Blood Groups: More than Inheritance of Antigenic Substances - Susceptibility to Some Diseases

Abstract

Blood group antigens represent polymorphic traits inherited among individuals and populations. The objective of this chapter is to review articles that have reported; the association between blood group antigens and susceptibility to some diseases. Findings showed that O blood group had a greater frequency of severe infections such as E coli, cholera and blood group A was associated with incidence of smallpox and some bacterial infections. These are principally based on presence or absence of “H-like” and “A and B-like” antigens markers. Antigens A, B and H are connected to N-glycans of vWF and reduces the half-life of the protein (10 hours) for group O while non-O groups, 25 hours. The loss of A, B, and H antigens as malignancy progresses was linked to potential metastasis. Similarly, some tumors have A or A-like antigens this explains the propensity of group A to develop tumors. Blood type incompatibility between mother and foetus sensitizes the mother to develop alloantibodies that could potentially cause death of the foetus in utero, a condition known hydrops. Reviewed articles have reported close link between blood group antigens and susceptibility diseases. More studies are required to rationalize the mechanism associated to this.

1. Introduction

Human blood groups since discovery in 1901 by Landsteiner have been widely studied and characterized. A total of 34 blood group systems have been recognized and documented by the International Society for Blood Transfusion (ISBT) [1, 2]. Each system is a series of red cell antigens, determined either by a single genetic locus or very closely linked loci. Alternative forms of a gene coding for red cell antigens at a particular locus are called alleles and individuals may inherited identical or non-identical alleles [3].

Many blood groups are receptors for toxins, parasites, and bacteria, where they can facilitate colonization or invasion or evade host clearance mechanisms [4]. Associations between the blood type and disease have been studied since the early 1900s when researchers determined that antibodies and antigens are inherited. However, due to lack of antigens of some blood groups, there have been some contentious issues with the association between the ABO blood group and vulnerability to certain infectious and non-infectious diseases [5].

Fung et al. [1] (Table 1) gives blood group antigens characterized by ISBT.

ISBT no	Blood group system name	Blood group symbol	Chromosome
001	ABO	ABO	9
002	MNS	MNS	4
003	P	P1	22
004	Rh	RH	1
005	Lutheran	LU	19
006	Kell	KEL	7
007	Lewis	LE	19
008	Duffy	FY	1
009	Kidd	JK	18
010	Diego	DI	17
011	Yt or Cartwright	YT	7
012	XG	XG	X
013	Scianna	SC	1
014	Dombrock	DO	12
015	Colton	CO	7
016	Landsteiner-Weiner	LW	19
017	Chido/Rogers	CH/RG	6
018	Hh/Bombay	H	199
019	Kx	XK	X
020	Gerbich	GE	2
021	Cromer	CROM	1
022	Knops	KN	1
023	Indian	IN	11
024	Ok	OK	19
025	Raph	MER2	11
026	JMH	JMH	6
027	Li	I	6
028	Globoside	GLOB	3
029	GIL	GIL	9
030	Rh-associated glycoprotein	RHAG	6

Table 1.

Blood group systems recognized by the International Society of Blood Transfusion.

IBST: International Society of Blood Transfusion, NO: Number.

2. ABO antigens linked to some diseases

2.1 Infectious disease

ABO gene products have been associated with some diseases [6, 7, 8]. The human body defense integrity against certain infections is characteristic of the presence or absence of blood group antigens and their corresponding antibodies. More so, data have shown that peptic ulceration was the first proven association to blood group gene products [9, 10]. H pylori is now known to be a causative agent leading to peptic ulceration and gastric cancer. H pylori has established colonies in the stomach of approximately one-half the world’s population [11].

Red blood cell surface markers act as receptors for attachment to infectious agents and result in vulnerability difference among individuals with diverse receptor profile [12]. Some pathogens share genetic properties with their host. The relationship between ABO antigens and infections as vibrio cholera was discovered by early studies [12]. Major variations in ABO groups in the world were due to H-like antigen on the bacterium (Vibrio cholera) and an A-like antigen on Small pox virus [13]. This confers resistance status to people who make corresponding antibodies to H and A antigens [8]. Once a person gets infected with Cholera (Vibrio cholera strain O 1, E 1, Tor and O 139), the O blood types have a greater frequency of severe infections than the non-O blood types. Increased incidence of cholera is strongly associated to blood group O whereas, blood group A is strongly associated to smallpox, Pseudomoniasis, gonorrhea, tuberculosis and streptococcus pneumoniae, Escherichia coli and Salmonellosis. Blood type AB is linked to increased incidence of small pox, E. coli and Salmonellosis. Principally, these are associated to the presence of H antigen on group O and anti-H on group A and B [8].

The GI expresses Lewis and ABH antigens which is strongly linked to vulnerability of norovirus infection. People known as non-secretors are susceptible to infections caused by Haemophilus influenzae, Neisseria meningitides, Streptococcus pneumoniae and UTI caused by E. coli. ABO blood type is connected to peptic ulcer. The blood type O is highly susceptible to peptic ulcer than other blood type. Helicobacter pylori has been implicated to peptic ulcer similarly, H. pylori attachment to the human gastric mucosa was mediated by the H type 1 and Le b fucosylated antigens. Soluble glycoproteins of Le b inhibit H. pylori binding of H. pylori. This justifies the decreased infectivity commonly observed in the blood type A, B, and AB compared to blood group O [14, 15, 16].

2.2 Coronavirus

The novel virus, COVID 19 caused by SARS-CoV-2 widely spread around the globe is yet to be fully understood. Factors that influence susceptibility to the disease are age, sex, comorbid chronic disease etc. ABO blood group may influence the susceptibility to COVID. Blood group A have been linked with significant increase risk compared to blood group O due to like virus surface proteins. Blood group O persons can easily recognize these proteins as foreign and by extension confers lower chances to establish the disease [17]. Furthermore, anti-A inhibit binds of glycosylated SARS-CoV S protein expressing cells to angiotensin -converting enzyme 2 on cell membrane thereby truncate the interaction between the virus and its receptors, providing protection. Angiotensin converting enzyme activity is much in blood group B. This explains the possibility non-O blood group have more mortality [18, 19].

2.3 Coagulation

ABO blood types have been significantly linked to susceptibility to arterial and venous thromboembolism. There is an association between ABO antigens and the structural protein backbone of coagulation factors vWF and factor VIII which affects coagulation. Hypercoagulable plasma potentially causes venous thromboembolism and is characteristically observed in non- group O individuals due to higher levels of vWF. Von Willebrand factor is a large glycoprotein synthesized by Weibel-palade components in the endothelial cells and alpha granules of platelets. It is the carrier of factor VIII and plays a crucial role in plaletet adhesion and aggregation. Blood group O people have lower levels of vWF due to lack of additional carbohydrate to the terminal sugar. Moreso, plasma vWF is proteolyzed by metalloprotease enzyme ADAMTS13. This is faster in group O than non-O groups vVWF, thereby degrading FVIII levels. Group A, B and AB then have more vWF therefore increases FVIII levels [20].

2.4 Cardiovascular diseases

Blood group antigens do not cause cardiovascular diseases yet strongly linked to influence susceptibility. The known primary causes of cardiovascular diseases are genetic traits and life style among others. The ATP-binding cassette 2 genes are located at locus 9q34 which plays a significant role in cholesterol regulation. The H antigen has a connection to the structural back bone of coagulation factors (vWF and VIII) glycoproteins. This phenomenon explains greater risk non-O groups have for ischemic heart disease [8, 21].

Preeclampsia is serious condition with leading cause of intrauterine growth restrictions, maternal and foetal morbidity/mortality. Placental protein 13 is galectin that binds to beta-galactoside (N-acetyl-galactosamine, galactose, and fucose) linked to ABO antigens. This protein is observed in a pregnant woman with preeclampsia at early onset [22].

2.5 Malignancy

There are numerous publications in literature that have reported strong association between red cells antigens and some malignancies. ABH antigens are found on epithelial cells of the GIT, prostate, lungs, breast, uterine cervix, mouth, and bladder and their expression diminishes as malignancy progresses. Blood type antigens play a crucial role in cell signaling, cell recognition and cell adhesion yet these antigens are missing from the red cell membrane glycoprotein/glycolipids of malignant cells. This has been linked to DNA methylation in the promoter region. Blood group A gene in this case may inhibit transcription of the transferase enzyme with resultant loss of A antigen [15, 23]. Factually, malignancy progression results to loss of ABH antigens and potential metastasis of tumor cells. This phenomenon complicates routine red cell typing. Some tumor cells have been observed to mimic blood group A antigen markers giving group A person higher risk of disease progression than non-A blood groups [15]. It is important to note that blood group antigens do not cause malignancy rather susceptibility.

3. Association of other blood types and diseases

3.1 Haemolytic disease of the foetus and new-born (HDFN)

Haemolytic disease of the foetus and new born is a major clinical disease associated to Rhesus, Kell, Kidd and Duffy incompatibility between maternal alloantibody (IgG) to foetal antigens with resultant hemolysis of foetal red cells or suppression of the foetal red cell progenitors (commo with Kell system) [24]. Anti-D is the most implicated and severe form of HDFN, yet routine antenatal anti-D prophylaxis has ameliorated it.

3.2 Malaria

In western regions of Africa, it has been reported that individuals with negative Duffy blood type are common and confers protection against malaria caused by Plasmodium vivax. The resetting phenomenon commonly seen in parasitized erythrocytes. Forming rosettes is significantly lower in O blood types than blood group A red cells. It was observed that blood type A and B antigens are receptors for resetting on uninfected erythrocytes [25]. Parasitized RBC express resetting which helps us appreciate malaria pathogenesis. In blood group O, plasmodium falciparum invades Rbcs and little rosette is formed yet unstable which binds to uninfected Rbcs to form clusters of cells with resultant narrowing of vascular system. Some gene products such as pfEMP-1 and RIFIN secreted by Rbcs and parasite respectively have been implicated in ABO blood types and susceptibility to malaria among non-group O individuals. This could probably explain the ABO type commonly seen where malaria is prevalent.

4. Conclusion

It is fair to state that blood group antigens are not the primary cause of diseases but are associated to susceptibility to some diseases. Blood group antigens play a role as receptors or ligands to some disease processes. In general, non-O blood types are more susceptible to diseases than O.