In the century since the discovery of the ABO blood groups, numerous associations between ABO groups and disease have been noted. However, the selection pressures defining the ABO distributions remain uncertain. We review published information on Plasmodium falciparum infection and ABO blood groups. DNA sequence information dates the emergence and development of the group O allele to a period of evolution before human migration out of Africa, concomitant with P falciparum's activity. The current geographic distribution of group O is also consistent with a selection pressure by P falciparum in favor of group O individuals in malaria-endemic regions. We critically review clinical reports of ABO and P falciparum infection, documenting a correlation between disease severity and ABO group. Finally, we review published data on the pathogenesis of P falciparum infection, and propose a biologic model to summarize the role of ABO blood groups in cytoadherence biology. Such ABO-related mechanisms also point to a new hypothesis to account for selection of the Le(a−b−) phenotype. Taken together, a broad range of available evidence suggests that the origin, distribution, and relative proportion of ABO blood groups in humans may have been directly influenced by selective genetic pressure from P falciparum infection.

Introduction

The ABO blood group system is arguably the best known, and yet the most functionally mysterious, genetic polymorphism in humans. In clinical practice, ABO is the most important system for blood group compatibility. In the century since their discovery, ABO antigen associations with infections and other diseases have been the subject of hundreds of publications.1,2  Some reports found unexpected associations, such as the susceptibility of group A individuals to salivary or gastric cancers.3  However, associations with diseases affecting humans after reproduction are not expected to exert any genetic selection. Thus, despite a large body of literature, the evolutionary basis for the origin and diversity of ABO blood group antigens remains uncertain. Much new information has emerged since a relationship between ABO and malaria was first suggested more than 40 years ago.4  We review literature in support of the hypothesis that Plasmodium falciparum malaria has shaped the distribution of ABO blood groups in humans.5 

We offer 4 arguments in support of this hypothesis. First, we review evidence that P falciparum was present at the time when ABO polymorphisms arose. Second, we note that the current worldwide distribution of ABO groups is consistent with an effect from P falciparum. Third, we critically review studies examining clinical outcomes during P falciparum infection. Fourth, we offer proposed biologic mechanisms relating host ABO group to the pathophysiology and lethality of P falciparum malaria.

P falciparum: the strongest force in the recent history of the human genome

P falciparum has been called “the strongest known force for evolutionary selection in the recent history of the human genome.”6  The signature of P falciparum has been its enormous toll on human life, especially children. Infectious diseases that kill children select for survival genes and effectively prevent transmission of genotypes unfavorable to survival. In the case of P falciparum, untreated children have a 20-fold higher case fatality rate than adults. Even today, the worldwide loss of human life is staggering, with almost all of the 1 million to 2.7 million annual deaths, one every 12 seconds, occurring among children younger than age 5.7  The ability of P falciparum to kill before reproduction has given it the capacity to select emerging polymorphisms as rapidly as can be witnessed in evolutionary time.

The coevolution of humans and P falciparum

Figure 1 shows the parallel coevolution of P falciparum and its human host. The 4 species of malaria that infect humans today (P vivax, P ovale, P malariae, and P falciparum) arose from an ancestral form 200 million years ago.8 P falciparum's closest genetic relative, P reichenowi, which infects chimpanzees, diverged from P falciparum 9 million to 10 million years ago, around the time that prehuman species diverged from chimpanzees and great apes.8  Thus, P falciparum long predated the development of modern humans.

Figure 1

Co-evolution of P falciparummalaria and humans.

Figure 1

Co-evolution of P falciparummalaria and humans.

Modern humans, Homo sapiens, began to emerge in Africa approximately 200 000 years ago9,10  and developed during a period overlapping with the current genetic form of P falciparum.11  Humans first emigrated out of Africa between 100 000 and 40 000 years ago to colonize Asia, Europe, and Oceania,12  and carried with them blood group polymorphisms that had developed under selection pressure of P falciparum.

During the period from 70 000 to 4000 years ago, multiple human erythrocyte mutations associated with a survival advantage in P falciparum infection are thought to have developed. These include structural hemoglobinopathies (Hb S, Hb C),13  quantitative hemoglobinopathies (the thalassemias),14  membrane mutations (spherocytosis, elliptocytosis, ovalocytosis),15  and enzymopathies (glucose-6-phosphate dehydrogenase [G6PD] deficiency).16  The prevalence of these malaria-selected mutations, as well as the pressure P falciparum exerted on the distribution of blood groups, may have further increased 10 000 years ago when the death toll from P falciparum is thought to have increased substantially.17  This increase in prevalence probably resulted from agriculture, forest-clearing, and animal domestication, all of which promoted success of the Anopheles mosquito. As a result, the most intense malarial selection pressures were effectively applied to the human genome in the relatively compressed period of the past few millennia, coincident with the observed development of multiple adaptive erythrocyte mutations.

P falciparum was present during genetic selection of group O alleles

The evolutionary story of the ABO genes sits squarely within this malarial timeline. Among modern humans, the most common allele for group O (termed O01) is identical to the group A allele (A01) for the first 261 nucleotides, at which point a guanosine base is deleted, resulting in a frame-shift mutation that produces a premature stop codon and failure to produce a functional A or B transferase. This single base deletion, from what would otherwise have been a functional group A gene, implies that group O individuals with allele O01 arose as a mutation from A01.18  The second most common allele for group O (termed O02) is considered to be an even more ancient O allele, and also shares the 261 deletion. Other less common group O alleles have been discovered18  and nearly all share deletion 261, leading Roubinet et al18  to conclude that virtually all group O alleles arose at a single time point in human evolution.

Because deletion 261 is found in all populations worldwide, it presumably arose during evolution in Africa before the outward migrations of early humans. Thus, whatever selection pressure favored the group O phenotype must have been active in Africa earlier than 50 000 to 100 000 years ago. P falciparum's established presence in Africa at the origin of modern humans makes it a plausible candidate to influence human blood groups. In fact, during the 150 000 years from the origin of H sapiens to the migration out of Africa, even a slight selective advantage of group O during P falciparum infection would have resulted in a gradual but persistent increase in the prevalence of group O individuals. After the migration, group O genes may have been further enriched among humans inhabiting malaria regions outside of Africa through the introduction of independent group O mutations at position 261. In summary, any infectious disease driving the distribution of ABO groups must be an agent that was active in Africa before the early migration of humans and must be lethal before or during the human reproductive years. P falciparum, considered to be one of the strongest forces in evolutionary history, was in the right place at the right time.

The worldwide prevalence of group O parallels malarial regions

Our hypothesis is that during infection with P falciparum, group O offers a survival advantage, group A confers a disadvantage, and group B has an intermediate effect. Given this hypothesis, one would expect to find that the ratio of group O to A is higher in geographic regions where malaria is currently, or was previously, endemic. This indeed appears to be the case (Table 1).19,,22  An especially high prevalence of group O coupled with a low prevalence of group A is found throughout subSaharan Africa, where P falciparum persists to this day. In the Western hemisphere, the distribution of group A and group O generally matches malaria's tropical distribution.19  From the tropical regions of Central and South America southward, the indigenous peoples are almost exclusively group O. In Asia, the prevalence of group O rises among peoples who live closer to the equator. For example, in Beijing, China (a cold weather zone), group O is 29% and group A 27%, but in Canton, China (a more tropical zone), group O is 46% and group A is 23%. Group O is the most common blood group in Turkey and Persia.19  In contrast, group A is the predominant blood group in the colder regions of the Earth, where malaria has not been endemic (Table 1). In fact, group A is found in highest frequency in Scandinavia, Greenland, and the subarctic regions of Europe and North America. Thus, if survival from malaria is associated with group O, and mortality is associated with group A, then the worldwide distribution of ABO groups is consistent with selective pressure from malaria.

Table 1

Prevalence of group O, group A, and non–group O in regions of current or previous malaria19,,22 

Country/peopleGroup O, %Group A, %Non–group O, %Ratio O to AMalaria area, current or past
Southeast Nigeria 87 13 11.0 Yes 
Sudan 62 16 38 3.86 Yes 
Kenya/Kikuyu 60 19 40 3.16 Yes 
African Bushmen 56 34 44 1.65 Yes 
Central African Republic 44 28 56 1.57 Yes 
Congo 52 24 48 2.17 Yes 
Eritrea/Somalia 60 22 40 2.73 Yes 
Ghana 47 23 53 2.04 Yes 
Namibia 47 10 53 4.70 Yes 
Central America; Amazon basin 90 < 10 10 > 9 Yes 
North American Indians/Navajo 73 27 27 2.70 Yes 
USA, general/Indians 79 16 21 4.94 Yes 
Persia 38 33 62 1.15 Yes 
Turkey 43 34 57 1.26 Yes 
Philippines 45 22 55 2.04 Yes 
Vietnam 42 22 58 1.91 Yes 
Papua New Guinea 41 27 59 1.52 Yes 
Finland 34 41 66 .83 No 
Austria & Hungary 36 44 64 .82 No 
Sweden 38 47 62 .81 No 
Switzerland 40 50 60 .80 No 
Norway 39 50 61 .78 No 
Bulgaria 32 44 68 .73 No 
Czech Republic 30 44 70 .68 No 
Portugal 35 53 65 .66 No 
Country/peopleGroup O, %Group A, %Non–group O, %Ratio O to AMalaria area, current or past
Southeast Nigeria 87 13 11.0 Yes 
Sudan 62 16 38 3.86 Yes 
Kenya/Kikuyu 60 19 40 3.16 Yes 
African Bushmen 56 34 44 1.65 Yes 
Central African Republic 44 28 56 1.57 Yes 
Congo 52 24 48 2.17 Yes 
Eritrea/Somalia 60 22 40 2.73 Yes 
Ghana 47 23 53 2.04 Yes 
Namibia 47 10 53 4.70 Yes 
Central America; Amazon basin 90 < 10 10 > 9 Yes 
North American Indians/Navajo 73 27 27 2.70 Yes 
USA, general/Indians 79 16 21 4.94 Yes 
Persia 38 33 62 1.15 Yes 
Turkey 43 34 57 1.26 Yes 
Philippines 45 22 55 2.04 Yes 
Vietnam 42 22 58 1.91 Yes 
Papua New Guinea 41 27 59 1.52 Yes 
Finland 34 41 66 .83 No 
Austria & Hungary 36 44 64 .82 No 
Sweden 38 47 62 .81 No 
Switzerland 40 50 60 .80 No 
Norway 39 50 61 .78 No 
Bulgaria 32 44 68 .73 No 
Czech Republic 30 44 70 .68 No 
Portugal 35 53 65 .66 No 

Relationship between ABO groups and the severity of malaria: a critical review of the literature

We critically reviewed literature published during the past 28 years that investigated the relationship between P falciparum infection and ABO groups. Studies in humans published through January 2007 were identified using Medline searches, textbook citations, and the reference lists from retrieved articles. Search terms included “Plasmodium falciparum,” “malaria,” and “ABO.” Related articles for relevant publications were also queried.

Flawed reports exploring associations

Although we found 22 reports that explored an association between ABO group and P falciparum malaria,23,,,,,,,,,,,,,,,,,,,43  there was no definitive study with adequate sample size investigating ABO group and survival from P falciparum infection. We focused, therefore, on studies that examined ABO group and severity of disease. The sample size of 12 studies was too small to ascertain variations in the distribution of the ABO blood groups.23,,,,,,,,,,34  Eleven studies were flawed by absent or inappropriate control groups.21,23,28,,,32,34,36,38  Several publications reported data on individuals unlikely to die of P falciparum, including 15 studies of individuals with asymptomatic infection/incidental parasitemia, mild infection, or infection of unspecified severity.21,26,,,,,,,,,,,,39  Finally, many studies failed to report outcomes among the most informative cohort, children younger than 5 years old, who have the highest morbidity and mortality. Given the small sample sizes, the flaws in study design, and unspecified or absent focus on clinical severity, it is not surprising that these studies failed to identify any association between ABO groups and outcomes from P falciparum infection.

Well-designed clinical studies of ABO and clinical severity of P falciparum infection

In contrast to these reports, Table 2 lists those controlled studies40,,43  that examined ABO distributions and clinical severity of P falciparum infection. Clinical severity, rather than incidence or prevalence of detectable parasitemia, is a more relevant outcome to assess ABO group and survival. Studies reporting clinical features such as cerebral malaria carry more weight than those reporting only laboratory markers such as percent parasitemia, because the latter does not always predict survival. For example, a low percentage of circulating parasitized red cells may either reflect less severe infection (good prognosis), or a greater degree of adhesion of parasitized cells to the vascular endothelium (bad prognosis).44,46  Conversely, among those with a well-developed humoral immunity, there is little correlation between high circulating parasitemia and severity of illness.47,48 

Table 2

Well-designed clinical studies of ABO distributions and clinical severity of P falciparum infection44,,47 

Author/year/localeSample sizeFocusFindings
Fischer et al40 /1998/Zimbabwe 209 mild malaria outpatients vs 280 severe malaria inpatients Coma and anemia severity by blood group Coma in 3% of group non-A vs 9% of group A, P = .008 
Lell et al41 /1999/Gabon 100 mild malaria cases vs 100 severe malaria cases Proportion of severe cases among ABO blood groups Group O: 46% severe group A: 71% severe, P < .01 
Pathirana et al42 /2005/Sri Lanka 243 malaria cases (163 mild, 80 severe) and 65 nonmalarial controls with other infections Blood group distributions among the mild vs severe, odds ratio for severe malaria if group O vs. non-O Blood group, mild/severe: group O, 48%/24%; group B, 23%/28%; group A, 25%/33%; group AB, 5%/16%; P < .001; odds ratio (severe malaria:controls) for group O status, 0.37; P < .001 
Loscertales et al43 /2006/The Gambia 41 primiparae with active placental infection. Maternal and infant hemoglobin; infant weight and size; placental weight; placental parasite count Placental weight group O, 2893 g; non–group O, 2639 g; P = .04 
Author/year/localeSample sizeFocusFindings
Fischer et al40 /1998/Zimbabwe 209 mild malaria outpatients vs 280 severe malaria inpatients Coma and anemia severity by blood group Coma in 3% of group non-A vs 9% of group A, P = .008 
Lell et al41 /1999/Gabon 100 mild malaria cases vs 100 severe malaria cases Proportion of severe cases among ABO blood groups Group O: 46% severe group A: 71% severe, P < .01 
Pathirana et al42 /2005/Sri Lanka 243 malaria cases (163 mild, 80 severe) and 65 nonmalarial controls with other infections Blood group distributions among the mild vs severe, odds ratio for severe malaria if group O vs. non-O Blood group, mild/severe: group O, 48%/24%; group B, 23%/28%; group A, 25%/33%; group AB, 5%/16%; P < .001; odds ratio (severe malaria:controls) for group O status, 0.37; P < .001 
Loscertales et al43 /2006/The Gambia 41 primiparae with active placental infection. Maternal and infant hemoglobin; infant weight and size; placental weight; placental parasite count Placental weight group O, 2893 g; non–group O, 2639 g; P = .04 

In 1998, Fischer et al40  reported favorable outcomes for group O individuals compared with group A among 489 patients in Zimbabwe with P falciparum malaria. They studied 209 outpatients and 280 severely ill inpatients. Coma was 3-times more common among group A individuals compared with non-A persons (9 of 104 group A versus 11 of 385 with non-A blood, χ2 = 7.0; p = .008; odds ratio, 3.6). Because patients with coma are at a higher risk for death, this study supports the hypothesis that group O individuals may have a survival advantage in severe malaria. However, the sample size was insufficient to observe an effect of ABO group on survival.

Lell et al41  compared 100 cases of severe P falciparum malaria with 100 cases of mild malaria in Gabon. Severe malaria was defined as either hyperparasitemia with more than 0.25 × 1012 infected red blood cells (RBCs) per L or more than 10% parasitemia; or severe anemia with Hb less than 50 g/L; or clinical signs of severe malaria. Mild malaria cases had minimal laboratory abnormalities and were treated as outpatients. The ratio of group A to group O in patients with severe malaria was 0.50, but was only 0.17 among those with mild malaria (3-fold relative risk). Among all group A individuals, 71% had severe malaria and only 29% had mild malaria (P < .01). In contrast, among all group O cases 46% had severe malaria and 54% had mild malaria (P = .21).

In Sri Lanka, Pathirana et al42  assessed 243 adult cases (mean age, 29.8 years) of P falciparum malaria (163 mild, 80 severe) compared with 65 control patients with other infections. Severe malaria was defined as the presence of cerebral malaria, severe malarial anemia, or multiple organ dysfunction syndromes. The proportion of group O in mild malaria cases was 48%, but was only 24% in severe malaria cases. In striking contrast, the proportion of group A in mild cases was 25%, but was 33% in severe cases (O-to-A ratio: 1.92 mild, .73 severe). The distribution of ABO groups was highly statistically different in severe malaria syndromes compared with uncomplicated malaria or the control population (χ2 = 28.66; P < .001). Once again, a case of severe malaria was nearly 3-times as likely to be group A as O (P = .005). This study provided the strongest statistical evidence of an association between ABO and disease severity in P falciparum infection.

Last year, Loscertales et al43  reported data collected before the HIV pandemic on pregnancy outcomes among women infected with P falciparum in The Gambia. Subjects of interest were pregnant women with no evidence of malaria infection of the placenta, placental malaria pigment without parasites (evidence of cleared placental infection), or active placental infection. Among 89 primiparae, 41 had active placental parasite infection. In this subset, there was a significantly higher birth weight of children born to group O mothers compared with non-group O mothers (2893 ± 362 g vs 2639 ± 323 g; P = .04). Infant length and placental weight were greater, and placental parasite count was lower among group O mothers compared with non-group O, although these values did not reach statistical significance, perhaps because of the small sample size. A larger study is needed to confirm any association between birth outcomes and ABO among women with P falciparum infection during pregnancy. Nevertheless, this initial study is intriguing because it suggests that a group O survival advantage in P falciparum infection may begin in utero during fetal development.

The definitive study to assess ABO groups and survival from infection with P falciparum has not yet been conducted. It will need to examine mortality, especially among pediatric patients, before the age of reproduction. In addition, because even a slight survival advantage for any blood group would accumulate over many generations, it should have a sufficient sample size to detect a small effect, analyze outcomes separately for A, B, O and AB, and control for other phenotypes known to be associated with malaria survival. Currently, the best available studies,40,,43  listed in Table 2, consistently suggest that group O hosts of P falciparum malaria tend to have milder disease and less severe clinical outcomes than group A hosts. These reports represent substantial, although not yet definitive, evidence for a survival advantage for group O individuals with P falciparum infection.

Possible mechanisms to explain P falciparum's selective genetic pressure in favor of group O and against group A

The adherence of parasitized RBCs to other cells is central to the pathophysiology of severe malaria syndromes including cerebral malaria, respiratory failure, multiorgan failure, and death.49,50  Parasitized RBCs adhere to the vasculature through a process termed “sequestration,” closely mimicking inflammatory leukocyte attachment.51  Furthermore, half of infected RBC isolates52  form occlusive intravascular aggregates, which consist not only of infected RBCs bound to each other (“autoagglutinates”)53  but also of infected RBCs bound to uninfected RBCs (“homotypic RBC rosettes”)54  and/or to platelets (“heterotypic RBC rosettes”).55  Sequestration and rosette formation impair blood flow, causing tissue ischemia and cell death.56  Not surprisingly, in vitro rosetting is more pronounced in parasite strains derived from patients with severe disease, particularly in cases of cerebral malaria.57,,60 

P falciparum is unique among malaria species in that infected erythrocytes express an adhesive determinant, termed P falciparum erythrocyte membrane protein-1 (PfEMP-1). PfEMP-1 is encoded by the parasite genome and is expressed on the outer surface of infected RBCs. PfEMP-1 binds to a variety of target molecules found on RBCs, platelets, and vascular endothelial cells.49,50  The structure of PfEMP-1 includes variable numbers of 2 types of adhesive binding domains: Duffy binding-like (DBL) regions and cysteine-rich interdomain regions (Figure 2).61  DBL-1α demonstrates lectin-like properties, causing it to bind primarily to cells bearing A and B blood group oligosaccharides, and to other glycosylated targets, such as the glycoprotein CD35 (CR1), and heparan sulfate–like glycosaminoglycan.62,63  Cysteine-rich interdomain region-1, however, binds principally to CD36 (platelet glycoprotein IV), thus targeting platelets and endothelium. We summarize literature here on the relationship between ABO, rosetting, and vascular cytoadherence. In Figures 3 and 4, we highlight known and proposed mechanisms by which ABO exerts its influence.

Figure 2

The PfEMP-1 molecule, protein domains, and gene structure.112  The cartoon at the top indicates that PfEMP-1 contains both a CD36-binding domain and a lectin-like binding domain. This depiction is used in Figures 3 and 4. A schematic of the expressed PfEMP-1 protein is shown in the center. DBL-1α, far left in stripe binds to blood group A or B determinants. The CD36-binding region (cysteine-rich interdomain region-1) is shown in black. Two different examples of var genes encoding PfEMP-1 are shown at the bottom. For each parasite, a single PfEMP-1 protein, selected from among 50 to 60 different var genes, is expressed on the RBC surface.112  HS, heparan sulfate; CR1, complement receptor 1; ICAM-1, intracellular adhesion molecule 1; CSA, chondroitin sulfate A; ATS, acid terminal segment.

Figure 2

The PfEMP-1 molecule, protein domains, and gene structure.112  The cartoon at the top indicates that PfEMP-1 contains both a CD36-binding domain and a lectin-like binding domain. This depiction is used in Figures 3 and 4. A schematic of the expressed PfEMP-1 protein is shown in the center. DBL-1α, far left in stripe binds to blood group A or B determinants. The CD36-binding region (cysteine-rich interdomain region-1) is shown in black. Two different examples of var genes encoding PfEMP-1 are shown at the bottom. For each parasite, a single PfEMP-1 protein, selected from among 50 to 60 different var genes, is expressed on the RBC surface.112  HS, heparan sulfate; CR1, complement receptor 1; ICAM-1, intracellular adhesion molecule 1; CSA, chondroitin sulfate A; ATS, acid terminal segment.

Lectin-like binding of parasitized erythrocytes with non-O blood group antigens

Figure 3 shows a hypothetical model to explain binding of parasitized RBCs to group A or B antigens. Three lines of evidence suggest a direct role for group A or B antigens in cytoadherence as measured by rosette formation: (1) higher rosette rates and larger rosette sizes among non–group O compared with group O RBCs; (2) rosette disruption by soluble group A or group B oligosaccharides; and (3) correlation of rosette formation with transcription of the lectin-specific binding domain of PfEMP-1. ABO effects on the frequency, size, and strength of rosette formation in vitro were first reported by Carlson et al64  in 1992. When RBCs from 52 donors of different ABO groups were incubated with O RBCs infected with P falciparum strain R + PA1, they found rosetting was greatest with group A/AB RBCs, lowest with O RBCs, and intermediate with B RBCs.

Figure 3

Hypothetical model for cytoadhesion of parasitized RBCs to blood group A or group B structures. Infected RBCs expressing PfEMP-1 can bind to group A (or to a lesser extent, group B) determinants on other cells. In the left panel, cytoadhesion from lectin-binding fails to occur because of the absence of group A or group B antigens. In the center panel, an infected RBC adheres to an uninfected RBC (homotypic adherence) via A or B antigens. The infected cell in turn adheres to endothelium either by binding to blood group antigen on endothelial cells or by binding to blood group antigens on platelets or VWF (heterotypic adherence). In the right panel, cytoadherence is blocked by soluble blood group substance present in the plasma of group A and/or B individuals with the Le(a−b−) Secretor phenotype. Copyright Kimberly Main Knoper; used with permission.

Figure 3

Hypothetical model for cytoadhesion of parasitized RBCs to blood group A or group B structures. Infected RBCs expressing PfEMP-1 can bind to group A (or to a lesser extent, group B) determinants on other cells. In the left panel, cytoadhesion from lectin-binding fails to occur because of the absence of group A or group B antigens. In the center panel, an infected RBC adheres to an uninfected RBC (homotypic adherence) via A or B antigens. The infected cell in turn adheres to endothelium either by binding to blood group antigen on endothelial cells or by binding to blood group antigens on platelets or VWF (heterotypic adherence). In the right panel, cytoadherence is blocked by soluble blood group substance present in the plasma of group A and/or B individuals with the Le(a−b−) Secretor phenotype. Copyright Kimberly Main Knoper; used with permission.

Udomsangpetch et al65  showed a strong association between rosette formation and ABO blood group, with group A and group B RBCs (A > B) forming rosettes more than group O cells in each of 8 tested strains (P < .001). Rowe et al60  confirmed that from among 154 isolates, RBCs from group O patients rosetted less (median rosette frequency, 2%; range, 0%-45%) than those from group A (median, 7%; range, 0%-82%; P < .01) or group AB (median, 11%; range, 0%-94%; P < .03). Chotivanich et al54  found the highest relative rosette ratios in vitro among RBCs from healthy donors who were group A (2.7 ± 1.4) and B (2.4 ± 1.1) compared with group O (1.6 ± 0.7; P = .05). Most recently, Barragan et al confirmed that group A targets formed the strongest rosettes. Furthermore, they reported that group A RBCs enzymatically converted to group O RBCs, and Bombay RBCs rosetted minimally and to the same degree.66  Thus, potentiation of rosetting appears specific (but not exclusive) to the A and B antigens.

The binding of parasitized RBCs to groups A and B determinants on endothelial cells67  has not yet been demonstrated experimentally but would be expected to contribute to cytoadherence. As proposed in Figure 3, such adherence may involve not only blood group antigens on endothelial cells but also antigens present on platelets or von Willebrand factor (VWF). Whether P falciparum has selected for individuals with weak subgroups of A or B and whether such individuals have improved survival during P falciparum infection is unknown at this time and deserves further research.

Lectin-like binding by parasitized RBCs is not limited to A and B antigens alone, as other heteropolysaccharides, such as the glycosaminoglycans, are also well-known targets. These include chondroitin sulfate A68,69  and the complement receptor CR1, which depends heavily for its function on extensive N-glycosylation.70,71  CR1 polymorphisms form the basis of the Knops blood group system.72  Knops-null cells fail to rosette. Mutations with reduced CR1 expression, such as the Sl(a−) (KN7) phenotype found in Africans or a phenotype found in 80% of Papua New Guineans, are associated with reduced rosetting and lower risk of cerebral malaria.73,74 

Disrupting rosettes with competitors of the lectin-binding domain of infected RBCs

Further evidence supporting a role for group A or B antigens in rosetting comes from inhibition experiments. Trisaccharides corresponding to the blood group A or B determinants reduced rosette formation from parasitized group A or B RBCs.65,66  In contrast, the monosaccharides were unable to disrupt rosettes. Given that soluble forms of group A and B antigen in plasma might reduce or disrupt rosette formation, higher plasma concentrations of these antigens might carry a selective advantage in P falciparum malaria (Figure 3). The action of 2 independent fucosyltransferases, the Secretor gene transferase and the Lewis gene transferase, directly influence the quantity of free A and B antigen found in the plasma of A and B individuals. The highest levels are seen among those with the combination of Secretor-positive and Le(a−b−) phenotypes.75,76  For example, sera from Le(a−b−) Secretor-positive group A individuals contained levels of group A glycoprotein over 200 ng/mL in 5 of 9 sera, which was an order of magnitude higher than the levels seen in Le(a + b−) or Le(a−b+) subjects.75 

Recent evidence has shown that the selective pressure in favor of the Secretor-negative phenotype probably results from protection afforded against viral gastrointestinal infections, which are known to cause lethal diarrhea in children.77  In contrast, no explanation has yet emerged to account for a selective genetic pressure in favor of the Lewis-negative phenotype. Although the Le(b) antigen has previously been a suggested binding site for Helicobacter pylori,78  it is difficult to attribute any strong selective genetic pressure to this nonlethal bacterial infection. However, given the high levels of soluble blood group substance found in the plasma of Le(a−b−) Secretor-positive individuals and given the in vitro evidence that soluble blood group substances can disrupt malaria rosette formation, we offer the new hypothesis that P falciparum may account for the 3-fold higher prevalence of the Le(a−b−) phenotype among people of African ancestry.79 

DBL-α domain's selective expression correlates with rosettes and disease severity

Recent analysis of P falciparum var gene expression suggests that host ABO blood group is relevant to disease severity. Var genes are the highly variable sequences that encode the polymorphic PfEMP-1 protein, including its outermost DBL-α domain (Figure 2). DBL-α domains fall into 2 groups: DBL-α1 and DBL-α0; only the former binds to A and B antigens. Each mature parasite clone within a generation selects for expression only one var gene80  from among 50-60 found across all 14 chromosomes.63  If group A or B expression is indeed pathogenically relevant, then DBL-α1 expression should be associated with severe, cytoadhesive complications. To investigate this, Kyriacou et al81  sequenced var gene tags found in parasite isolates obtained from 9 children with cerebral malaria compared with 8 children with an equally high parasite burden without cerebral symptoms. Eighty percent of the isolates from patients with cerebral malaria transcribed var genes coding for the DBL-α1 domain. In contrast, only 25% of isolates of children with equivalent degrees of parasitemia but without cerebral malaria contained DBL-α1 var genes (P < .001, χ2). Furthermore, parasite rosette frequency was higher among children with cerebral malaria, with a significant correlation between rosette formation and DBL-α1 gene expression (P = .009, Spearman rank correlation.) This study links cerebral malaria to DBL-α1 expression, rosette formation, and adhesion to group A or group B structures (Figure 3).

Despite these intriguing reports, the overall importance of ABO antigens in pathologic adhesion may thus far have been underestimated for various reasons. Previous studies have almost uniformly been conducted using O RBCs. It is also difficult to dissociate the role played by ABO sugars from the contribution of other glycosylated adhesion molecules (CD36,82  ICAM,83  CR170 ). In addition, host ABO group may affect other aspects of malaria pathogenesis. For example, Chung et al84  recently reported that group A1 RBCs were more likely to be invaded in vitro by P falciparum than group A2, O, or B RBCs. Group A1 cells were more easily invaded by both sialic acid–dependent and sialic acid–independent parasite strains. Invasion of A1 RBCs was specifically reduced by enzymatic conversion of group A to group O cells. These findings, if confirmed and supported by in vivo observations, would lend additional support to the hypothesis that P falciparum has affected the distribution of ABO blood groups.

Recently, Fernandez et al53  identified other rosette-forming surface molecules, termed “rosettins,” with a tropism for the abundant carbohydrate antigens on RBCs. The non-PfEMP1 rosettins, known as “rifins,” encompass the diverse protein products of approximately 200 different rif genes.85,87  Currently, little is known about the relationship between rifins and ABO blood group antigens, and more research is needed to understand their contribution to the lectin-binding properties of malaria-parasitized RBCs.

P falciparum, CD36, platelets, and VWF

Throughout most of the vasculature, parasitized RBCs expressing cysteine-rich interdomain region-1 can tether and roll on endothelial adhesion molecules, with final direct adhesion to CD36. In addition to direct endothelial binding, infected RBCs may also bind to platelets, in turn adhering to endothelial cells. Platelet-mediated RBC adhesion may be especially relevant to cerebral malaria because CD36 is not strongly expressed on cerebral endothelial cells.88  Combes and Wassmer reviewed previous research on cerebral malaria and concluded that platelets “serve as a bridge” between parasitized RBCs and endothelium. In one set of experiments, Wassmer et al89  co-incubated infected RBCs with CD36-deficient brain microvascular endothelial cells grown to confluence in vitro. Adherence of infected RBCs to endothelial cells under both static and flow conditions depended on the presence of platelets. The adhesion of infected RBCs to platelets was mediated by platelet CD36, and could be blocked by anti-CD36. Electron microscopy showed platelets localized between the infected RBCs and the endothelium.89  Thrombocytopenia is common in severe malaria and platelet localization to brain endothelium was found to be higher in children who died from cerebral malaria compared with uninfected coma controls.90 

The mechanism by which platelets promote adhesion of parasitized RBCs is not fully understood. A mechanism is proposed in Figure 4. Central is the role of VWF. VWF function is directly related to ADAMTS13 activity and the VWF of group A individuals is more resistant to proteolysis by ADAMTS13 than that of group O individuals.91  The lower levels of VWF found in group O individuals compared with non-O92  may contribute to the apparent genetic advantage of group O in malaria.

Figure 4

Proposed model for cytoadhesion of parasitized RBCs to CD36. Infected RBCs expressing PfEMP-1 can bind to CD36 (platelet glycoprotein IV) determinants on other cells. On the left, an infected cell binds to endothelial CD36 (direct sequestration). In the center, an infected cell binds to CD36 expressed on activated platelets, which in turn bind to endothelial cells via VWF. The lower levels of VWF in group O patients may confer a survival advantage. Inflammation, endothelial activation, NO depletion, reduced ADAMTS13 activity, and procoagulant microparticles may contribute to cytoadhesion. TNF-α, tumor necrosis factor α; ADAMTS13, a disintegrin-like and metalloprotease with thrombospondin type 1 motifs. Copyright Kimberly Main Knoper; used with permission.

Figure 4

Proposed model for cytoadhesion of parasitized RBCs to CD36. Infected RBCs expressing PfEMP-1 can bind to CD36 (platelet glycoprotein IV) determinants on other cells. On the left, an infected cell binds to endothelial CD36 (direct sequestration). In the center, an infected cell binds to CD36 expressed on activated platelets, which in turn bind to endothelial cells via VWF. The lower levels of VWF in group O patients may confer a survival advantage. Inflammation, endothelial activation, NO depletion, reduced ADAMTS13 activity, and procoagulant microparticles may contribute to cytoadhesion. TNF-α, tumor necrosis factor α; ADAMTS13, a disintegrin-like and metalloprotease with thrombospondin type 1 motifs. Copyright Kimberly Main Knoper; used with permission.

Evidence for an important role of VWF in malaria is emerging. Hollestelle et al93  have shown that cerebral malaria is associated with increased levels of VWF propeptide. VWF propeptide is released from endothelial storage sites in response to endothelial damage or activation by cytokines found in children with malaria.94,95  Although ADAMTS13 levels have not been measured in malaria, reduced hepatic release resulting from inflammation96  would further enhance VWF-mediated platelet adhesion. In addition, reduced levels of nitric oxide (NO) probably contribute to the adhesive pathophysiology of malaria. Reduced NO promotes platelet activation and VWF-mediated adhesion,97  and worsened survival in a rodent model of cerebral malaria.98  Moreover, NO antagonists were observed to increase cytoadherence of parasitized cells to human endothelial cells under flow conditions in vitro.99  Low levels of NO would be expected to occur in malaria as a result of arginase release during hemolysis and arginine deficiency from malnutrition. In fact, low arginine and low nitrite levels (an indirect marker of NO availability) were associated with the development of cerebral malaria in Tanzanian children.100  Finally, multiple classes of cellular microparticles, including endothelial microparticles resulting from cell injury, platelet microparticles resulting from platelet activation, and RBC microparticles resulting from hemolysis, probably exert a pro-adhesive effect in the setting of active P falciparum infection.101  Recently, microparticles have been described in malaria and to correlate with disease severity.102,103  Microparticles may worsen clinical outcomes in malaria not only by acting as small adhesive intermediates of heterotypic cellular adhesion, but also through tissue factor expression and procoagulant activity that generates thrombin, resulting in additional platelet activation.104  Thus, multiple lines of evidence suggest that VWF may be central to heterotypic cell adhesion in malaria. As a result, the consistently lower levels of VWF found in group O subjects may provide an additional selection advantage among group O individuals infected with P falciparum.

Conclusions

We have proposed that human and P falciparum coevolution has shaped the proportions of ABO antigens observed in humans across geographic regions. However, we recognize that the distribution of ABO has also been influenced by other events,105,106  including the migration of peoples with founder effects, population splitting from wars and famine, and other lethal pediatric diseases in which survival may be associated with a specific ABO antigen. For example, the possibility that the isohemagglutinins found in group O individuals provide broader immunity against various pathogens has been previously suggested.107,108 

Our review of published data serves to emphasize the role of ABO in cytoadherence, rather than P falciparum invasion of RBCs, which depends instead on glycophorin A. P falciparum thus contrasts with P vivax, in which another particular blood group (Duffy) is essential to invasion.

Although our review highlights the reduced cytoadherence of P falciparum among group O individuals, survival after infection is known to depend on a highly complex interaction between both host and parasite genes.41,109,110  Indeed, the full extent of the selective pressure exerted by P falciparum on the human genome has yet to be realized, and new examples of host survival genes continue to be discovered. Examples include recent evidence that a point mutation in the gene for NO synthetase provides as much protection against severe malaria as sickle cell trait,111  or the discovery that the abca-1 gene deletion protects against cerebral malaria through reduced procoagulant microparticle generation.112  Furthermore, because cell adhesion and malarial lethality also depend on parasite gene expression, the evolution of parasite genes has direct bearing on the selective pressure favoring different blood groups. Thus, the influence of P falciparum infection on the relative proportion of ABO antigens is mutually complex. Malaria is known to have affected many erythrocyte genes, including those concerned with globin synthesis, membrane proteins, and RBC enzymes. Given the importance of RBCs in malaria, an influence on genes encoding the most abundant antigens on the RBC membrane is not surprising. Our review suggests that P falciparum was in the right position during evolutionary history to affect the origin and relative proportion of ABO antigens; that the geographic distribution of ABO antigens worldwide is consistent with a survival advantage in malaria among group O individuals; that clinical studies provide supporting evidence in favor of an effect of ABO group on disease severity; and that recent discoveries suggest biologic mechanisms linking disease pathogenesis to ABO antigen expression. Taken together, these findings suggest that the evolution and distribution of ABO blood groups is linked to P falciparum infection.

Acknowledgments

The authors express their appreciation to Dr Christopher Stowell for his critical reading of the manuscript.

This work was supported in part by a grant from the Evelyn and Robert Luick Memorial Fund.

Authorship

Contribution: C.C. and W.D. contributed equally to the intellectual content, research, graphics design, and text.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Christine M. Cserti, MD, University Health Network, Toronto General Hospital (Blood Transfusion Laboratory), 200 Elizabeth Street, 3EC-306, Toronto ON M5G-2C4; e-mail: christine.cserti@uhn.on.ca.

References

References
1
Moulds
JM
Moulds
JJ
Blood group associations with parasites, bacteria, and viruses.
Transfusion Med Rev
2000
14
302
311
2
Frattali
A
Spitalnik S
L
Blancher
A
Klein
J
Socha
WW
Blood Group Antigens as Receptors for Pathogens.
Molecular Biology and Evolution of Blood Group and MHC Antigens in Primates
1997
Heidelberg
Springer
268
304
3
Aird
I
Bentall
HH
Fraser Roberts
JA
A relationship between cancer of the stomach and the ABO blood groups.
Br Med J
1953
1
799
801
4
Athreya
BH
Coriell
LL
Relation of blood groups to infection: I A survey and review of data suggesting possible relationship between malaria and blood groups.
Am J Epidemiol
1967
86
292
304
5
Athreya
BH
Coriell
LL
Relation of blood groups to infection: I. A survey and review of data suggesting possible relationship between malaria and blood groups.
Am J Epidemiol
1967
86
292
304
6
Kwiatkowski
DP
How malaria has affected the human genome and what human genetics can teach us about malaria.
Am J Hum Genet
2005
77
171
192
8
Rich S
M
Ayala F
J
Dronamraju
KR
Arese
P
Evolutionary Origins of Human Malaria Parasites.
Malaria: Genetic and Evolutionary Aspects
2006
New York
Springer
9
Cann
RL
Stoneking
M
Wilson
AC
Mitochondrial DNA and human evolution.
Nature
1987
325
31
36
10
The Y chromosome consortium
A nomenclature system for the tree of human Y-chromosomal binary haplogroups.
Genome Res
2002
12
339
348
11
Rich
SM
Ayala
FJ
The recent origin of allelic variation in antigenic determinants of Plasmodium falciparum.
Genetics
1998
150
515
517
12
Cavalli-Sforza
LL
Feldman
MW
The application of molecular genetic approaches to the study of human evolution.
Nat Genet
2003
33
266
275
13
Desai
DV
Dhanani
H
Sickle Cell Disease: History And Origin.
J Hematol
2004
1
599
600
14
Zaino
EC
Paleontologic Thalassemia.
Ann NY Acad Sci
1965
119
402
412
15
Allen
SJ
O'Donnell
A
Alexander
ND
et al
Prevention of cerebral malaria in children in Papua New Guinea by southeast Asian ovalocytosis band 3.
Am J Trop Med Hyg
1999
60
1056
1060
16
Kay
AC
Kuhl
W
Prchal
J
Beutler
E
The origin of glucose-6-phosphate-dehydrogenase (G6PD) polymorphisms in African-Americans.
Am J Hum Genet
1992
50
394
398
17
Carter
R
Mendis
KN
Evolutionary and historical aspects of the burden of malaria.
Clin Micro Rev
2002
15
564
594
18
Roubinet
F
Despiau
S
Calafell
F
et al
Evolution of the O alleles of the human ABO blood group gene.
Transfusion
2004
44
707
715
21
Uneke
CJ
Ogbu
O
Nwojiji
V
Potential risk of induced malaria by blood transfusion in South-eastern Nigeria.
McGill J Med
2006
9
8
13
22
Mourant
AE
Kopec
AC
Domaniewska-Sobczak
K
The distribution of the human blood groups and other polymorphisms
2 nd ed.
London
Oxford University Press
1976
23
Martin
SK
Miller
LH
Hicks
CU
David-West
A
Ugbode
C
Deane
M
Frequency of blood group antigens in Nigerian children with falciparum malaria.
Trans Roy Soc Trop Med Hyg
1979
73
216
218
24
Facer
CA
Brown
J
ABO blood groups and falciparum malaria.
Trans Roy Soc Trop Med Hyg
1979
73
599
600
25
Singh
T
Malaria and ABO blood groups.
Indian Pediatr
1985
22
857
858
26
Bayoumi
RA
Bashir
AH
Abdulhadi
NH
Resistance to falciparum malaria among adults in central Sudan.
Am J Trop Med Hyg
1986
35
45
55
27
Joshi
H
Raghavendra
K
Subbarao
SK
Sharma
VP
Genetic markers in malaria patients of Delhi.
Indian J Malariol
1987
24
33
38
28
Akinboye
DO
Ogunrinade
AF
Malaria and loaisis among blood donors at Ibadan, Nigeria.
Trans R Soc Trop Med Hyg
1987
81
398
399
29
Pant
CS
Gupta
DK
Sharma
RC
Gautam
AS
Bhatt
RM
Frequency of ABO blood groups, sickle-cell haemoglobin, G-6 PD deficiency and their relation with malaria in scheduled castes and scheduled tribes of Kheda district, Gujurat.
Indian J Malariol
1992
29
235
239
30
Pant
CS
Gupta
DK
Bhatt
RM
Gautam
AS
Sharma
RC
An epidemiological study of G-6-PD deficiency, sickle cell haemoglobin, and ABO blood groups in relation to malaria incidence in Muslim and Christian communities of Kheda, Gujarat, (India).
J Com Dis
1992
24
199
205
31
Thakur
A
Verma
IC
Malaria and ABO blood groups.
Indian J Malariol
1992
29
241
244
32
Pant CSSrivastava HCYadav RS.
Prevalence of malaria and ABO blood groups in a seaport area in Raigad, Maharashtra.
Indian J Malariol
1998
35
225
228
33
Migot-Nabias
F
Mombo
LE
Luty
AJF
et al
Human genetic factors related to susceptibility to mild malaria in Gabon.
Genes Immun
2000
1
435
441
34
Beiguelman
B
Alves
FP
Moura
MM
et al
The association of genetic markers and malaria infection in the Brazilian western Amazonian region.
Mem Inst Oswaldo Cruz
2003
98
455
460
35
Kassim
OO
Ejezie
GC
ABO blood groups in malaria and schistosomiasis haematobium.
Acta Tropica
1982
39
179
184
36
Montoya
F
Restrepo
M
Montoya
AE
Rojas
W
Blood groups and malaria.
Rev Inst Med trop Säo Paulo
1994
36
33
38
37
Singh
N
Shukla
MM
Uniyal
VP
Sharma
VP
ABO blood groups among malaria cases from district Mandla, Madhya Pradesh.
Ind J Malariol
1995
32
59
63
38
Mombo
L-E
Ntoumi
F
Bisseye
C
et al
Human genetic polymorphisms and asymptomatic Plasmodium falciparum malaria in Gabonese schoolchildren.
Am J Trop Med Hyg
2003
68
186
190
39
Santos
SEB
Salzano
FM
Franco
MHLP
Freitas
MJM
Mobility, genetic markers, susceptibility to malaria and race mixture in Manaus, Brazil.
J Hum Evol
1983
12
373
381
40
Fischer
PR
Boone
P
Short report: Severe malaria associated with blood group.
Am J Trop Med Hyg
1998
58
122
123
41
Lell
B
May
J
Schmidt-Ott
RJ
et al
The role of red blood cell polymorphisms in resistance and susceptibility to malaria.
Clin Infect Dis
1999
28
794
799
42
Pathirana
SL
Alles
HK
Bandara
S
et al
ABO-blood-group types and protection against severe Plasmodium falciparum malaria.
Ann Trop Med Parasitol
2005
99
119
124
43
Loscertales
M-P
Brabin BJABO phenotypes and malaria related outcomes in mothers and babies in The Gambia: a role for histo-blood groups in placental malaria?
Malaria J
2006
5
1
6
44
Newbold
C
Warn
P
Black
G
et al
Receptor-specific adhesion and clinical disease in Plasmodium falciparum.
Am J Trop Med Hyg
1997
57
389
398
45
Gravenor
MB
van Hensbroek
MB
Kwiatkowski
D
Estimating sequestered parasite population dynamics in cerebral malaria.
PNAS
1998
95
7620
7624
46
Hearn
J
Rayment
N
Landon
DN
Katz
DR
de Souza
JB
Immunopathology of cerebral malaria: morphological evidence of parasite sequestration in murine brain microvasculature.
Infect Immun
2000
68
5364
5376
47
Kinde-Gazard
IJ
Gnahoui
I
Massougbodji
A
The risk of malaria transmission by blood transfusion at Cotonou, Benin.
Sante
2000
10
389
392
48
Marsh
K
Forster
D
Waruiru
C
et al
Indicators of life-threatening malaria in African children.
N Engl J Med
1995
322
1399
1404
49
Miller
LH
Baruch
DI
Marsh
K
Doumbo
OK
The pathogenic basis of malaria.
Nature
2002
415
673
679
50
Sherman
IW
Eda
S
Winograd
E
Cytoadherence and sequestration in Plasmodium falciparum: defining the ties that bind.
Microbes Infect
2003
5
897
909
51
Ho
M
Hickey
MH
Murray
AG
Andonegui
G
Kubes
P
Visualization of Plasmodium falciparum-endothelium interactions in human microvasculature: mimicry of leukocyte recruitment.
J Exp Med
2000
192
1205
1210
52
Wahlgren
M
Carlson
J
Ruangjirachuporn
W
et al
Geographical distribution of Plasmodium falciparum erythrocyte rosetting and frequency of rosetting antibodies in human sera.
Am J Trop Med Hyg
1990
43
333
338
53
Fernandez
V
Treutiger
CJ
Nash
GB
Wahlgren
M
Multiple adhesive phenotypes linked to rosetting binding of erythrocytes in Plasmodium falciparum malaria.
Infect Immun
1998
66
2969
2975
54
Chotivanich
KT
Udomsangpetch
R
Pipitaporn
B
et al
Rosetting characteristics of uninfected erythrocytes from healthy individuals and malaria patients.
Ann Trop Med Parasitol
1998
92
45
56
55
Pain
A
Ferguson
DJP
Kai
O
et al
Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria.
Proc Nat Acad Sci
2001
98
1805
1810
56
Serghides
L
Smith
TG
Patel
SN
Kain
KC
CD36 and malaria: friends or foes?
Trends Parasitol
2003
19
461
469
57
Carlson
J
Helmby
H
Hill
AVS
Brewster
D
Greenwood
BM
Wahlgren
M
Human cerebral malaria: association with erythrocyte rosetting and lack of anti-rosetting antibodies.
Lancet
1990
336
1457
1460
58
Ho
M
Davis
TME
Silamut
K
Bunnang
D
White
NJ
Rosette formation of Plasmodium falciparum-infected erythrocytes from patients with acute malaria.
Infect Immun
1991
59
2135
2139
59
Treutiger
CJ
Hedlund
I
Helmby
H
et al
Rosette formation in Plasmodium falciparum isolates and anti-rosette activity of sera from Gambians with cerebral or uncomplicated malaria.
Am J Trop Med Hyg
1992
46
503
510
60
Rowe
A
Obeiro
J
Newbold
CI
Marsh
K
Plasmodium falciparum rosetting is associated with malaria severity in Kenya.
Infect Immun
1995
63
2323
2326
61
Smith
JD
Gamain
B
Baruch
DI
Kyes
S
Decoding the language of var genes and Plasmodium falciparum sequestration.
Trends Parasitol
2001
17
538
545
62
Chen
Q
Heddini
A
Barragan
A
Fernandex
V
Pearce
SF
Wahlgren
M
The semiconserved head structure of Plasmodium falciparum erythrocyte membrane protein 1 mediates binding to multiple independent host receptors.
J Exp Med
2000
192
1
9
63
Chen
Q
Schlichtherle
M
Wahlgren
M
Molecular aspects of severe malaria.
Clin Micro Rev
2000
13
439
450
64
Carlson
J
Wahlgren
M
Plasmodium falciparum erythrocyte rosetting is mediated by promiscuous lectin-like interactions.
J Exp Med
1992
176
1311
1317
65
Udomsangpetch
R
Todd
J
Carlson
J
Greenwood
BM
The effects of hemoglobin genotype and ABO blood group on the formation of rosettes by Plasmodium falciparum-infected red blood cells.
Am J Trop Med Hyg
1993
48
149
153
66
Barragan
A
Kremsner
PG
Wahlgren
M
Carlson
J
Blood group A antigen is a coreceptor in Plasmodium falciparum rosetting.
Infect Immun
2000
68
2971
2975
67
Le Pendu
J
Caillard
T
Mollicone
R
et al
Expression of ABH and X (Lex) antigens in various cells.
Biochimie
1988
70
1613
1618
68
Fried
M
Duffy
PE
Adherence of Plasmodium falciparum to chondroitin sulphate A in the human placenta.
Science
1996
272
1502
1504
69
Chai
W
Beeson
JG
Lawson
AM
The structural motif in chrondroitin sulphate for adhesion of Plasmodium falciparum-infected erythrocytes comprises disaccharide units of 4-O-sulfated and non-sulfated N-acetylgalactosamine linked to glucuronic acid.
J Biol Chem
2002
277
22438
22446
70
Lublin
DM
Griffith
RC
Atkinson
JP
Influence of glycosylation on allelic and cell-specific Mr variation, receptor processing, and ligand binding of the human complement C3b/C4b receptor.
J Biol Chem
1986
261
5736
5744
71
Rowe
JA
Moulds
JM
Newbold
CI
Miller
LH
P falciparum rosetting mediated by parasite-variant erythrocyte membrane protein and complement-receptor 1.
Nature
1997
388
292
295
72
Reid
ME
Lomas-Francis
C
The Blood Group Antigen Facts Book
2004
2nd ed
New York
Elsevier Academic Press
73
Thathy
V
Moulds
JM
Guyah
B
Otieno
W
Stoute
JA
Complement receptor I polymorphisms associated with resistance to severe malaria in Kenya.
Malaria J
2005
4
1
7
74
Cockburn
IA
Mackinnon
MJ
O'Donnell
A
et al
A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria.
PNAS
2004
101
272
277
75
Holburn
AM
Masters
CA
The radioimmunoassay of serum and salivary blood group A and Le (a) glycoproteins.
Br J Haematol
1974
28
157
167
76
Tilley
CA
Crookston
MC
Brown
BL
Wherrett
JR
A and B and A1 Le(b) substances in glycosphingolipid fractions of human serum.
Vox Sang
1975
28
25
33
77
Thorven
M
Grahn
A
Hedlund
KO
et al
A homozygous nonsense mutation (428G3A) in the human secretor (FUT2) gene provides resistance to symptomatic norovirus (GGII) infections.
J Virol
2005
79
15351
15355
78
Boren
T
Falk
P
Roth
KA
et al
Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens.
Science
1993
262
1892
1895
79
Daniels
G
Human Blood Groups.
2nd ed
Oxford
Blackwell Science
1995
80
Scherf
A
Hernandez-Rivas
R
Buffet
P
et al
Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum.
EMBO J
1998
17
5418
5426
81
Kyriacou
HM
Stone
GN
Challis
RJ
et al
Differential var gene transcription in Plasmodium falciparum isolates from patients with cerebral malaria compared to hyperparasitaemia.
Mol Biochem Parasitol
2006
150
211
218
82
Stockelberg
D
Hou
M
Rydberg
L
Kutti
J
Wadenvik
H
Evidence for an expression of blood group A antigen on platelet glycoproteins IV and V.
Transfus Med
1996
6
243
248
83
Jiménez
D
Roda
P
Springer
TA
Casasnovas
JM
Contribution of N-linked glycans to the conformation and function of intercellular adhesion molecules (ICAMs).
J Biol Chem
2005
7
5854
5861
84
Chung
WY
Gardiner
DL
Hyland
C
Gatton
M
Kemp
DJ
Trenholme
KR
Enhanced invasion of blood group A1 erythrocytes by Plasmodium falciparum.
Molec Biochem Parasitol
2005
144
128
130
85
Carlson
J
Holmquist
G
Taylor
DW
Perlmann
P
Wahlgren
M
Antibodies to a histidine-rich protein (PfHRP1) disrupt spontaneously formed Plasmodium falciparum erythrocyte rosettes.
Proc Nat Acad Sci
1990
87
2511
2515
86
Helmby
H
Cavalier
L
Pettersson
U
Wahlgren
M
Rosetting Plasmodium falciparum-infected erythrocytes express unique strain-specific antigens on their surface.
Infect Immun
1993
61
284
288
87
Kyes
SA
Roew
JA
Kriek
N
Newbold
CI
Rifins: a second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum.
Proc Natl Acad Sci USA
1999
96
9333
9338
88
Silamut
K
Phu
NH
Whitty
C
et al
A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain.
Am J Pathol
1999
155
395
410
89
Wassmer
SC
Leopolard
C
Traore
B
Pouvelle
B
Grysin
J
Grau
GE
Platelets reorient Plasmodium falciparum-infected erythrocyte cytoadhesion to activated endothelial cells.
J Infect Dis
2004
189
180
189
90
Grau
GE
Platelet accumulation in brain microvessels in fatal pediatric cerebral malaria.
J Infect Dis
2003
187
461
466
91
Bowen
DJ
An influence of ABO blood group on the rate of proteolysis of von Willebrand factor by ADAMTS13.
J Thromb Haemost
2003
1
33
40
92
Jenkins
PV
O'Donnell
JS
ABO blood group determines plasma von Willebrand factor levels: a biologic function after all?
Transfusion
2006
46
1836
1844
93
Hollestelle
MJ
Donkor
C
Mantey
EA
et al
von Willebrand factor propeptide in malaria: evidence of acute endothelial cell activation.
Br J Haematol
2006
133
562
569
94
Gordeuk
VR
Kasvosve
I
van Dijk
J
et al
Altered Immune Response in Severe Malaria Anemia in Children [abstract].
Blood
2006
108
381a
95
Shi
Q
Wang
J
Wang
XL
VandeBerg
JL
Comparative analysis of vascular endothelial cell activation by TNF-alpha and LPS in humans and baboons.
Cell Biochem Biophys
2004
40
289
303
96
Zheng
X
Niiya
MX
Zheng
L
Pollak
ES
Isolation and Characterization of Human ADAMTS13 Gene Promoter Region – Control of ADAMTS13 Gene Expression by Hepatic Transcription Factors and Inflammatory Cytokines [abstract].
Blood
2006
108
459a
97
Morrell
CN
Matsushita
K
Chiles
K
et al
Regulation of platelet granule exocytosis by S-nitrosylation
Proc Natl Acad Sci USA
2005
102
3782
3787
98
Gramaglia
I
Sobolewski
P
Meays
D
et al
Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria.
Nat Med
2006
12
1417
1422
99
Serirom
S
Raharjo
WH
Chotivanich
K
Loareesuwan
S
Kubes
P
Ho
M
Anti-ahhesive effect of nitric oxide on Plasmodium falciparum cytoadherence under flow.
Am J Pathol
2003
162
1651
1660
100
Lopansri
BK
Anstey
N
Weinberg
J
et al
Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production.
Lancet
2003
361
676
678
101
Van der Heyde
HC
Nolan
J
Combes
V
Gramaglia
I
Grau
GE
A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction.
Trends Parasitol
2006
22
503
508
102
Combes
V
et al
Circulating endothelial microparticles in Malawian children with severe falciparum malaria complicated with coma.
JAMA
2004
291
2542
2544
103
Combes
V
Coltel
N
Faille
D
Wassmer
SC
Grau
GE
Cerebral malaria: role of microparticles and platelets in alterations of the blood-brain barrier.
Int J Parasitol
2006
36
541
546
104
Francischetti
IMB
Seydel
KB
Monteiro
RQ
Plasmodium falciparum-infected monocytes induce tissue factor expression in endothelial cells and support the assembly of multimolecular coagulation complexes.
J Thromb Haemostas
2007
5
155
165
105
Mielke
JH
Konigsberg
LW
Relethford
JH
Human Biological Variation.
Oxford
Oxford University Press
2005
106
Sabeti
PC
Schaffner
SF
Fry
B
et al
Positive natural selection in the human lineage.
Science
2006
312
1614
1620
107
Oliver-Gonzalez
J
Torregrosa
MR
A substance in animal parasites related to the human isoagglutinogens.
J Infect Dis
1944
74
173
177
108
Harrison
J
Ridley
DS
Heterologous reactions involving parasites, blood group antibodies and tissue components.
Trans R Soc Trop Med Hyg
1975
69
312
317
109
Hill
AVS
Malaria resistance genes: a natural selection.
Trans R Soc Trop Med Hyg
1992
86
225
226
232
110
Williams
TN
Human red blood cell polymorphisms and malaria.
Curr Opin Microbiol
2006
9
389
394
111
Kun
JF
Mordmuller
B
Lell
B
Lehman
LG
Luckner
D
Kremsner
PG
Polymorphism in promoter region of inducible nitric oxide synthase gene and protection against malaria.
Lancet
1998
351
265
266
112
Combes
V
Coltel
N
Alibert
M
et al
ABCA1 gene deletion protects against cerebral malaria.
Am J Pathol
2005
166
295
302