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Clinica Chimica Acta 444 (2015) 6671

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Clinica Chimica Acta


journal homepage: www.elsevier.com/locate/clinchim

Invited critical review

Evolutionary aspects of ABO blood group in humans


Massimo Franchini , Carlo Bonfanti
Department of Hematology and Transfusion Medicine, Azienda Ospedaliera Carlo Poma, Mantova, Italy

a r t i c l e

i n f o

a b s t r a c t

Article history:
Received 12 January 2015
Received in revised form 4 February 2015
Accepted 5 February 2015
Available online 14 February 2015

The antigens of the ABO blood group system (A, B and H determinants) are complex carbohydrate molecules
expressed on red blood cells and on a variety of other cell lines and tissues. Growing evidence is accumulating
that ABO antigens, beyond their key role in transfusion medicine, may interplay with the pathogenesis of
many human disorders, including infectious, cardiovascular and neoplastic diseases. In this narrative review,
after succinct description of the current knowledge on the association between ABO blood groups and the
most severe diseases, we aim to elucidate the particularly intriguing issue of the possible role of ABO system in
successful aging. In particular, focus will be placed on studies evaluating the ABO phenotype in centenarians,
the best human model of longevity.
2015 Published by Elsevier B.V.

Keywords:
ABO blood group
Cancers
Infections
Cardiovascular diseases
Longevity

Contents
1.
2.

Introduction . . . . . . . . . . . .
ABO blood group and human diseases
2.1.
ABO and infectious diseases . .
2.2.
ABO and cancers . . . . . . .
2.3.
ABO and cardiovascular disease
2.4.
Other diseases . . . . . . . .
3.
ABO blood group and evolution . . .
4.
Conclusions . . . . . . . . . . . .
Conicts of interest . . . . . . . . . . .
References . . . . . . . . . . . . . . .

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1. Introduction
The ABO blood group system, discovered in 1901 by the Austrian
Nobel Prize Karl Landsteiner [1], consists of three main alleles, two
co-dominant A and B and one recessive O, and is controlled by a single
gene located on the terminal portion of the long arm of chromosome
9 (9q34.2) [24]. The A and B alleles encode slightly different glycosyltransferases that act by adding N-acetylgalactosamine and D-galactose
to H substance, a joint precursor side chain which is hence ultimately
transformed into A- or B-antigen. Owing to a frameshift mutation, the O
allele does not encode a functional enzyme. Therefore, OO carriers
who lack the active form of these transferase enzymes continue to
express the basic and unmodied H structure, with a solitary terminal

Corresponding author. Tel.: +39 0376201234; fax: +39 0376220144.


E-mail address: massimo.franchini@aopoma.it (M. Franchini).

http://dx.doi.org/10.1016/j.cca.2015.02.016
0009-8981/ 2015 Published by Elsevier B.V.

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fucose moiety attached [5]. The variable combinations of the three


main alleles generate four major phenotypes, A, B, AB and O, which
are characterized by the presence (or absence) of A and B antigens on
the surface of red blood cells (RBCs) and by the presence of natural
antibodies against the antigen absent at the RBC surface in serum [1].
However, along with their expression on RBCs, ABO antigens are also
widely expressed in body uids and tissues/cell surfaces, including epithelial cells, sensory neurons, platelets and endothelia of blood vessels [6].
The term histo-blood group ABO is often used to reect the wide distribution of ABO antigens. Recent evidence suggest that the ABO system
could extend its clinical importance beyond immunohematology,
transfusion and transplantation medicine, thus playing a role in the
pathogenesis of cardiovascular, neoplastic and several other human disorders [710]. However, despite the fact that ABO antigens have been
known for more than a century, their biological signicance remains
largely elusive. Therefore, the aim of this narrative review is to summarize the current knowledge on the clinical signicance of the ABO

M. Franchini, C. Bonfanti / Clinica Chimica Acta 444 (2015) 6671

system, providing a tentative interpretation of the available literature


data according to an evolutionary perspective.
2. ABO blood group and human diseases
Although several investigators tried to authenticate the potential
association between ABO blood group and a variety of diseases over
the last 60 years, the results were controversial and somehow
disappointing [11]. In the following paragraphs and in Table 1, the
most striking associations are described.
2.1. ABO and infectious diseases
Microbial agents and humans have interacted for several thousands
of years, and it is now rather clear that infectious diseases may inuence
population genetics as well as the evolution of human genome through
selection of specic alleles able to modify the pathogenesis [12]. Since
infectious agents often use cell-surface glycosylated receptors for their
attachment, it can be easily appreciated how ABO determinants play a
key role in determining a differential susceptibility among individuals
to various infectious disorders by affecting hostpathogen interactions
through their different degrees of glycosylation. In support of this
close interaction, certain microbial parasites display a strong molecular
mimicry and share blood group antigens with their hosts [13]. A
number of examples can be found in this setting, the most interesting
involving Plasmodium falciparum and gastro-enteric pathogens.
The association between malaria and ABO system is known since
nearly 50 years [14]. It has recently been suggested that this severe
infection may have played an important role in driving the current
ABO distribution among populations in endemic areas [1523]. In a
recent review, Cserti and Dzik critically analyzed the literature on the
association between the ABO system and P. falciparum malaria, showing
that group O subjects tend to exhibit a favorable outcome than group A
individuals [18]. In their experimental studies, Fry and colleagues [22]
and Rowe and colleagues [21] provided a biological explanation for
this clinical nding. Specically, the authors found that rosettes of
P. falciparum, which are formed between parasitized and uninfected
RBCs and are responsible of vas occlusion and severe disease through
adhesion to vascular endothelium, were consistently reduced in group
O Malian children compared with non-O blood groups. The selective
survival advantage against malaria conferred by O blood type is hence
consistent with the geographic distribution of ABO antigens worldwide.
Two genome wide association studies (GWAS) conrmed the suggestive association between non-O haplotypes and severe malaria [22,23].
The association between ABO and gastric ulcer was the rst to be
identied. In the 1954 Aird and colleagues already described the higher
susceptibility of group O individuals to peptic ulcers [24]. It was later
recognized that Helicobacter pylori is the causative agent of peptic
ulcer, a disease that can be efcaciously treated by eradicating the
bacterium with antibiotics and acid secretion inhibitors. In 1993,
Boren and colleagues demonstrated that H. pylori binds to blood group

67

O Lewis b (Leb) but not A Leb, thus providing a reasonable background


for explaining the greater susceptibility of group O secretors to this
infectious agent [25]. Although subsequent studies demonstrated that
not all strains are specic for O Leb, it can be generally assumed that
H. pylori has an approximately 5-fold increased binding afnity for O
Leb compared with A Leb [26]. It is now clear that the ABO/Leb blood
group antigens represent one of the major functional receptors for
H. pylori in the gastric epithelium, and the blood group antigenbinding adhesin (BabA) has been identied as the leading mediator of
this binding [27]. The interaction is important not only for H. pylori adhesion to the stomach surface, but also to anchor the bacterial secretion
system to the host cell surface, so that bacterial virulence factors,
namely the cytotoxin associated gene (CagA), can be effectively injected
into the host cell cytosol [27].
Susceptibility to norovirus infection, which is responsible for the
vast majority of cases of acute gastroenteritis in humans, is also closely
associated with expression of ABH and Le antigens in the gastrointestinal tract [28,29]. The early study published by Hutson and colleagues in
2002 showed that individuals with an O phenotype were more likely to
be infected with norovirus (odds ratio [OR]: 11.8; 95% CI: 1.3103),
whereas subjects with a B blood group antigen had a reduced risk of infection (OR: 0.096; 95% CI: 0.0160.56) and symptomatic disease (OR:
0; 95% CI: 00.999) [30]. Further studies have disclosed that norovirus
GI-1 (Norwalk virus) binds preferably to O secretor cells, whereas
GII-3 and GII-4 strains bind preferably to A secretor cells [31,32], thus
suggesting that the association of ABO blood group antigens with
susceptibility to norovirus infection could be strain-dependent rather
than genogroup-dependent.
Association between ABO blood group antigens and other enteric
pathogens has also been described. Harris and colleagues showed that
the phenotype group O confers a greater likelihood of severe infection
from Vibrio cholerae than non-O blood group phenotypes [33]. Accordingly, Glass and colleagues suggested that the low prevalence of group
O and the high prevalence of B blood group observed in the Ganges
Delta in Bangladesh could be directly related to selective pressure
from this infectious disease, which is reportedly endemic in that area
[34]. Similarly, in an outbreak of gastrointestinal infections caused by
Escherichia coli O157 in Scotland in 1996, 87.5% (14/16) of patients
who died were from group O [35].
2.2. ABO and cancers
Another area that has been extensively studied over the last ve
decades is that of the association between the ABO blood group types
and cancer, with and the most consistent relationship being observed
for pancreatic and gastric cancers [36]. In the Nurses' Health Study
and Health Professionals Follow-up Study, Wolpin and colleagues [37]
found that participants with blood groups A, AB or B were more likely
to develop pancreatic cancer compared to those with blood group O
(adjusted hazard ratio [aHR] 1.44; 95% CI: 1.141.82). Further studies
conrmed the protective effect of O group and showed that the A1 allele

Table 1
ABO blood groups and diseases: summary of clinical evidences on the association.
Category

Disease

ABO association

References

Infectious diseases

Plasmodium falciparum malaria


Helicobacter pylori-associated peptic ulcer
Norovirus-associated acute gastroenteritis
Vibrio cholerae infection
Escherichia coli infection
Pancreatic cancer
Gastric cancer
VTE
MI, IS and PAD
Parkinson's disease
Incident cognitive impairment

O blood type protects against severe malaria


O Leb is associated with H. pylori infection
O blood type is associated with norovirus infection
O blood type is associated with severe infection
O blood type is associated with severe infection
O blood type has a protective effect against pancreatic cancer
A blood type is associated with an increased risk of gastric cancer
Non-O blood type is associated with an increased VTE risk
O blood type has a protective effect against MI, IS, and PAD risks
B blood group is associated with Parkinson's disease
AB blood group is associated with incident cognitive impairment

[1423]
[2427]
[2832]
[33,34]
[35]
[37,38]
[39,40]
[50,51,56,57]
[5355]
[65]
[67]

Cancers
Cardiovascular diseases
Other diseases

Abbreviations: VTE, venous thromboembolism, MI, myocardial infarction, IS, ischemic stroke, and PAD, peripheral arterial disease.

68

M. Franchini, C. Bonfanti / Clinica Chimica Acta 444 (2015) 6671

(which is responsible for an increased glycosyltransferase activity)


confers a greater risk of pancreatic cancer than the A2 allele [38].
As regards gastric cancer, the higher prevalence of blood group A in
patients with carcinoma of the stomach historically observed by several
studies [36] has been recently conrmed in a large prospective
population-based study involving more than one million of Scandinavian blood donors, who were followed for up to 35 years (OR 1.20;
95% CI: 1.021.42) [39]. A similar nding emerged also in the recently
published Golestan Cohort Study, which analyzed the association
between the ABO blood groups, overall and cause-specic mortality in
over 50,000 people recruited between the 2004 and 2008 [40].
Although the underlying mechanisms linking the ABO blood group
system and cancer are still largely unknown, one plausible hypothesis involves the ABO blood group-driven regulation of circulating levels of several inammatory adhesion molecules (i.e., soluble E-selectin, P-selectin
and intercellular adhesion molecule-1), which may play a key role in the
process of tumorigenesis [36]. Moreover, the recent discovery that von
Willebrand factor (VWF), which carries the ABO blood group determinants, is an important modulator of angiogenesis and apoptosis offers
an alternative, particularly intriguing pathogenetic hypothesis [41].
2.3. ABO and cardiovascular disease
The ABO blood group system exerts a profound inuence on hemostasis, particularly on VWF and, consequently, on factor VIII (FVIII) plasma levels, which are both important prothrombotic risk factors [42]. It is
well known, indeed, that individuals of non-O blood group status have
VWF and FVIII plasma levels that are approximately 25% higher than
the O blood group subjects [43]. The molecular basis of this phenomenon is consistent with the presence of ABH antigenic structures on
circulating VWF, which are hence capable to modulate VWF activity
through different degrees of glycosylation [44]. Indeed, the addition of
A and B antigens generated by A and B glycosyltransferase enzymes
on the existing VWF H oligosaccharides has been found to positively
modulate VWF levels and activity [44]. With this background, it this
not surprising that a number of studies were planned to investigate
the existence of an association between the ABO blood type and cardiovascular disease over the last 50 years [44,45]. In this chapter, we focus
on the contribution of our group to this eld. To assess the hypothesis

that ABO subtypes carry different thrombotic risks (see Fig. 1), we rst
performed three systematic reviews and meta-analysis to analyze the
existing literature on the association between the ABO blood group
and hemostasis abnormalities [4648]. In the rst meta-analysis, including 38 studies with 10,305 VTE cases of venous thromboembolism
(VTE), we concluded that a non-O blood group phenotype carries an approximately twofold increased risk of venous thrombosis (pooled OR:
2.08; 95% CI: 1.83, 2.37; P b 0.00001) [46]. A weaker, but still signicant, association was found between the non-O blood type and arterial
thrombosis (OR of 1.28 [95% CI: 1.171.40; P b 0.001] for myocardial infarction and 1.17 [95% CI: 1.011.35; P = 0.03] for ischemic stroke) in
another more recent systematic review conducted on 28 studies enrolling 12,231 patients with myocardial infarction or ischemic stroke [47].
The fact that the association between the non-O blood group and the arterial vascular risk seems to lower than that between the non-O blood
group and VTE is particularly intriguing, also considering that higher
VWF and FVIII levels are predictors of an increased venous, rather
than arterial, risk [49]. If these two meta-analyses highlighted the important role of the non-O blood type in the pathogenesis of thrombosis,
in another meta-analysis evaluating 22 studies with 9468 bleeding patients, we demonstrated that the O blood group was associated with
VWF levels 2535% lower than the non-O blood groups, as well as
with a moderately increased hemorrhagic risk (pooled OR 1.33; 95%
CI: 1.251.42; P b 0.001) [48]. Following these three meta-analyses, results were validated in our clinical experience. In a casecontrol study
comparing the ABO blood group distribution in 77 consecutive patients
with cerebral vein thrombosis (CVT) and 4272 blood donors, we observed a higher prevalence of the non-O blood type in CVT patients
(75% versus 55%) [50]. Therefore, carriers of the non-O blood group
were found to have a 2.4-fold increase of risk of CVT (OR 2.44; 95% CI:
1.424.26; P = 0.0008). Even more impressive results emerged from
another study which analyzed the relationship between the ABO
blood group and the occurrence of residual vein obstruction (RVO) in
268 patients with a rst episode of deep vein thrombosis [51]. Surprisingly, the non-O blood type was independently associated with an
almost 4-fold increased risk of RVO persistence (OR 3.71; 95% CI:
1.618.56; P b 0.01). Another eld of our investigation was that of the
association between the ABO blood type and arterial thrombosis, in
which the evidence of the literature was less robust than that regarding

Fig. 1. The hypothesis of ABO-related thrombotic risk.

M. Franchini, C. Bonfanti / Clinica Chimica Acta 444 (2015) 6671

the non-O blood group and venous thrombosis [52]. In a retrospective


casecontrol study, we observed a statistically signicant difference of
the prevalence of the O blood group in patients with coronary heart
disease versus healthy controls (40.9% versus 44.5%; P = 0.01) [53].
Therefore, the O blood group was found to confer a 10% protective effect
against the risk of developing coronary artery disease, which was
maintained also in a logistic regression model including possible
confounding factors. A similar protective effect for the O group was
also observed for the risk of developing peripheral arterial thrombosis
in patients with atrial brillation [54]. Thanks to our research and that
of other investigators [5557], the ABO blood type has now been included in a number of scores evaluating the thrombotic risk. For instance,
Yang and colleagues assessed the association of blood groups with the
National Institute of Health Stroke Scale (NIHSS) score in young stroke
patients, and identied the AB subtype as a major predictor of stroke
severity [58]. In addition, Gong and colleagues investigated the relation
of the ABO blood type and the severity of coronary atherosclerosis
assessed by Gensini score, and concluded that blood group A was an independent risk factor (OR 1.44; 95% CI: 1.161.80; P = 0.001), whereas
group O was a protective factor (OR 0.77; 95% CI: 0.65-0.92; P = 0.004)
for serious coronary atherosclerosis [59].
Concerning the suggested moderately increased hemorrhagic risk
associated with the O blood type [48], another interesting eld of research is to investigate whether or not the O group could be implicated
in the development of hemorrhagic adverse events in patients with
other concomitant bleeding risk factors. To address this issue, we
established the relationship existing between the ABO blood group
and bleeding risk during treatment with vitamin K antagonists (VKA)
by comparing the ABO distribution between VKA patients with (n =
183) and without (n = 166) hemorrhage [60]. Although we could not
nd an association between the ABO blood group and the risk of developing VKA-related bleeding complications, we observed a higher prevalence, although not statistically signicant, of subjects with the O blood
group among patients with more severe hemorrhages. This evidence
suggests that the O blood group could be involved in the degree of severity of bleeding complications. To further elucidate this hypothesis,
we conducted a retrospective cohort study on 676 patients with major
hemorrhagic events, 99 of whom were undergoing VKA therapy [61].
Notably, we found a signicantly higher prevalence of the O blood
type in orally anti-coagulated patients with gastrointestinal hemorrhage than in those with cerebral hemorrhage (60% versus 33%, P =
0.01), thus showing that the O blood group (which has the lowest
VWF levels among the ABO blood groups) is an important risk factor
for severe mucosal hemorrhage in patients with other concomitant
risk factors for bleeding. This nding is not particularly surprising if
one considers that the hemostatic role of VWF is particularly critical at
mucosal sites. Indeed, patients with congenital von Willebrand disease
experience a bleeding diathesis predominantly at mucosal sites, rather
than soft tissue bleeding, intracranial hemorrhage and hemarthroses
which are, however, more frequent in patients with severe congenital
hemophilia [62].

69

2.4. Other diseases


Among the various areas of research in this setting, there is a particular interest toward the association between the ABO blood type and
neurological disorders, also considering that the ABO groups play a
key role in neurogenesis [4]. A few studies have addressed this issue,
and conicting results were generated. The most consisting data regard
patients with Parkinson's disease. Although no signicant difference
was found in the ABO blood group distribution in Parkinson's disease
patients compared with controls in two studies conducted by Strang
[63] and by Chia and Liu [64], in another study published by Kak and
Gordon an excess of blood group B was described [65]. No signicant
association with the ABO blood groups was reported by Renvoize in
patients with Alzheimer's disease [66], while in a recent study the
blood group AB and higher FVIII were associated with incident cognitive
impairment [67]. This latter nding is very interesting, and is seemingly
in agreement with previous observations of an involvement of a
coagulation system in the pathogenesis of some neurodegenerative
disorders [68].
3. ABO blood group and evolution
The ABO blood group polymorphism represents an admirable example of evolutionary adaptation. An effective means to study this
phenomenon is that of investigating the association between the ABO
and various diseases. Another important issue to be addressed is whether the ABO blood groups may contribute or not to favor individuals' lifeextension by eluding most serious diseases. For instance, the hypothesis
that the non-O blood types could confer a survival advantage to early
humans by protecting them from hemorrhages is particularly intriguing. A similar argument has been raised for the occurrence of the gainof-function prothrombotic mutations factor V Leiden and prothrombin
20210GA, which emerged approximately 20,00025,000 years ago
and have been signicantly associated with a lower bleeding-related
risk of death during pregnancy [69,70].
Different approaches have been attempted to elucidate the role of
the ABO blood type on successful aging, as summarized in Table 2
[71]. In particular, investigators focused their research on centenarians,
who represent a particularly suitable model for studying the possible
factors contributing to extreme longevity [72]. A signicant increase of
the A blood type was observed by Murray in a study conducted more
than half a century ago in healthy elderly males from the UK, although
very few subjects were over 100 years of age [73]. In a study carried
out on a small sample of very long-lived Turkish population, no similar
association was found [74]. Likewise, in a more recent study conducted
in Sicilian centenarians, the ABO blood groups did not appear to affect
longevity [75]. In a survey of 269 Japanese centenarians, B allele was
found to be associated with longevity [76]. By contrast, in a further
study conducted in the US by Brecher and Hay [77], the authors retrospectively reviewed the blood group distribution in a cohort of patients
stratied by a decade of death, and found that the group B patients had

Table 2
Main studies on the association between ABO blood groups and longevity.
First author, year

Country

Study population

Main results

Ref.

Murray, 1961
Sturgeon et al., 1969
Shimizu et al., 2004

United Kingdom
Turkey
Japan

633 persons aged over 64 years/1482 blood donors


50 persons aged 90140 years/110 controls
269 centenarians/7153 controls

[73]
[74]
[76]

Vasto et al., 2011


Brecher and Hay, 2011
Mengoli, 2014
Coppola, 2003

Italy
USA
Italy
Italy

38 centenarians/59 controls
772 patients died
28,129 subjects aged 0103 years
74 centenarians/110 controls

An excess of group A was observed in healthy elderly males


No association was found between ABO blood groups and longevity
B blood type was more frequent among centenarians than among
controls (29.4% versus 21.9%, P = 0.04)
No association was found between ABO blood groups and longevity
The percentage of patients with group B declined with age (P b 0.01)
The percentage of subject with group B declined with age (P b 0.001)
No statistical signicant difference was found in O blood type distribution
between centenarians and controls (43% versus 35%, P = NS).a VWF levels
were signicantly higher in centenarians than in controls regardless of the
ABO blood type

Chi square analysis.

[75]
[77]
[78]
[80]

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M. Franchini, C. Bonfanti / Clinica Chimica Acta 444 (2015) 6671

an overall decreased survival. This latter nding is in keeping with


results of another recent study, with a similar design, published by our
group. In brief, a negative association between the B blood group and
life-expectancy was found in a large cohort (n = 28,129) of Italian
subjects [78]. An explanation for this occurrence could be brought as
an association between the B blood type and some aging-associated
conditions, including degenerative neurological and neoplastic disorders, reported by some investigators [79]. Another interesting result
from our study was that seven out of the ten centenarians (70%)
subjects were of the O blood type, which, as previously mentioned,
has been found to be a protective factor against cardiovascular diseases
through its effect on VWF levels in several studies and meta-analyses.
This specic issue was analyzed by Coppola and colleagues [80] in a
casecontrol study comparing the VWF levels and ABO blood group
distribution in 74 centenarians and 110 controls. Surprisingly, the antigenic and functional (ristocetin cofactor) plasma levels of the VWF were
signicantly higher in centenarians than in controls without signicant
difference between the blood group O or non-O, thus suggesting
the existence of mechanisms other than those playing a key role in
successful aging. Indeed, a series of genome-wide association studies
demonstrated that the ABO locus is a main determinant of the serum
levels of soluble intercellular adhesion molecule-1 (sICAM-1), P-selectin,
S-selectin and interleukin-6 (IL-6) [8185]. Since these inammatory
biomarkers are involved in several diseases, including cardiovascular
disorders, they may hence play a key role in longevity as well.
4. Conclusions
There is a growing evidence that the ABO blood groups may be able
to inuence the individuals' predisposition to several disorders through
their capacity of modulating the hemostatic system and the inammatory response. In particular, the different prevalence of the ABO group
genotypes among populations in various geographical areas was
found to be driven by some pathogens, most notably P. falciparum and
Vibrio cholera. Other consistent data involve an association between
the non-O blood type and cardiovascular disease, especially VTE, so
that the addition of the ABO phenotype to the current thrombotic risk
scores will probably allow the more accurate calculation of the thrombotic risk of each patient, in order to better tailor primary or secondary
antithrombotic prophylaxis.
The possibility that the ABO gene may be implied in longevity is still
a matter of debate. The studies on the ABO phenotype in centenarians,
the best example of successful aging, are largely inconclusive. The ndings from Brecher and Hay [77] and our [78] studies that the B allele is a
marker for earlier death rather than for longevity are particular intriguing, but need to be supported by further evidences from larger studies.
In conclusion, the issue of longevity is particularly challenging. According to the current knowledge, the biological explanation is seemingly
multifactorial, being the results of several inherited (i.e., polymorphisms
in the ABO, HLA [human leukocyte antigen] and inammatory response
regulating genes) and environmental factors (i.e., dietary, physical,
mental and social activity, air quality) that interplay to cope with the
aging process [86].
Conicts of interest
The authors declare that they have no conicts of interest regarding
this manuscript.
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