ABO BLOOD GROUP POLYMORPHISM
PETER J. D'ADAMO
Copyright 1989, 2001,
D'Adamo. All rights reserved.
Letter for Doctors, September 1990
the recognized importance of the ABO, MNS, and Lewis antigens in blood
typing, few physicians appreciate the extraordinary complexity of this
system, its association with human disease, fascinating phylogenetic
heritage and usefulness in describing physiologic parameters, especially
digestive and secretory. These antigens are found in secretions throughout
the body and on the surface of endothelial and epithelial cells.
The first description of a human blood
group system was published by Landsteiner in 1900, working to understand
the unpredictability of hemolytic reactions resulting from early attempts
at transfusion. Using the newly discovered lectins abrin and ricin,
recently isolated by Stillmark, he was able to describe classically what
has still remained the major blood group of clinical interest. Many other
blood grouping systems based either on membrane or sera antigen
antibody interactions have also been discovered. The most clinically
relevant of these are the MNS and Lewis antigen systems. It is estimated
that there are in excess of 400 blood type antigens now known.
are now set parameters which determine if an antigen possesses blood group
activity. Most blood group antigens are carbohydrates extending outward
from membrane bound glycolipids and glycoproteins. These membrane glyco
conjugates are typically rich in sialic acids whose high degree of
hydrophilicity and negative ionic charge results in their projection
outward from the cell membrane. Sialic acids do not appear to have a role
in ABO blood group specificity, but high or low concentrations may enhance
or interfere with the expression of blood group activity.
ABO and Lewis systems possess a common basic structure and their
individual specificity is determined by the sequence and linkage of sugars
at the end of the carbohydrate chains. It has been estimated that of the
oligosaccharides projecting from the cell surface, 100 per 300,000 bear
blood group antigenic determinants.
are two types of backbone structures: Type I chains, which contain
galactose linked 6-(1-3) to N-acetylglucosamine, and Type 2 chains where
the linkage is 13-(1-4). Oligosaccharides with these terminal ends do not
possess blood group specificity, but can and do cross react
immunologically with many bacterial polysaccharides.
antigens are synthesized from an oligosaccharide intermediate, H
substance, which is produced by the presence of the monosaccharide fucose
on either Type 1 or 2 chains. Group A or B activity is produced by the
addition of a single sugar on the nonreducing end of H chain. The
addition of this sugar markedly reduces the reactivity of the H substance.
Adding the glycoprotein N-acetylgalactosamine to the end of the chain
results in blood group A antigenicity, whereas with blood group B the
terminal carbohydrate and B group antigen is the monosaccharide galactose.
There is no O antigen: group O cells contain the H antigen, but the
designation group H has been maintained for historical reasons. The
terminal carbohydrate of O(H) antigen is the monosaccharide fucose.
was first shown by Lehrs in 1930 that some people do and others do not
secrete into their saliva antigens corresponding to their ABO blood group.
Sakes found that the ability to secrete behaved as a simple Mendelian
function dominant to non-secretion. Group A, B, and AB persons who are
secretors secrete the antigens corresponding to their blood groups. Group
H persons who secrete the H substance, as do all other secretors; to a
somewhat less extent. The secretor gene is identified as Sec to
distinguish it from the Ss blood group.
was long ago discovered that genetic secretors secrete their blood group
antigens not only into their saliva but in numerous
ABH and Lewis glycoproteins possess a common basic structure and their
blood group specificity is determined by the sequence and linkage. There
are two Lewis antigens, termed Lea and Leb. The presence of fucose linked
to C4 of N-acetylglucosamine on a Type 1 chain results in Lea activity,
but a Type 2 oligosaccharide containing fucose linked to C-3 of
N-acetylglucosamine on a Type 2 chain results in very weak Lea activity.
The appearance of a second fucose on a type one chain results in the
appearance of a new antigenic determinant, Leb, and the loss of most H and
Lea antigenicity. A Type 2 difucosyl chain has very weak Leb activity.
genetics of the system seem to imply that the N antigen is actually a
precursor substance and the N gene is an amorph which leaves the N antigen
unchanged while the M gene of the heterozygote converts part of the N
antigen into M, and in the homozygote converts nearly all of the precursor
to M. The MN antigens seem to have a direct interaction with membrane
bound sialic acids, as M and N specificities seem to be linked to the
presence of sialic acid variations. It has been suggested that the
antigenic variations may result from specific sialyl transferase activities,
which transfer sialic acids to disaccharides bearing specific T and Tn
specificities that characterize specific cryptic antigens. Mourant
considers this blood group of interest only to the geneticist, due to a
lack of disease association, however several diverse associations have
surfaced including: an association of ankylosing spondylitis with
homozygous MM (Sharon) and an association between heterozygous MN and
homozygous NN with environmental induced hyperlipidemia (Martin). Cruz et.
al. studied the tendency of Easter Islanders to become "hypertensive"
upon moving to the mainland and concluded that homozygous NN was
significantly more liable to develop hypertension. These are interesting
disease associations, yet probably result more from co-dependent alleles
than from a direct membrane bound antigen interaction.
incompatibility is the major cause of hemolytic disease of the newborn,
however very few searches have been made for any other kinds of disease
associations of the Rh groups. Rh- status is largely a European gene
(40%), with its highest frequency among the Basques of Spain, a remarkably
homogenous group, originally late paleolithic or early mesolithic
inhabitants of the Pyrenee Mountains. The U.S population is approximately
15% Rh- and 85% Rh+.
Fya and Fyb antigens were discovered in the 1950's. Sanger discovered
that a high percentage of African Negroes are of the phenotype Fy (a- b-),
which is apparently a third gene termed Fyx which does not react with anti-Fya
or anti Fyb. In 1975 Miller was able to show that this type is probably
specifically resistant to Vivax malaria, to which Africans have long been
known to be resistant.
PI antigen is found in hydatid cyst fluid, and in a considerable variety
of worm, both parasitic and free living. It is probably not uncommon that
anti-P1 is not infrequently found in the sera of humans in response to
worm infestation. The distribution of the p2 allele runs north to south
and way from 180 degrees E. The highest frequencies reported by Blangero
for the P2 allele are Circumpolar people, Oriental, and Pacific Islanders,
people with a tradition of fish eating, reindeer and caribou hunting/
herding and aquatic mammal diets. Thus the high P2 allele may result from
antigen scarcely qualify as a blood grouping system. Anti-I antibodies
are common, yet more common are anti-IH antibodies which is distinct from
I or H but is presence on cells containing both. Anti-I is a cold
agglutinin, so termed because its activity is enhanced at low temperature.
This antibody is often seem in the serum of patients with infectious
human genetic variations of clinical interest include: the ability to
taste phenylthlocarbamide (associated with certain thyroid
susceptibilities), ear wax types (associated with carcinoma of the
breast), aryl hydrocarbon hydoxylase (lung cancer), the Group Specific
Component globulins (vitamin D transport), protease inhibitors, protease
inhibitors, G6PD and a variety of hemoglobins.
of the ABO Groups
first attempted racial classification based on blood groups. However the
limited information available at that time made for strange bedfellows
(including a "Hunan" group composed of Japanese, Southern
Chinese, Hungarians and Rumanian Jews). It was not surprising that
anthropologists took one look at the list, shuddered, and said, in effect,
"No thanks; I'll take vanilla."
more recent attempt by Lavory, who was aware that racial classification
based merely on ABO groups would in many cases give results which would
not fit well with older ideas about race. He also incorporated M and N
types and occasional other blood factors to distinguish populations not
clearly differentiated by A and B. He distinguished the following races:
1) Europeans (Nordics and Alpines of Europeans of the Near East); 2)
Mediterranean; 3) Mongolian (Central Asia and Eurasia); 4) African
(Blacks); 5) Indonesian; 6) American Indian; 7) Oceanic (including
Japanese); 8) Australian (a sub variety of Oceanic). Lavory failed however
to realize that the characteristics needed to define race, such as
morphology or skin color are independent of each other.
has proposed the following racial classification, based largely on ABO and
Rh factors: 1) Caucasoid group (highest incidence of Rh-, relatively
high incidence of genes for Rh- and A2, moderately high incidence of all
other types); 2) Negroid group (highest incidence of RhO, moderate frequency
of Rh-, high relative incidence of genesA2 and the rare intermediate A and
Rh genes); 3) Mongoloid group (virtual absence of Rh- gene and gene
A2). Using MN data, he then further classified the Mongoloid group into an
Asiatic group, a Pacific Island and Australian group, and a group
including American Indians and Eskimos.
O is almost universally considered the original blood group, or at least
the blood type present as the overwhelming majority in 'ancient' or
'isolated' peoples. This seems to bear out well as the O(H) antigen is the
precursor to both A and B.
has been an often stated assertion that all full-blooded Amerindians are
group O, Wyman and Boyd, in ingenious fashion, were able to blood type
remains of early prehistoric Amerindian (Basket Maker and aboriginal)
remains, finding sufficient group A to cast some doubt on this.
Nonetheless, even recent studies on largely intermingled Amerindian
populations shows a very (67-80%) predominance of group O, implying that
their migration was perhaps earlier that previously thought, and most
definitely seems to be a paucity of group B. Additionally, it has been
shown that introduction of these genes into the population does result in
mutation rates much higher than expected. Studies on Egyptian mummies
shows the group B was fairly well distributed (if, as some have asserted,
it comes from India) in Egypt at least 5,000 years ago. These serological
variations in race apparently can not be explained simply by mutation;
selection, migration and random genetic drift must also be accounted
group A seems to have followed significant numbers only after group O,
appearing during the lce Age (30,000 to 100,000 years ago), and perhaps
representing an adaptation to cold. Its minor subtypes A-intermediate, Ax
and A-Bantu seem to be adaptations to parasitic infection.
B would seem to have reached appreciable numbers last. Lewontin has
conjectured that the complete absence of the gene in Amerindian and
Australian aboriginal populations suggested that its origin would have
occurred after the rise in sea levels that accompanied the melting of the
continental glaciers, 10,000 years ago.
AB (a product of A and B parents) seems to be a recent phenomenon also.
Studies on prehistoric grave exhumations in Hungary showed a distinct lack
of this blood group into the Langobard age (4th to 7th century AD).
Populations in Europe also seem to
differ serologically from most other populations of
world, except perhaps the African. There !sat present time no other human
(or anthropod) group with proportionally more A2 than the average
European. This gene has been speculated to perhaps convey some
disadvantage, which under more stringent selection in Asia was eliminated.
In Paleolithic European man the gene, although perhaps inferior to A1,
is good evidence for considerable effects of selection on blood type
distribution. Although most recent work has centered on malignant or
degenerative disease associations between the ABO groups, infection
undoubtedly accounted for the majority of natural selection in
prehistoric populations. This can be explained by the phenomenon of
"horror auto toxicus": i.e. the body has an inherent aversion
to producing antibodies to self antigens. Thus group AB which produced
no antibodies with either A or B specificity would be at selective
disadvantage to organisms possessing either A or B antigenicity.
has pointed out the inherent fault in a simple mutation theory of blood
group distribution: Given the time frame, these mutations would have had
to occur in humans at a rate four times faster than Drosophila!. However
as will be seen, the effect of selection via infectious disease on small
populations (with added random genetic shift) does explain the blood group
variation in a far shorter time frame.
Disease Associations and ABO Group
was the first to hypothesize that the relatively high distribution of A in
areas with historically high incidence of plague (Turkey, Greece, Italy)
would point to selective disadvantage for group O, proven
immunochemically by blood group studies on various Yersinia species.
Antigenic similarity exists between the blood groups and a great variety
of bacterial, rickettsial and helminthic species, including: typhoid,
streptococci (group A), staphylococci (group O), Shigella and Proteus.
Blood group A antigen is virtually identical with Pneumoccus
polysaccharide antigen, which would suggest an association between group A
and this organism, which indeed does exist. The generation of isoagglutinins
via pneumoccocal vaccination was so great (fourfold) that the
manufacturers advised doctors not to administer the vaccine to
premenopausal women, fearing hemolytic difficulties in ABO incompatible
pregnancies. Urinary tract infections have shown great ABO correlation.
Ratner showed that anti-B agglutinogens provided greater protection
against UTI than anti-A, and was able to demonstrate a significantly
greater incidence of UTI from Pseudomonas, Kelbsielia and Proteus in
group B. Group O which does produce anti-B, but in much lower titers than
group A was,
of allergic dermatosis and tropical
eosinophilia show high group A frequencies. Damian gives many examples of
blood group-like antigens in parasitic worms, especially of A and B-like
ones such as Ascaris lumbricoides.
is a general paucity of information on blood groups other than ABO.
Paciokiewicz showed a general deficiency of Rh+ in mumps, infectious
mononucleosis and viral meningitis. It is interestingly to note that
viruses tend to attack the non-antigenic types of both the Rh and ABO
systems (O and Rh-), respectively. Mourant mentions an association between
granulomatous disease and the Kell system, which explains the recognized
autosomal dominance noted with this syndrome.
studies imply that the development of isoagglutinins results from cross
sensitization between bacterial polysaccharides and immature gut wall of
the infant. One study shows a persistent sensitization of infant red cells
resulting from E. Coli enteritis.
Disease Associations and ABO Groups
with the exception of Giardiasis, there have been no significantly new
disease associations noted between the ABO groups since my 1981 review
article. However the classic studies will be reviewed again here.
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“Oh my aching stomach!” Witby Republican. December 12 1993