|Year : 2022 | Volume
| Issue : 3 | Page : 193-197
Linkages between blood groups and malaria susceptibility
Minu Nain1, Amit Sharma2
1 ICMR-National Institute of Malaria Research, New Delhi 110077, India
2 ICMR-National Institute of Malaria Research, New Delhi 110077; Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
|Date of Submission||27-Aug-2021|
|Date of Acceptance||26-Mar-2022|
|Date of Web Publication||08-Dec-2022|
ICMR-National Institute of Malaria Research, New Delhi-110077
Source of Support: None, Conflict of Interest: None
Blood typing has revolutionized the field of medical science since its discovery about a century ago. Besides its established role in life-saving blood transfusions, researchers have always been curious about the relationship between blood groups and human ailments. The effect of blood groups on disease outcomes, susceptibility, and mortality has been widely explored. According to a particular school of thought, the endemicity of diseases shapes the distribution of blood group frequency in human populations and exert selection pressure favoring one blood type over another. Here we discuss the scope and association of different blood groups in the context of malaria.
Keywords: Blood groups; malaria; selection pressure; severity; study design; susceptibility
|How to cite this article:|
Nain M, Sharma A. Linkages between blood groups and malaria susceptibility. J Vector Borne Dis 2022;59:193-7
| Introduction|| |
Blood groups are determined by the presence of specific antigens on red blood cells, plasma cells, leukocytes, platelets, and via body secretions such as gastric, saliva, sweat, breast milk, urine, seminal fluid, and amniotic fluid. These are composed of antigens encoded by either a single gene or a pair of homologous genes. The ABO blood group antigens were the first genetic markers known and were discovered by Karl Landsteiner in 1900 on red blood cells (RBCs). Since then, ABO is the main blood group system to determine safety during transfusions and has deep applications in clinical research. Blood group typing checks for the presence of specific antigens on RBCs. Several analytical techniques are available for blood typing, including classical serological methods for recording agglutination, PCR amplification for molecular genotyping in absence of serological methods, and other more advanced methods like ultraviolet backscattering and elastic laser radiation scattering methods for monitoring agglutination reactions. International Society for Blood Transfusion has recognized more than 30 blood group systems to date. The role of these blood group systems in malaria, a vector-borne infectious disease that claims millions of lives every year, has been a topic of a great number of studies to date. Some of these blood group systems with a crucial role in malaria pathogenesis are (1) the Duffy system as determined by the presence of Fy glycoprotein on RBC cell surface where it can act as a receptor for Plasmodium vivax (2) ABO(H) system, where presence or absence of A, B, and H antigen on RBCs determine the blood type (3) the rhesus system characterized by the presence of Rh factor or D antigen on the cell surface. It is the second most clinically significant blood typing system after ABO. (4) Knops blood group that consists of nine antigens presented on complement receptor 1 (CR1) molecule. It is a membrane glycoprotein located on RBCs and plays a crucial role in immune complex removal and rosette formation is associated with severe malaria. The Knops blood group (KN) (5) MNS system that includes sialic acid-rich RBC cell surface glycoproteins, glycophorin A, B, and E whereas the glycophorin C and D constitute the Gerbich blood group.
Blood groups and malaria
P. vivax and P. falciparum pose the greatest disease and death risk among the five species of Plasmodium known to cause malaria in humans. The most important gateway for disease development by Plasmodium parasites is entry and infection of erythrocytes. As the parasite is dependent on RBC to complete its life cycle in the human host, several blood group antigens present on RBCs might play a crucial role in parasite infection and hence blood groups can have a direct association with the susceptibility and severity of malaria infection. One such blood group antigen is Duffy antigen or Duffy antigen associated receptor for chemokines (DARC) on RBCs that acts as a receptor for P. vivax and P. knowlesi. Two main antigens Fya and Fyb of the Duffy system forms four phenotypes i.e., Fy(a+b+), Fy(a+b–), Fy(a–b+), and Fy(a–b–) among which Fy(a–b–) shows protection against P. vivax and P. knowlesi due to complete absence of DARC on RBC cell surface and hence the inability of the parasite to enter RBCs. The absence of P. vivax malaria in most malaria-endemic countries in Africa has been attributed to the wide prevalence of the Fy(a–b–) phenotype. A few in vitro and in vivo studies show that heterozygous phenotypes are about 30–80% less susceptible to P. vivax when compared to Fy(a+b+) phenotype as the antigen density on erythrocyte surface is decreased leading to a significant decrease in adherence of PvDBP (P. vivax Duffy binding protein) and hence reduced susceptibility to P. vivax infection. However, there is a significant difference in the binding efficiency of PvDBP to Fa and Fb antigens. PvDBP binds much more efficiently to Fb antigen than Fa, making Fb phenotypes more susceptible to P. vivax infection as compared to Fa,. A recent study has supported this where it has been shown that taking Fy(a+b+) as a reference, Fy(a+b–) phenotype is less susceptible to clinical P. vivax in comparison to Fy(a–b+). The difference in adherence to these two antigens is however not significant in the case of P. knowelsi. More studies need to be conducted to check P. vivax susceptibility and pathogenesis in heterozygous individuals. Also, unlike thought earlier that Duffy negative phenotype is completely resistant to P. vivax infection, there is an increase in P. vivax infection and active transmission in Africa where the Duffy negative allele is near to fixation,. It can be attributed to either improved diagnostics or a continuous evolutionary race between P. vivax and the host. The parasite might be evolving to DARC negativity by using some alternative entry route to RBCs,. It is possible via either duplication of PvDBP (P. vivax Duffy binding protein) or the use of other non DBP ligands such as PvEBPs (P. vivax erythrocyte binding proteins), PvRBPs (P. vivax reticulocyte binding proteins), PvMSP-1(P. vivax merozoite surface protein-1 paralog) or PvGAMA (P. vivax glycosylphos-phatidylinositol-anchored micronemal antigen) by P. vivax for binding and entry into DARC negative individuals. The P. vivax parasitemia is however low in DARC negative individuals and infection is usually asymptomatic and mild. But in the case where P. vivax is evolving, there are chances that it can adapt efficiently to Duffy negative phenotype in the future and might become a serious healthcare problem in the African population especially, where Duffy negative phenotype is predominant,,.
Unlike for the Duffy antigen, studies on the relationship between ABO types and P. vivax are limited. Few reports have suggested that group O individuals are more prone to P. vivax associated anemia as compared to non-O group individuals,,. A recent study has described that O group infected individuals have higher levels of IgG and IgM autoantibodies and also antibody-mediated erythro-phagocytosis of nRBCs causing anemia. Similarly, P. falciparum malaria severity has also been correlated with the ABO system. This correlation between severity and ABO antigen is mainly attributed to sequestration and rosetting of infected erythrocytes (IE),. These expressed proteins such as RIFIN and PfEMP1 (Erythrocyte membrane protein 1) which interact with several host cell surface receptors including blood group determinants viz., A or B antigen on neighboring uninfected erythrocytes form large cell clusters called rosettes,,. Rosetting protects infected cells from antibody-mediated cell death which further intensifies infection,. Also, the presence of A or B antigen on endothelial cells helps in the sequestration of these IEs. Due to the absence of A or B antigen on RBCs of group O individuals, the rosette formed is very small and is thus available for antibody-mediated cell death,,,,. In line with these molecular functions of A and B antigen in sequestration and rosetting, studies have shown that A and B blood group individuals are more susceptible to developing severe malaria infection in comparison to O group individuals. Although, the O blood group is protective against developing severe P. falciparum infection, however, differences in parasitemia and hemoglobin levels among different blood groups have been found insignificant in most of the studies. Several contradictory reports are showing enhanced susceptibility of the O blood group to P. falciparum as compared to A, B, and AB. However, a recent meta-analysis suggests no significant correlation between blood group polymorphism and susceptibility to uncomplicated and asymptomatic malaria.
In the case of placental P. falciparum malaria, primiparous women with O blood group are shown to be more prone to active infection than non-O blood type primiparous women. Thus, studies so far on ABO and malaria susceptibility and severity have concluded that ABO type does not influence human contact with mosquitoes but influences the malaria outcome by affecting malaria pathogenesis once the parasite has entered into the host body,. These studies have implications in designing vaccines or drugs targeting rosette formation and disruption to avoid and treat severe P. falciparum infection along with the preferable use of O blood group for transfusion in severe malaria cases whenever possible. The ABO blood group distribution is consistent with malaria prevalence across the world as the O blood group is prevalent over A in malaria-endemic regions like sub-Saharan Africa whereas A is dominant in non-endemic regions. This provides evidence that selective genetic pressure from P. falciparum might have played a crucial role along with other endemic diseases persisting in the same region in shaping ABO polymorphism. A few studies have also checked the association of Rh blood groups frequency with malaria prevalence and susceptibility. Most of these studies did not find any significant correlation between the Rh factor and malaria infection,. These findings are however inconclusive due to small sample size and the fact that Rh positive is highly dominant in the population when compared to Rh negative.
Besides Duffy and ABO blood systems, there are other blood groups including Knops, MNS, and Gerbich that play crucial roles in malaria susceptibility and severity,,,. The CR1 antigen of Knops interacts with P. falciparum erythrocyte membrane protein 1 (PfEMP1) to form rosettes. The Helgeson phenotype where individuals express less than 100 CR1 per RBCs is thus thought to be defensive against acute malaria due to the inability to form large rosettes like the ABO blood group system. The CR1 is highly polymorphic with some Single Nucleotide Polymorphisms (SNPs) (low expression allele, L) protecting against severe malaria while others (High expression allele, H) alleviate susceptibility to P. falciparum,,. The studies on the association of CR1 levels and malaria susceptibility and severity have been contradictory so far, with some studies concluding that the L1 allele confers protection against severe malaria while others show either no protection against severe malaria or increased susceptibility to severe malaria by L1 allele,,. A study done in India tried to address these variations where they stated that in low transmission settings, stunted CR1 levels are associated with acute malaria whereas high CR1 levels are related to disease severity in high transmission region. These studies emphasize that rosetting might not be the sole criteria for malaria severity and that disease pathogenesis may vary with population and malaria endemicity.
Glycophorins are sialic acid-rich glycoproteins on RBCs where they not only determine blood group but also act as pathogen receptors. Glycophorin A (GYPA) and Glycophorin B (GYPB) interact with P. falciparum erythrocyte-binding antigen 175 (EBA-175) and erythrocyte-binding ligand 1 (EBL-1) of P. falciparum merozoites respectively to facilitate their entry into RBCs,. Gerbich blood group antigens, Glycophorin C (GYPC), and its variant Glycophorin D (GYPD) also act as receptors for a few strains of P. falciparum Several glycophorin variants have been identified across populations to provide protection against malaria including the under-glycosylated GYPA variant in Africa affecting malaria susceptibility and complete absence of Glycophorin B which is quite common in central Africa and provide protection against malaria. One such variant, Dantu, a hybrid of Glycophorin A and B with GYPB extracellular domain and GYPA intracellular domain, has been shown to provide ~74% protection against severe malaria in homozygous individuals which is equivalent to sickle cell trait. A recent study has demonstrated the actual mechanism by which Dantu confers protection against malaria where it was suggested that Dantu RBCs resist merozoite invasion due to their high membrane tension. Besides GYPA and GYPB, GYPC and GYPD lacking phenotype (Gerbich negative phenotype) provide protection but are rare whereas their protective variants are widespread in Melanesians especially in Papua New Guinea. Despite the crucial role of glycophorins and their variants in malaria pathogenesis, there are not enough studies to conclude their effect on malaria outcomes as well as selection pressure against Glycophorin distribution across populations. More intensive studies with a larger sample size and diverse ethnic populations are required to reach a definite conclusion.
| Conclusion|| |
Though the above association studies provide interesting links between disease susceptibility and blood groups, almost all of them focus on the presence or absence of a particular blood group antigen. They do not fully address the underlying genetic polymorphism and functional aspects within these blood types. As the disease outcome is a very complex process, so along with these association studies, particular host survival genes and interplay of host-parasite genes needs to be elucidated before deriving conclusions. Moreover, most of the studies are not conclusive due to either a very small sample size, inappropriate control groups, or exclusion of the most susceptible population viz., pediatric population, pregnant ladies, and people with co-morbidities. So, well-designed studies are a prerequisite for addressing the links between severity and blood type. The association between malaria prevalence and blood group distribution also suggests the role these diseases play by natural selection of the blood group genotype with a survival advantage. Nevertheless, the presented association studies are crucial in determining the high-risk populations and in the adoption of preventive strategies in case of any malaria outbreak. As malaria progresses towards elimination, assessment of blood types in regions where malaria persists despite best interventions may be a worthwhile question to address.
Ethical statement: Not applicable
Conflict of interest: None
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