TRANSFUSION
MEDICINE
REVIEW
Vol 26, No 2
ABO Research in the Modern Era of Genomics
Fumiichiro Yamamoto, Emili Cid, Miyako Yamamoto, and Antoine Blancher
Research on ABO has advanced significantly in recent
years. A database was established to manage the
sequence information of an increasing number of novel
alleles. Genome sequencings have identified ABO ortho-
logues and paralogues in various organisms and enhanced
the knowledge on the evolution of the ABO and related
genes. The most prominent advancements include clar-
ification of the association between ABO and different
disease processes. For instance, ABO status affects the
infectivity of certain strains of Helicobacter pylori and
Noroviruses as well as the sequestration and rosetting of
red blood cells infected with Plasmodium falciparum.
Genome-wide association studies have conclusively
linked the ABO locus to pancreatic cancer, venous
ANDSTEINER'S DISCOVERY OF the ABO
L system opened the venue to a safer blood
transfusion as routine medical practice. It demon-
strated that blood should not be transfused from a
donor to a recipient in a combination that would
result in red blood cell (RBC) agglutination in the
recipient. The system consists of the A and B
antigens on RBCs and their corresponding anti-
bodies in the sera of individuals who do not express
those antigens. Based on RBC agglutination
patterns, individuals could be divided into 4 major
groups (A, B, AB, and O). They exhibit simple
Mendelian mode of inheritance, and the ABO blood
groups became one of the first human polymorphic
traits that were demonstrated to be inherited
through generations. The frequency of individuals
with different ABO blood groups varies widely in
different races and populations. For this reason, the
ABO blood groups have been a fundamental topic
in genetics, anthropology, and population studies.
In addition, ABO has become a major subject in
carbohydrate research and glycobiology for its
Transfusion Medicine Reviews, Vol 26, No 2 (April), 2012: pp 103-118
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April 2012
thromboembolism, and myocardial infarction in the pre-
sence of coronary atherosclerosis. These findings suggest
ABO's important role in determining an individual's
susceptibility to such diseases. Furthermore, our under-
standing of the structures of A and B transferases and
their enzymology has been dramatically improved. ABO
has also become a research subject in neurobiology and
the preparation of artificial/universal blood and became a
topic in the pseudoscience of “blood type diets.” With
such new progress, it has become evident that ABO is a
critical player in the modern era of genomic medicine. This
article provides the most up-to-date information regarding
ABO genomics.
© 2012 Elsevier Inc. All rights reserved.
antigenic structures. The immunodominant struc-
tures of A and B antigens consist of GalNAcα1-N
3(Fucα1-N2)Gal- and Galα1-N3(Fucα1-N2)Gal-,
respectively, whereas the immunodominant struc-
ture of the H antigen, which is abundantly found in
group O individuals, is Fucα1-N2Gal-. These
structures are present as portions of glycoproteins
and glycolipids as well as free oligosaccharides.
The expression of these antigens occurs not only in
From the Institut de Medicina Predictiva i Personalitzada del
Càncer (IMPPC), Badalona, Spain, and Laboratoire
d'Immunogénétique Moléculaire, Faculté de Médicine,
Université Paul Sabatier (UPS), Toulouse, France.
Conflict of Interest: The authors confirm that there are no
conflicts of interest, real or perceived.
Address reprint requests to Fumiichiro Yamamoto, PhD,
Institut de Medicina Predictiva i Personalitzada del Càncer
(IMPPC), Ctra. de Can Ruti, Camí de les Escoles s/n, 08916
Badalona, Spain.
E-mail: fyamamoto@imppc.org
0887-7963/$ - see front matter
© 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.tmrv.2011.08.002
103
104 YAMAMOTO ET AL

RBCs but also in other types of cells (mostly
epithelial and endothelial cells). Therefore, these
blood group antigens are also called histo-blood
group antigens. Accordingly, ABO matching is not
only critical in blood transfusion but also important
in cell/tissue/organ transplantation. Because these
antigens are present on RBCs, skin, hair, and also in
secretions such as saliva and seminal fluid, ABO
typing has been routinely performed on the
biospecimens obtained at crime scenes as well.
The functional A/B alleles at the single genetic
locus, ABO, specify the expression of A/B antigens.
However, these antigens are not the primary gene
products. Instead, the A/B alleles encode the
proteins named A/B glycosyltransferases (A/B
transferases) that catalyze the final step of A/B
oligosaccharide biosynthesis. The H antigen pre-
cursor acts as the common acceptor substrate. Either
an N-acetyl-D-galactosamine (GalNAc) or a D-
galactose (Gal) residue from donor substrates
nucleotide-sugars UDP-GalNAc or UDP-Gal, re-
spectively, is transferred (see Table 1). Although
these 2 enzymes transfer different sugars, the same
α1,3-glycosidic linkage is formed. Because of these
similar but distinct specificities of A and B trans-
ferases, these enzymes provide enzymologists and
structural biologists with an interesting model to
study the relationship between structure and func-
tion. A and B antigen expressions are not limited to
humans. There also exist other enzymes with
specificities similar to A and B transferases.
Therefore, an interesting opportunity is provided
to study the evolution of ABO orthologous and
paralogous genes. ABH antigen expression is not
stable and can be altered during various biological
processes. In addition, ABO polymorphisms may
also affect both the physiology and pathology of
cells and individuals. For these reasons, the study of
ABO cannot merely be limited to transfusion and
transplantation medicine.
Since our elucidation of the molecular genetic
basis of the ABO system, we have witnessed much
advancement in various fields of ABO research.
Thanks to the Human Genome Project and the
efforts on sequencing the genomes of varied
species, enormous progress has been made in the
areas of genetics and genomics. In this review, we
attempt to introduce a few of the most exciting
developments that have taken place in those areas
of ABO research.
MOLECULAR GENETICS OF ABO
ABO Alleles and the Blood Group Antigen Gene
Mutation Database
The timeline of major discoveries in ABO
research is shown in Table 2. The allelic basis of
the ABO system was elucidated at the molecular
level in 1990 [1]. The soluble form of human A
transferase was isolated, and the A, B, and O allelic
complementary DNAs (cDNAs) were cloned and
sequenced [1-3]. Four amino acid substitutions

Table 1. Structures of ABH and Related Antigens and α1,3Gal(NAc) Glycosyltransferases That Catalyze Their Biosynthesis

NOTE. The donor nucleotide sugars and acceptor substrates as well as the enzymatic reaction products are shown for the individual
functional enzymes of the α1,3Gal(NAc) transferase gene family.

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ABO RESEARCH IN THE MODERN ERA OF GENOMICS
were identified between A and B transferases
(R176G, G235S, L266M, and G268A). Two
kinds of O alleles were identified that are different
from one another by several nucleotide substitu-
tions, but both types contained a single nucleotide
deletion (261delG) that were relatively close to the
N-terminus of the coding sequence. It was con-
cluded that O alleles are nonfunctional because of a
frameshift of codons. Using the single nucleotide
polymorphisms (SNPs) that discriminated between
A/B and O alleles and those that discriminated A/O
from B alleles, the first ABO genotyping was
successfully performed. It was also shown that the
identified SNPs were commonly present in the
human population. Because the SNPs directly
correlated to the expression of A/B antigens, the
central dogma of the ABO was demonstrated:
functional A and B alleles at the ABO genetic locus
encode A and B transferases, which catalyze the last
step of biosynthesis of oligosaccharide A and B
antigens, respectively.
Since the molecular characterization of the 3
major alleles, many others have been identified and
sequenced. This was possible because ABO blood
typing is routinely performed on large numbers of
samples destined for transfusion at blood centers all
over the world. The identification of weak sub-
groups of A and B is relatively easy using the
established protocols of forward and reverse typing
by the immunological method. Those samples
suspected of having alleles other than the 3 major
ones were later subjected to PCR and DNA
sequencing. Together with collaborators, we iden-
tified mutations in an A2 allele, an A3 allele, an Ax
allele, a B3 allele, a cis-AB allele, and a B(A) allele.
We also identified another type of O allele that does
not possess 261delG but contains nucleotide
changes resulting in amino acid substitutions, one
of which being the G268R substitution at the fourth
position of the 4 amino acid substitutions that
differentiate A and B transferases. Other groups of
scientists played a crucial role in the identification of
additional subgroup alleles, cis-AB and B(A)
alleles, and additional mutations and SNPs in the
ABO gene. The nature of the mutations found is
diverse, although missense mutations are the most
common. The other kinds include an initiation
codon mutation, a Golgi localization mutation,
frameshift mutations due to nucleotide deletions or
insertions, splicing mutations, and nonsense muta-
tions. In addition, alleles that seemed to have
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105
resulted from recombination have also been identi-
fied. Occasionally, different molecular mechanisms
appear to be responsible for seemingly identical
phenotypes. An example is found with the B3
phenotype, which may be caused by a missense
mutation (R352W in B301 allele, F216I in B302,
D83Y in B304, etc) or a splicing mutation (B303). It
should be noted that there exist several A1 and B1
alleles. This is because A and B subgroups have
been defined immunologically. All the A alleles
encoding A transferases that use both unbranched
and branched acceptor H substrates and biosynthe-
size A antigens on RBCs that are sufficient to elicit
A1-specific hemagglutination reactions with anti-A,
anti-A,B, and anti-A1 reagents are inclusively called
A1 alleles, irrespective of the presence/absence of
mutations or differences in the nucleotide and amino
acid sequences. For references, see reviews of
Yamamoto [4] and Storry and Olsson [5].
The Blood Group Antigen Gene Mutation
(BGMUT) database was established in 1999 by
Blumenfeld [6]. The used nomenclature repre-
sented ABO alleles by the phenotype followed by
a 2-digit number in the order of discovery. The
alleles identified by us were named A101, A102,
B101, O01, O02, O03, A201, A301, Ax01, B301,
cis-AB01, and B(A)01. The nucleotide and amino
acid sequences of the A101 were used as the
reference sequences. The BGMUT database was
later transferred to the National Center for Biotech-
nology Information (NCBI) and renamed dbRBC
(the online access Web addresses of this and other
databases mentioned in this article are listed in
Table 3). It currently houses information on poly-
morphisms and mutations of 28 blood group
systems. As of now, 212 alleles have been posted
in the ABO database. Because the sequenced
regions vary among the alleles, there seems to be
some overlap. However, the alleles specifying
different ABO phenotypes (A1, A2, A3, Ael,
Aint, Am, Aw, Ax, B(B1), B3, Bel, Bw, Bx, cis-
AB, and B(A)) are covered. The Web links to the
original reports describing the individual alleles can
also be found in this database.
ABO Information in Other Databases
In addition to the dbRBC database, more
information on ABO can be obtained from other
databases. Its disease associations may be accessed
through the Online Mendelian Inheritance in Man
database. The information on chromosomal
106 YAMAMOTO ET AL

Table 2. Major Events/Discoveries in the Molecular Genetics/Genomics and Evolution Studies of ABO
Year Genetics/genomics Molecular genetics/genomics study of ABO Evolution study of ABO

1900 Rediscovery of Mendel's work Discovery of the ABO blood groups

1924 1 gene-3 alleles model of inheritance
Chemical structures of A/B/H antigens
were revealed
1953 Double helix was discovered
1959 Biosynthetic pathway of A/B antigens
was proposed
A/B Transferase activity detected ABH antigens and ABO polymorphisms
in other species studied
1982 GenBank was created
1989 α1,3GalT cDNA was cloned
1990 Human Genome Project Human A transferase was purified Mutations in human GGTA1 gene
was started Human A transferase cDNA was cloned were identified
Molecular genetic basis of ABO system
was elucidated
First ABO genotyping was achieved
Amino acids crucial for differential sugar
specificity were identified
1991 Nonfunctional hgt4 sequence was found
1992 Mutations in an A2 allele were revealed Primate ABO genes were partially cloned
1993 Mutations in A3, Ax, B3, cis-AB, and B(A)
alleles were identified
O allele without the single nucleotide
deletion was identified
1995 ABO genomic DNA was cloned
1996 Importance of codons 266 and 268 for FS cDNA was cloned
differential sugar specificity was confirmed
1997 Vertical transmission of ABO gene was
demonstrated
1999 Ensembl was launched BGMUT was established
2000 iGb3 cDNA was cloned
2001 Mouse cis-AB gene was revealed
Pig AO system was elucidated
3D structures of α1,3GalT were revealed
2002 HapMap Project was initiated 3D structures of A and B transferases Nonallelic A and B genes were found in rats
were determined
2003 Human Genome Project
was completed
2005 GWAS studies were initiated E coli B transferase gene was cloned
2006 BGMUT was transferred to become
dbRBC in NCBI
2007 GLT6D1 sequences were found, and
evolution through recurrent duplication and
deletions was proposed
2008 Associations were identified by GWAS O allele was found in Neanderthal
between ABO and serum-levels of soluble H mustelae A transferase gene was
TNF-α, ICAM-1 or alkaline phosphatase identified
2009 Associations were identified by GWAS
between ABO and individual's susceptibility
to VTE or pancreatic cancer or serum-level
of soluble E-selectin, but no association was
found between ABO and severe malaria
2010 Associations were identified between ABO ABO orthologue was found in protozoan,
and serum levels of soluble P-selectin or and horizontal transmission of ABO gene
phytosterol or angiotensin-converting was suggested
enzyme activity or
hematological/biochemical traits

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ABO RESEARCH IN THE MODERN ERA OF GENOMICS 107

Table 2. (continued)
Year Genetics/genomics Molecular genetics/genomics study of ABO Evolution study of ABO

2011 GWAS linked ABO with cardiovascular 58 ABO gene orthologues in 29 species, 28
disease risk GGTA1 genes from 20 species, 31
A3GALT2 genes from 26 species, and 31
GBGT1 genes from 30 species are listed in
Ensembl database
NOTE. The major events/discoveries in the history of the molecular genetics/genomics and evolution studies of ABO, which are mentioned
in the text, are below listed in the timeline. Abbreviation: 3D, 3-dimensional.

location, gene organization, nucleotide and de-
duced amino acid sequences, orthologous and
paralogous genes, and others, is found in several
DNA sequence databases: GenBank (NCBI),
Ensembl (EMBL), and DNA Data Bank of Japan
(CIB-DDBJ) among others. However, it should be
noted that the information is not always correct. For
example, no protein is annotated for the ABO gene
(ENSG00000175164) on chromosome 9:
136,130,563-136,150,630 in the GRCh37 version
of Ensembl database. This is because the reference
DNA is that of the O allele with a 261delG, which
causes a frameshift and early termination.
The SNP database at NCBI (Build 132) contains
30 443 455 SNP identifications. The SNP for the O
allele–specific 261delG was given the reference
number rs8176719. The SNPs at codons 266 and
268, which determine the GalNAc/galactose spec-
ificity of the encoded A/B transferases, were
Table 3. Web Addresses for Online Access toward the Useful
Databases
dbRBC: http://www.ncbi.nlm.nih.gov/projects/gv/rbc/xslcgi.
fcgi?cmd=bgmut/home
OMIM Database: http://www.ncbi.nlm.nih.gov/omim
GenBank (NCBI): http://www.ncbi.nlm.nih.gov/genbank/
Ensembl (EMBL): http://www.ensembl.org/index.html
DNA Data Bank of Japan (CIB-DDBJ): http://www.ddbj.nig.ac.
jp/index-e.html
SNP Database at NCBI: http://www.ncbi.nlm.nih.gov/projects/
SNP/
CAZy Database: http://www.cazy.org/Home.html
GWAS Database: http://www.genome.gov/gwastudies/
COSMIC Database: http://www.sanger.ac.uk/genetics/CGP/
cosmic/
Consortium for Functional Glycomics: http://www.
functionalglycomics.org/
NOTE. The Web addresses of the databases, which are
mentioned in the text and which may be useful for future ABO
research, are listed. Abbreviations: OMIM, Online Mendelian
Inheritance in Man; CAZy, Carbohydrate-Active enzymes; COS-
MIC, Catalogue Of Somatic Mutations In Cancer.
registered as rs8176746 and rs8176747, respective-
ly. Most of the SNPs that were identified in the
common ABO alleles have already been uploaded.
However, there are mutations in rare alleles that are
yet to be included. Some of the SNPs in the
common ABO alleles have also been incorporated
into the DNA microarrays (or beadchips), which are
available in the market for genome-wide associa-
tion studies (GWASs). Those DNA microarrays
have been used successfully to correlate ABO to
pancreatic cancer and other diseases (see below).
EVOLUTION OF THE ABO GENES
ABO Genes
The timeline of major discoveries in ABO
research in evolution is shown in Table 2. We
determined the partial nucleotide and deduced
amino acid sequences of the ABO genes in several
species of primates [7]. The kind of ABO types
varies depending on species. For example, only A
and O groups are known to exist in chimpanzees,
whereas only the B group is found in gorillas. This
is in contrast to A, B, AB, and O groups that are
found in humans [8,9]. We constructed the
phylogenetic trees of the ABO gene and demon-
strated the A to B conversion in at least 3 different
occasions during the ABO gene evolution in
primates [10]. Nullifying mutations found in the
chimpanzee and macaques were different from
those in humans, demonstrating the recursive
appearance of silent alleles in various primate
species [11]. The limited repertoire of ABO groups
is also observed in mammals other than primates.
For instance, only A and O are found in pigs. We
found that pig O gene lacks a major portion of the
gene [12]. We also showed that mouse ABO gene
encodes an enzyme with dual specificity that is
capable of synthesizing both A and B antigens in
vitro, although B antigen is rarely produced in vivo
[13]. Because of DNA sequencing efforts, genes

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108 YAMAMOTO ET AL

Table 4. Genome-Wide Association Studies That Associated the SNPs in the ABO Gene to Diseases/Traits
Risk allele frequency
Disease/trait Investigator and reference Strongest SNP-risk allele in control⁎ P OR

Serum TNF-α Melzer et al [32] rs505922-? 0.34 7 × 10−40

Serum soluble ICAM-1 Pare et al [31] rs507666-G 0.20 5 × 10−29
Serum ALP Yuan et al [36] rs657152-T 0.39 2 × 10−30
VTE Tregouet et al [27] rs505922-C 0.35 4 × 10−15 1.81 (1.56-2.11)
Pancreatic cancer Amundadottir et al [72] rs505922-C 0.35 5 × 10−8 1.2 (1.12-1.28)
Serum soluble E-selectin Paterson et al [33] rs579459-C 0.20 1 × 10−29
Angiotensin-converting Chung et al [38] rs495828-A 0.17 3 × 10−8
enzyme activity
Serum soluble P-selectin Barbalic et al [35] rs579459-T NR 2 × 10−41
Serum soluble ICAM-1 rs649129-T NR 1 × 10−15
Serum soluble E-selectin Qi et al [34] rs651007-T 0.22 2 × 10−82
Serum ALP Kamatani et al [37] rs495828-T 0.28 4 × 10−59
RBC rs495828-T 0.28 3 × 10−12
Hgb rs495828-T 0.28 1 × 10−11
Ht rs495828-T 0.28 6 × 10−10
MCHC rs8176746-T 0.18 4 × 10−8
Campesterol Teupser et al [39] rs657152-T 0.383 9 × 10−13
Cardiovascular disease risk factor Reilly et al [28] rs514659-C 0.37 8 × 10−9 1.21 (1.13-1.28)
(AngCAD/MI)
CAD Schunkert et al [29] rs579459-C 0.21 4 × 10−14 1.1 (1.07-1.13)
NOTE. This table was produced from data obtained by the keyword search with ABO at “A Catalog of Published Genome-Wide
Association Studies” Web site.
The OR, which is the ratio between the fraction (probability) with the risk variant (carriers) vs the fraction with nonrisk variant (noncarriers) in the
groups of affected vs the controls, was calculated using the following equation: OR = [Pr(c|A)/Pr(nc|A)]/(Pr(c|C)/Pr(nc|C)], where Pr indicates
probability; c, carriers; A, affected; nc, noncarriers; C, controls.
Abbreviations: NR, not reported; Hgb, hemoglobin; HT, hematocrit; MCHC, mean corpuscular hemoglobin concentration; AngCAD,
angiographic coronary artery disease; MI, myocardial infarction.

orthologous to ABO have been identified in various
species of organisms. In the current version of the
Ensembl database, a total of 58 ABO orthologues in
29 species, including African clawed frog and
zebrafish, are deposited.
A/B antigens can be expressed in microbes as well.
For example, gram-negative Escherichia coli O86
exhibits strong blood group B and weak blood group
A activity by the O-polysaccharide antigen. The B
transferase gene from E coli and the A transferase
gene from Helicobacter mustelae were initially
cloned and sequenced [14,15]. Homologous se-
quences to these genes have been identified in several
dozen bacterial species and a cyanophage [16].
α1,3Gal(NAc) Transferase Family of Genes
In addition to the A and B transferases, additional
enzymes with similar specificities exist. They are
α1,3-galactosyltransferase (α1,3GalT), isoglobo-
side b3 synthase (iGb3S), and Forssman glycolipid
synthase (FS). The glycosylation reactions cata-
lyzed by these enzymes are also shown in Table 1.
α1,3GalT is involved in the biosynthesis of the
α1,3Gal epitope, which is present in many species
of mammals. These include some primates but
exclude Old World monkeys and anthropoid apes
such as humans. The species without the epitope
produce natural antibodies against it [17]. Together
with A/B transferases, these α1,3Gal(NAc) trans-
ferases were classified into the GT6 family in the
Carbohydrate-Active enZymes Database [18]. For-
ssman glycolipid synthase exhibits the same
GalNAc specificity as A transferase, whereas the
α1,3GalT and iGb3S exhibit the same galactose
specificity as B transferase. A and B transferases
use fucosylated acceptor substrates, whereas the
other enzymes use unfucosylated acceptor sub-
strates instead.
The Ensembl database also houses ABO para-
logous genes (28 GGTA1 genes from 20 species,
31 A3GALT2 genes from 26 species, 31 GBGT1
genes from 30 species, and 39 GLT6D1 sequences
from 32 species). The GGTA1, A3GALT2, and
GBGT1 genes may encode α1,3GalT, iGb3S, and
FS, respectively. No activity has been reported for
the proteins encoded by GLT6D1 sequences. The
phylogenetic trees of the ABO orthologous and
paralogous genes clearly demonstrate vertical gene

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ABO RESEARCH IN THE MODERN ERA OF GENOMICS 109

Fig 1. The ABO-targeted and GWAS are compared, and the differences are schematically shown with several examples of associations
and nonassociations [27,31,61,72]. The degree of the association is indicated by the thickness of line in the targeted studies and in the
−log10 (P value) in the GWAS studies. FV indicates factor V locus.

transfer during the evolution of higher animals (the
most up-to-date results may be found in the
GeneTree ENSGT00400000022032 in the Ensembl
database) [7,10,11,19-22]. There is, however, a gap
between bacteria and vertebrates. Recently, it has
been proposed that the bacterial genes may be of
vertebrate origin, and that bacteria incorporated
them into the O-antigen synthesis to enhance
mimicry of host glycans [23].
ABO AND DISEASES
Transfusion of ABO-incompatible blood may
result in RBC hemagglutination, kidney failure, and
occasional death of the recipient. Transplantation of
ABO-incompatible cells/tissues/organs may, with-
out immunosuppression, result in acute rejection.
Although the ABO incompatibility in these exam-
ples is the result of artificial medical practices, it
also occurs naturally in the form of ABO-incom-
patible pregnancy. Although it may cause hemolytic
disease of the newborn (HDN), the symptoms are
mild and usually do not require any treatment. There
are additional diseases to which ABO has been
related. We have selected cardiovascular diseases,
infectious diseases, and cancer for discussion.
Cardiovascular Diseases
ABO blood group is a major determinant of
factor VIII and von Willebrand factor (vWF)
plasma levels [24]. Blood group O individuals
have approximately 25% lower plasma levels of
these glycoproteins than A individuals. This
association is of clinical importance. Although
low plasma levels may cause excessive bleeding,
high levels may increase the risk of ischemic heart
disease and venous thromboembolism (VTE)
[25,26]. These effects are thought to be mediated
primarily through different rate of vWF synthesis,
secretion, and/or clearance that lead to differential
plasma vWF levels. Recent GWAS studies have
revealed associations between the ABO locus and
VTE and coronary artery disease (CAD) (Table 4
and Fig 1) [27-29]. By analyzing 317 000 SNPs in
453 VTE cases and 1327 controls, 3 SNPs were
identified as having a genome-wide significant level
of 1.7 × 10 −7: 1 located in the factor V locus (P =
8.1 × 10 −10 ) and the other 2 (rs505922 and

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110
rs657152) located in ABO locus (P = 1.5 × 10 −14
and 2.2 × 10 −13, respectively) (Fig 1) [27]. No other
loci were found strongly associated with VTE.
Further ABO genotyping of 1700 cases and 1400
controls at 3 additional SNPs that tag A2
(rs8176750), B (rs8176746), and O (rs8176719)
confirmed that individuals with O and A2 groups
are at lower risk for VTE. Similarly, ABO was
linked to myocardial infarction in the presence of
coronary atherosclerosis [28]. Surprisingly, the top
11 SNPs with highest associations were mapped at
the ABO locus (odds ratio [OR], 1.21; P = 7.6 ×
10 −9 for rs514659) [28]. The OR for A/B/AB vs O
was calculated to be 1.44. A primary relation of A/B
transferase activity with coronary thrombosis, rather
than atherosclerosis, was previously suggested [30].
A meta-analysis of 14 GWAS studies of CAD
comprising 22 233 cases and 64 762 controls of
European descent followed by genotyping of top
association signals in 56 682 additional individuals
identified rs579459 SNP in the ABO locus as having
the fifth highest association with an OR of 1.1 [29].
Furthermore, other GWAS studies have linked
the SNPs at the ABO locus to the serum levels of
soluble intercellular adhesion molecule 1 (ICAM-1)
[31], tumor necrosis factor α (TNF-α) (although
assay specific) [32], soluble E-selectin [33,34],
soluble P-selectin [35], alkaline phosphatase
[36,37], angiotensin-converting enzyme [38], cam-
pestrol [39], hematocrit, and the mean corpuscle
hemoglobin level concentration [37] (Table 4 and
Fig 1). In addition to vWF, some of these factors
may play a vital role in the differential susceptibility
to VTE and other ABO-associated diseases.
Infectious Diseases
Infectious diseases may influence population
genetics and the evolution of the human genome
by selecting against host susceptibility alleles that
modify pathogenesis. Because infectious agents
often use cell-surface glycoconjugates as receptors
for attachment, glycosylation polymorphisms such as
ABO may affect host-pathogen interactions and
result in differential susceptibility among individuals
with different glycosylation profiles. It should be
remembered that certain microbial parasites share
blood group antigens with their hosts (molecular
mimicry). Early etiological studies identified associ-
ations between ABO and infectious diseases such as
cholera [40]. (See the textbook by Mourant et al [41]
for a review on the topic.) In this article, we have
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YAMAMOTO ET AL
selected Helicobacter pylori, Noroviruses, Plasmo-
dium falciparum, and retroviruses for discussion.
H Pylori and Peptic Ulcer. The association
between ABO and peptic ulcer was one of the first to
be identified [42]. It was shown that group O
individuals had higher susceptibility to peptic
ulcers. The relative incidences reported were 0.73
(A/O) and 0.80 (B/O) for duodenal ulcers and 0.87
for gastric ulcers (both A/O and B/O). The relative
risk for nonsecretors/secretors was calculated to be
1.9 [43]. Gastritis and ulceration of stomach/duo-
denum were later correlated to infection with the
bacterium H pylori [44]. It was also found that
patients could be cured from peptic ulcer by
eradicating the bacteria with antibiotics and acid
secretion inhibitors. It was reported that the
fucosylated antigens H type 1 and Lewis b (Le b)
mediate H pylori attachment to human gastric
mucosa and that soluble glycoproteins presenting
Le b or antibodies to the Le b antigen could inhibit
the bacterial binding [45]. Furthermore, the conver-
sion of Le b to ALe b by the addition of a terminal
GalNAc diminished the bacterial binding. This may
explain the reduced infectivity of groups A/B/AB
individuals as compared with group O individuals.
However, later studies examining different strains
of H pylori showed that sugar specificity vary
among strains, complicating the understanding of
the interactions between blood group antigens and
blood group antigen–binding adhesin (BabA).
Actually, more than 95% of the strains that bind
fucosylated blood group antigens do not exhibit
group O preference. They bind A, B, and H antigens
instead (generalists). Only 5% of the strains
specifically bind H antigens (specialists), with the
percentage being higher (60%) among South Amer-
ican Amerindian strains [46]. It was suggested that the
specialization of H pylori coincided with the unique
predominance of group O in Amerindians. It was also
proposed that cycles of selection for increased or
decreased bacterial adherence may have contributed
to BabA diversity and that those cycles may have
gradually replaced generalist binding by specialist
binding in the group O–dominant population. Higher
percentage of specialist strains of H pylori in
Amerindians may provide an example of positive
selection of pathogens due to the abundance of a
specific host population group, as opposed to
negative selection of a specific host population
group caused by infectious agents.
ABO RESEARCH IN THE MODERN ERA OF GENOMICS
Noroviruses and Viral Gastroenteritis. Noro-
viruses (NoVs), with Norwalk virus (NV) as their
prototype, are a leading cause of viral gastroenter-
itis in humans. Noroviruses cause 90% of epidemic
nonbacterial acute gastroenteritis worldwide. Some
people are resistant to the viral infection. Because
NV uses H type 1–based structures as its primary
receptor, nonsecretor individuals with 2 mutated
FUT2 alleles who are devoid of H type 1 epitopes
were shown to be resistant to NV infection [47].
ABH and Lewis antigens are present on gut
epithelial cells. Therefore, it is not surprising that
ABO phenotype may affect virus infection. The
initial study found that group O individuals were
more likely to be infected with NV (OR, 11.8),
whereas B individuals had decreased risk of
infection (OR, 0.096) and symptomatic disease
(OR, 0) [48]. The resistance to NoV infection was
then shown to be multifactorial because a portion of
the susceptible population that possessed a func-
tional FUT2 gene were resistant to infection [49]. It
was later suggested that the association between
susceptibility to NoV infection and being a secretor
might be restricted to genogroup I NoV. In fact, the
protection of the individuals with the group B was
shown to be restricted to genogroup I, and not to
genogroup II, NoVs [50]. No association was
observed between the ABO phenotype and clinical
infection with genogroup II NoVs [51]. Subse-
quently, strain-dependent association, rather than
genogroup-dependent association, was proposed
between ABO and NoV infection [52].
P falciparum and Severe Malaria. It has
recently been proposed that malaria may have played
an important role in shaping the current distribution of
the ABO blood group polymorphism in the world
[53]. The association between ABO and malaria was
first suggested in 1967 when Athreya and Coriell [54]
reported that group B confers a selective advantage to
malarial infection. By 1978, a marked excess of group
A patients, as compared with groups O and B, was
recognized from combined data analysis. However,
the types of malaria were rarely mentioned in the
literature. In 2007, Cserti and Dzik [55] published a
review article critically analyzing the literature that
reported the association/nonassociation between ABO
and P falciparum malaria. They focused their
attention on the association between ABO and the
disease severity. Of 22 articles on the topic, they
excluded studies that had too small of a sample size
for statistical analysis, lacked appropriate controls,
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111
failed to categorize severity, or did not include
children younger than 5 years. Four studies that
satisfied the criteria showed that group O individuals
tend to exhibit a favorable outcome when compared
with group A individuals. Based on this analysis, they
proposed a biological model emphasizing the role of
ABO in cytoadhesion.
Sequestration and rosetting are linked to the
pathogenesis of severe malaria. The former is the
process whereby P falciparum–infected RBCs roll
on and adhere to the microvascular endothelium
and then disappear from the circulation. The latter
signifies the formation of aggregates by infected
RBCs with uninfected RBCs and/or platelets. The
microcirculatory obstruction by cytoadhesion may
result in reduced oxygen and substrate supply [56].
The higher affinity of rosette binding of group
A/B/AB vs O RBCs was reflected in larger rosettes
[57]. The A and B antigen terminal mono- and
trisaccharides, the H disaccharide, and fucose were
shown to specifically inhibit the rosetting of
the parasites grown in group A/B RBCs, and the
selective enzymatic digestion of A antigen from the
surface of uninfected RBCs totally abolished
the preference of the parasite to form rosettes with
those RBCs [58]. Parasite-encoded P falciparum
erythrocyte membrane protein 1 mediates this
adhesion behavior, and a repertoire of human host
proteins interacts with it. The A antigen seems to
bind to the semiconserved head structure of the
parasite protein to form rosettes [59].
Fry et al [60] studied the association between
severe malaria and SNPs at the ABO locus. Both
population- and family-based studies were per-
formed using SNPs rs8176719: A/B vs O and
rs8176746: A/O vs B. The A/B alleles producing
functional transferases were associated with greater
risk of severe malaria (particularly with severe
malarial anemia) in comparison with the O allele
with 261delG: OR, 1.18; P = 2 × 10 −7. One year
later, in 2009, Jallow et al [61] reported the GWAS
study on severe malaria. It identified hemoglobin-β
(HBB) and 18 other loci exhibiting significant
association with the threshold of P b 10 −4. The peak
of the signal at HBB coincided precisely at the
position of the S-hemoglobin (a variant form of
hemoglobin found in people with sickle cell disease)
causal variant. However, no SNPs at the ABO locus
were associated by the GWAS study (Fig 1).
Inhibition of Infection by Natural Antibodies and
Lectins. Because the transmission of type C
112
retroviruses that are endogenous to various non-
primate species to humans and other Old World
primates is restricted and because this inhibition
parallels with the presence of anti–α-galactosyl
epitope antibodies, it was postulated that natural
antibodies in serum inhibit the interspecies viral
infection [62]. This hypothesis was supported by
experimental results. The blockage or depletion of
anti–α-galactosyl epitope antibody allowed infection
of both amphotropic and ecotropic murine retrovi-
ruses. Furthermore, the retroviruses were not neu-
tralized by New World primate serum unless
exogenous anti–α-galactosyl epitope antibody was
added. Enzyme-linked immunosorbent assay
revealed that the α1,3Gal epitope was expressed on
the retroviral envelope glycoprotein gp70. Down-
regulation of this epitope on the surface of murine
cells rendered them as well as the viral particles
liberated from those cells resistant to inactivation by
human serum complement. When porcine α1,3GalT
is expressed in human cells, the cells and the
retroviruses they produced became sensitive to
human serum [63]. Sensitization to human serum
by α1,3-galactosylation was also observed with
rhabdo-, lenti-, and spumaviruses [64].
A similar inhibitory role has been proposed for
anti-A and anti-B antibodies in intraspecies
infection of viruses that exhibit A and B antigen,
respectively. In that hypothesis, the viruses
produced in cells expressing A/B antigen are not
neutralized in the host due to the absence of anti-
A/anti-B antibody, respectively. However, if those
A/B antigen–expressing viruses are transmitted to
another host with a different blood group that
contains the corresponding antibody, they may be
inactivated. Actually, there are experimental re-
sults supporting this hypothesis. For instance, HIV
viruses prepared from peripheral blood mononu-
clear cells from group A donors were specifically
neutralized by a monoclonal antibody against A
antigen, whereas the viruses prepared from
peripheral blood mononuclear cells from group B
or O donors were not [65]. Using the measles
viruses and HeLa cells transfected with cDNA
encoding of either human A transferase, B
transferase, an inactive truncated O protein, or a
porcine α1,3GalT, Preece et al [66] showed that
viral particles expressing A, B, and α1,3Gal
epitopes were partially neutralized with human
preimmune sera in a complement-dependent man-
ner. These results suggest that polymorphic
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YAMAMOTO ET AL
carbohydrates may play a role in the defense
against intraspecies infection. Despite these inter-
esting in vitro observations, no influence of the
ABO phenotype on the sensitivity to HIV infection
in vivo was observed [67].
In addition to the natural antibodies, 2 innate
immune lectins, galectins 4 and 8, were shown to
possess an inhibitory function in bacterial infection
[68]. These lectins are expressed in the intestinal
tract and killed E coli that expressed B antigens but
failed to alter the viability of other E coli strains or
other gram-negative or gram-positive organisms
both in vitro and in vivo. The killing was
accompanied by disruption of membrane integrity
and occurred rapidly and independently of comple-
ment. Cummings speculates that those lectins
provide direct protection against the pathogens
displaying particular blood group antigens.
Cancer
Changes in the A/B Antigen Expression. The
expression of ABH and related antigens is not
constant. It undergoes alterations during cellular
differentiation, development, and aging as well as
pathologic phenomena, most evidently in carcino-
genesis. For many years, decreased levels of A, B,
or H antigen have been noted in patients with
hematologic malignancies, especially of the mye-
loid lineage. Changes in ABH antigen expression
have also been reported with solid tumors. Some of
the changes have become useful prognostic
markers. “Incompatible” A antigen expression was
also reported in tumors of groups B and O patients.
Because A transferase activity was also detected, it
was speculated that the incompatible A antigen is
the result of the expression of an O gene–derived
transferase by an undetermined mechanism. The
molecular mechanisms of A/B antigen expression
loss in cancer have been studied. The down-
regulation of A/B transferase messenger RNA was
found to be associated with the disappearance of
A/B antigens. An inverse correlation was also found
between the ABO gene expression and the promoter
DNA methylation. (See the reviews by Yamamoto
[4] and Hakomori [69] for the references on the
changes in ABH and related antigens in cancer and
the analyses of the molecular mechanisms.)
Several glycosyltransferases often share and
compete for the same acceptor substrates. In
addition, the interactions among glycosyltrans-
ferases, glycosidases, nucleotide sugar transporters,
ABO RESEARCH IN THE MODERN ERA OF GENOMICS
and others determine the glycosylation profiles
including that of the A/B antigens. Therefore,
studying solely the expression of the ABO gene is
insufficient. Future studies will have to take all the
players into account and clarify the roles of each
one in the complex network of biosynthetic and
degradation pathways.
ABO Phenotype and Differential Susceptibility. A
higher incidence of stomach cancer was reported
in group A individuals [70]. Later studies reported
a 25% increase of getting stomach and pancreatic
cancer in individuals bearing non-O alleles [41].
Wolpin et al [71] conducted 2 large independent
prospective cohort studies that collected data on
107 503 US health professionals. During 927 995
person-years of follow-up, 316 participants devel-
oped pancreatic cancer. The ABO group was found to
be associated with the risk of developing pancreatic
cancer (P = .004). Compared with group O
participants, the ORs of those with groups A, AB,
and B were 1.32, 1.51, and 1.72, respectively.
Overall, 17% of the pancreatic cancer cases were
attributed to inheriting a non-O group. The incidence
rates per 100 000 person-years were calculated to
be 27, 36, 41, and 46 for participants with groups O,
A, AB, B, respectively. A GWAS study was
published 5 months later (Table 4 and Fig 1) [72].
Amundadottir et al [72] genotyped 558 542 SNPs in
1896 individuals with pancreatic cancer and 1939
controls and conducted a combined analysis of
these groups plus additional 2457 affected in-
dividuals and 2654 controls. Three regions were
identified, and the strongest association to pancre-
atic cancer was observed with SNP rs505922
(combined P = 5.37 × 10 −8), which was mapped
in the ABO gene (Fig 1). As opposed to previous
studies that targeted ABO, these results were
obtained from the screening of half a million
anonymous SNPs scattered over the human ge-
nome. Therefore, it was thought that the ABO locus
is one of the most important, if not the best, among
25 000-plus genes in the human genome in
determining susceptibility to pancreatic cancer.
The following study determined the degrees of
influence of specific ABO alleles on susceptibility
[73,74]. Wolpin et al [73] determined the ABO
genotypes of 1534 cases and 1583 controls that
were analyzed in the earlier GWAS study using
rs687289 (A/B vs O) and rs8176746 (A/O vs B),
which perfectly correlated (r 2 = 1) with the O and B
alleles. Compared with group O, the ORs for groups
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113
A, AB, and B were 1.38, 1.47, and 1.53,
respectively. The incidence rates for groups O, A,
AB, and B were calculated to be 28.9, 39.9, 41.8,
and 44.5 cases per 100 000 subjects per year. An
increase in risk was observed with the addition of
each non-O allele. Compared with OO genotype,
subjects with AO and AA genotype had ORs of
1.33 and 1.61, whereas subjects with BO and BB
genotypes had ORs of 1.45 and 2.42. The
population fraction attributable to non-O group
was estimated to be 19.5%. In a joint model with
smoking, current smokers with non-O group had an
OR of 2.68 compared with group O nonsmokers. A
conclusion was elicited that the ABO genotypes are
significantly associated with pancreatic cancer risk.
The work was further extended to determine the
differences between A1 and A2 alleles and between
2 O allele variants (O01 and O02) [74]. Compared
with subjects with genotype O/O, genotypes A2/O,
A2/A1, A1/O, and A1/A1 had ORs of 0.96, 1.46,
1.48, and 1.71, respectively. Similar ORs were
obtained for O01 and O02 variant O alleles.
Compared with O01/O01, the ORs for O02/O01,
A1/O01, and A2/O01 were 1.00, 1.38, and 0.96,
respectively (O01 vs O02, P = .94; A1 vs A2, P =
.004). Secretor phenotype was not an effect
modifier. It was concluded that ABO alleles
corresponding to increased transferase activity
were associated with increased risk of pancreatic
cancer. However, it should be noted that the genes
that affect the susceptibility and the genes that cause
disease may be either the same or different. In
pancreatic cancer, activating mutations in KRAS
and CTNNB1 protooncogenes and/or inactivating
mutations in TP53, CDKN2A, and SMAD4 tumor
suppressor genes are the primary driving forces of
carcinogenesis (see the Catalogue Of Somatic
Mutations In Cancer database). The ABO polymor-
phism affects the susceptibility, but A/B alleles do
not cause pancreatic cancer.
OTHER DEVELOPMENTS
Role in Neurogenesis
There have been some advances in understand-
ing ABO's role in neurogenesis. Mollicone et al
[75] first reported the expression of B and H
antigens in primary sensory cells of the rat
olfactory apparatus and inner ear. Villarroya et al
[76] also suggested that the A gene or a gene
closely linked to the ABO locus is responsible for
114
the susceptibility to experimental allergic enceph-
alomyelitis in rabbits. In mice, the primary sensory
neurons in both the main and accessory olfactory
systems express H antigen, whereas a subset of
vomeronasal neurons in the developing accessory
olfactory system expresses A antigen. St John et al
[77] performed both loss-of-function and gain-of-
function experiments, manipulating the expression
of those antigens in the olfactory system. They
demonstrated the following: (1) a delay was
observed in the maturation of the main olfactory
bulb glomerular layer in null mutant mice that
lacked the α1,2-fucosyltransferase and therefore
the H antigen and (2) ubiquitous expression of A
antigen on olfactory axons in a gain-of-function
transgenic mice caused misrouting of axons in the
main olfactory bulb glomerular layer and led to
exuberant growth of vomeronasal axons in the
accessory olfactory bulb. These results provided
the first in vivo evidence that implicated the
functionality of specific cell surface blood group
carbohydrates in the development of the olfactory
nerve connectivity.
Reducing A/B Antigenicity
Advances have also been made in attempts to
tackle and overcome limited blood supply. These
include improved surgical procedures that mini-
mize bleeding, the use of erythropoietin and novel
erythropoiesis-stimulating protein, preparations of
hemoglobin-based oxygen carriers and perfluoro-
carbon-based oxygen carriers, and the generation of
RBCs in vitro from hematopoietic stem cells of
diverse origins [78,79], from embryonic stem cells
[80], and from induced pluripotent stem cells [81].
Efforts have been made to produce genetically
modified pig RBCs for xenotransfusion. The use of
group O swine abbreviates the problem of AO
incompatibility [12]. To curtail the α1,3Gal epitope
problem, GGTA1 gene–knockout pigs were creat-
ed [82,83]. Hemagglutination, immunoglobulin
M/immunoglobulin G antibody binding, and com-
plement-dependent cytotoxicity were examined
using human sera [84]. Further modifications/
manipulations will be required.
The removal of A/B antigenicity from A/B/AB
RBCs has also been challenging. In the so-called
stealth RBCs approach, polyethylene glycol (PEG)
and its derivatives have been used to mask antigens
on the RBC membrane by PEGlyation [85].
Unfortunately, PEG turned out to be immunogenic
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YAMAMOTO ET AL
[86]. A 25% occurrence of anti-PEG antibody was
reported in healthy blood donors [87]. Rapid
clearance of PEGylated asparaginase was observed
for up to one third of patients treated for acute
lymphoblastic leukemia [88]. As opposed to the
introduction of a small quantity of an enzyme,
transfusion implicates the introduction of extremely
large numbers of RBCs into circulation. Therefore,
the immunogenic response against the masking
molecules has to be fully resolved before imple-
menting this technology. Another approach uses
glycosidases that hydrolyze the α1,3-glycosidic
linkage [89,90]. Enzyme-converted group O (ECO)
RBCs have been produced from group B RBCs at
the whole unit scale and subsequently transfused to
humans with some success [91]. α-Galactosidase of
green coffee bean origin was used in most cases
[89]. Such treated cells have normal in vivo life
spans in both group A and O recipients. However,
some patients developed anti-B antibody, probably
elicited by leftover B antigens. Moreover, 40% of
group O and 20% of group A sera weakly
agglutinated the B-derived ECO RBCs, manifesting
the need for a more complete enzymatic conversion
[92]. The same problem was encountered in a
greater extent with ECO RBCs prepared from A
RBCs using α-N-acetylgalactosaminidase [89].
Novel glycosidases have recently been discovered
from bacteria that hydrolyze more efficiently [93].
The ECO RBCs prepared from group A1 and B
RBCs using those glycosidases proved not to react
with anti-A monoclonal antibodies. However, they
still reacted with polyclonal human antibodies [90].
ABO Pseudoscience
ABO has also become a topic of pseudoscience.
In his book, “Eat Right 4 Your Type,” D'Adamo
[94] claimed that human ABO blood type is the
most important factor in determining a healthy
diet. He proposed distinctive diets for individuals
with different ABO groups. He reasoned that the
reactions to lectins present in food depend on the
ABO group of the individual and that the food
containing incompatible and harmful lectins would
better be avoided to minimize the toxic reactions
caused by lectin-A/B antigen interactions. No data
were presented that correlated the kinds of lectins
present in the diets and their ABO specificity.
Actually, lectins possessing high affinity to a
particular ABO group are uncommon in food,
except for some beans (see the Consortium for
ABO RESEARCH IN THE MODERN ERA OF GENOMICS
Functional Glycomics database). It is difficult to
propose “blood type diets” without knowing
which lectins are contained or absent in which
foods. Therefore, the promotion of these diets is
wrong. It may potentially harm people by
suggesting diets omitting foods of nutrient value
because of his mistaken assignments. In addition,
his contention that O, A, B, and AB groups
originated 30 000, 20 000, 10 000, and 1000 years
ago, respectively, does not fit with the current
evolutionary theory of the ABO gene [10,22]. The
genetic change responsible for the O group in
humans predates the modern human and Nean-
derthal divergence [95].
Understanding A/B Transferase Structure
There has also been progress in our understanding
of the structural bases of A and B transferases as well
as their evolutionarily related GT6 glycosyltrans-
ferases. Paralogous enzymes possess structurally
conserved regions, and in at least 1 example, a
segment was replaceable between 2 enzymes,
conferring different sugar specificity [96]. Three-
dimensional structures of A/B transferases were
determined, and the amino acid residues involved
in the recognition of donor nucleotide sugars
and acceptor substrates as well as the catalytic
center have been pinpointed [97]. These advance-
ments in enzymology and structural biology will be
separately reviewed.
IN THE FUTURE
Technological developments in the genomics
field are rapid and immense. Although DNA
microarrays are primarily used in GWAS, accom-
modating all the SNPs in the human genome will
become impossible as the number skyrockets after
genome sequencing of different individuals and
different populations. It is reasonable to assume
that exome sequencing will soon take over the
DNA microarray hybridization approach, and, in
turn, it will also be replaced by the whole genome
sequencing approach in a couple of years. As the
demand surges, the costs of these technologies will
plummet. When the goal of the $1000 genome
becomes a reality, the genotyping of ABO and
other blood group genes will be a part of genome
sequencing. When the time comes, it will no longer
be possible to call individual alleles by names.
Another nomenclature that lists all the differences
from a reference sequence may replace the current
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115
ones. For example, the O01 allele may be denoted
as ABO(261delC: 88fs+truncation) and B101
allele as ABO(297ANG; 526CNG; 657CNT;
703GNA; 796CNA; 803GNC; 930GNA: R176G;
G235S; L266M; G268A), with the A101 allele as
the standard.
Many of the associations observed between ABO
and diseases by the ABO-targeted studies will be
reevaluated by GWAS. If an association is strong,
the SNPs in the ABO locus will be identified, and
the ABO gene will be ranked high among all the
genes in the human genome. In this era of genomics
whether the association is statistically significant is
of secondary value to the ranking of the ABO gene
in the order of association. However, this does not,
in the least, mean that the results obtained from
mostly old targeted studies are useless. Actually,
targeted studies had discovered the associations
between ABO and VTE, CAD, or pancreatic cancer
long before GWAS confirmed them. Probably,
many of the associations that have been reported
over the years may be corroborated by future
GWAS studies. It should be noted, however, that
GWAS might not confirm all the associations
previously reported by targeted studies. One such
example was presented above of the association
between ABO and severe malaria, where no SNPs in
the ABO locus were identified by GWAS. Because
ABO genotyping confirmed the association with the
same specimens used for GWAS, the previous
finding was real and reproducible. This may simply
mean that the degree of association was weaker with
ABO than with HBB and 18 other loci that were
identified by GWAS.
We anticipate that future GWAS will also
identify many novel associations with ABO. As
the number increases, the time may come when no
physiological or pathological processes are dis-
cussed without considering the direct/indirect
involvement of ABO polymorphism. Then the
idea that the ABO blood type is partially related
to personality and human behavior may be
accepted, although all the claims currently made
in this regard are groundless. However, GWAS is
not almighty. As opposed to false positives
obtained by the targeted approach, false-negative
results may be problematic with the GWAS
approach. Because of the absence of appropriate
SNPs in DNA microarrays (at least in the current
format), important associations may be missed.
Certain conditional associations, strain-specific
116
associations of H pylori or NoVs, for example, will
not be identified unless the conditions are sorted out
correctly. Furthermore, care must be taken when
interpreting the results. Nonetheless, compared
with the advances we have witnessed during the
past 20 years, progress in the next few decades of
the genomics era will be extraordinary. The
characterization of the molecular mechanisms of
those associations will surely help to better
understand the roles and functions the ABO
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YAMAMOTO ET AL
genes, A/B transferases, and A/B oligosaccharide
antigens may play in a variety of physiological and
pathological processes.
ACKNOWLEDGMENTS
The authors thank Kenneth Nesmith and Ami
Yamamoto for their editorial assistance.
Funding, in part, is acknowledged for Institut de
Medicina Predictiva i Personalitzada del Càncer for
research support.
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