P. vivax* [168]. There are six types of Duffy antigens (Fya , Fyb , Fy3, Fy4, Fy5, and Fy6), out of which only Fy3 has a clinical significance. Duffy antigens are also receptors for chemicals secreted by blood cells during inflammation [169].

Duffy-Antigen Chemokine Receptor (DARC) is a glycosylated transmembrane protein receptor which, among other roles, serves as a receptor for *P. vivax*. DARK crosses the membrane seven times and has an extracellular epitope, N-terminal domain responsible for RBC invasion by *P. vivax* merozoites [170, 171]. Two exons (FyA and FyB) of FY gene are encoded by the co dominant FyA and FyB alleles located on human chromosome 1 [172]. The difference between these two alleles is a non-synonymous mutation, specifically substitution of guanine to adenine at nucleotide 125, which was enough to determine the two antithetical antigens [173]. Based on this variation, four phenotypes within Duffy Blood Group System were identified: Fy (a + b-), Fy (a-b+), Fy (a-b-) and Fy (a + b+) [174]. The nonfunctional allele Fy\*O is the consequence of a mutation in the gene promoter at −33 nucleotide that changed thymine to cytosine which abolish its expression in the erythrocyte cell lineage [175, 176].

Individuals with Fy (a-b-) phenotype are resistant to *P. vivax* invasion [177]. This was shown in the study which included 11 volunteers. The individuals affected with malaria were Fy (a+) or Fy (b+). In the countries of West Africa, frequency of the Fy (a-b-) phenotype is a high while the incidence of *P. vivax* malaria is low [178]. Virtual absence of *P. vivax* malaria in populations with widespread DARC negativity is the proof of the substantial importance of the Duffy binding protein (DBP)–DARC interaction [179]. It is important to emphasize that Fy (a − b−) does not protect from *P. falciparum* which therefore can infect RBCs of any Duffy phenotype [169].

While *P. falciparum* can enter human RBCs through series of receptors on their surface, RBCs invasion by *P. vivax* depends on an interaction with the Fya or Fyb antigens [169, 180]. Therefore, in the regions of Africa where Fy (a-b-) phenotype is stable within various ethnic groups, the transmission of *P. vivax* is not usual [181]. On the other hand, individuals with Fy (a-b+) or Fy (a + b-) genotypes that express half the level of Duffy antigens on RBCs compared to Fy (a-b-) homozygotes are less sensitive to blood stage infection by *P. vivax*. Therefore, parasitemia by *P. vivax* might be inhibited by total or partial restriction access of *P. vivax* to Duffy antigen [182, 183].

Phenotypic differences in susceptibility to malaria are the results of Fy gene polymorphism. Individuals that carry Duffy antigen-negative allele hidden within heterozygous genotype have significantly reduced adherence of the DBP ligand domain (DBPII) to erythrocytes [184]. On the other hand, people with Fya phenotype have 30–80% lower risk of clinical *vivax* malaria, but not for falciparum malaria [185]. In the countries of Southeast Asia that are the source of *P. vivax*, the Fya allele is fixed [186], while Fyb is represented in the populations in North and Northern-central Europe. This kind of distribution of Fy alleles indicates a selective advantage against *P. vivax* malaria [185].
