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Invited critical review

Evolutionary aspects of ABO blood group in humansMassimo Franchini ⁎ , Carlo BonfantiDepartment of Hematology and Transfusion Medicine, Azienda Ospedaliera Carlo Poma, Mantova, Italy

a b s t r a c ta r t i c l e i n f o

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

Available online 14 February 2015

Keywords:ABO blood groupCancersInfectionsCardiovascular diseasesLongevity

The antigens of the ABO blood group system (A, B and H determinants) are complex carbohydrate moleculesexpressed on red blood cells and on a variety of other cell lines and tissues. Growing evidence is accumulatingthat 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 themost severe diseases, we aim to elucidate the particularly intriguing issue of the possible role of ABO system insuccessful 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.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. ABO blood group and human diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

2.1. ABO and infectious diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.2. ABO and cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.3. ABO and cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.4. Other diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. ABO blood group and evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Con icts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

The ABO blood group system, discovered in 1901 by the AustrianNobel Prize Karl Landsteiner [1], consists of three main alleles, twoco-dominant A and B and one recessive O, and is controlled by a singlegene located on the terminal portion of the long arm of chromosome9 (9q34.2) [2– 4]. The A and B alleles encode slightly different glycosyl-transferases that act by adding N-acetylgalactosamine and D-galactoseto H substance, a joint precursor side chain which is hence ultimatelytransformed into A- or B-antigen. Owing to a frameshift mutation , the Oallele does not encode a functional enzyme. Therefore, OO carrierswho lack the active form of these transferase enzymes continue toexpress the basic and unmodi ed H structure, with a solitary terminal

fucose moiety attached [5] . The variable combinations of the threemain alleles generate four major phenotypes, A, B, AB and O, whichare characterized by the presence (or absence) of A and B antigens onthe surface of red blood cells (RBCs) and by the presence of naturalantibodies against the antigen absent at the RBC surface in serum [1].However, along with their expression on RBCs, ABO antigens are alsowidely expressed in body uids and tissues/cell surfaces , including epithe-lial cells, sensory neurons, platelets and endothelia of blood vessels [6].The term histo-blood group ABO is often used to re ect thewide distri-bution of ABO antigens. Recent evidence suggest that the ABO systemcould extend its clinical importance beyond immunohematology,transfusion and transplantation medicine, thus playing a role in thepathogenesis of cardiovascular, neoplasticand several otherhumandis-orders [7– 10]. However, despite the fact that ABO antigens have beenknown for more than a century, their biological signi cance remainslargely elusive. Therefore, the aim of this narrative review is to summa-rize the current knowledge on the clinical signi cance of the ABO

Clinica Chimica Acta 444 (2015) 66 – 71

⁎ Corresponding author. Tel.: +39 0376201234; fax: +39 0376220144.E-mail address: [email protected] (M. Franchini).

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system, providing a tentative interpretation of the available literaturedata according to an evolutionary perspective.

2. ABO blood group and human diseases

Although several investigators tried to authenticate the potentialassociation between ABO blood group and a variety of diseases overthe last 60 years, the results were controversial and somehow

disappointing [11] . In the following paragraphs and in Table 1 , themost striking associations are described.

2.1. ABO and infectious diseases

Microbial agents and humans have interacted for several thousandsof years,andit is nowratherclear that infectious diseases mayin uencepopulation genetics as well as the evolution of human genome throughselection of speci c alleles able to modify the pathogenesis [12]. Sinceinfectious agents often use cell-surface glycosylated receptors for theirattachment, it can be easily appreciated how ABO determinants play akey role in determining a differential susceptibility among individualsto various infectious disorders by affecting host – pathogen interactionsthrough their different degrees of glycosylation. In support of thisclose interaction, certain microbial parasites display a strong molecularmimicry and share blood group antigens with their hosts [13] . Anumber of examples can be found in this setting, the most interestinginvolving Plasmodium falciparum and gastro-enteric pathogens.

The association between malaria and ABO system is known sincenearly 50 years [14] . It has recently been suggested that this severeinfection may have played an important role in driving the currentABO distribution among populations in endemic areas [15 – 23] . In arecent review, Cserti and Dzik critically analyzed the literature on theassociation between theABOsystemand P. falciparum malaria, showingthat group O subjects tend to exhibit a favorable outcome than group Aindividuals [18]. In their experimental studies, Fry and colleagues [22]and Rowe and colleagues [21] provided a biological explanation forthis clinical nding. Speci cally, the authors found that rosettes of P. falciparum , which are formed between parasitized and uninfectedRBCs and are responsible of vas occlusion and severe disease throughadhesion to vascular endothelium, were consistently reduced in groupO Malian children compared with non-O blood groups. The selectivesurvival advantage against malaria conferred by O blood type is henceconsistent with the geographic distribution of ABO antigens worldwide.Two genome wide association studies (GWAS) con rmed the sugges-tive association between non-O haplotypes and severe malaria [22,23] .

The association between ABO and gastric ulcer was the rst to beidenti ed. In the 1954 Aird and colleagues already described the highersusceptibility of group O individuals to peptic ulcers [24]. It was laterrecognized that Helicobacter pylori is the causative agent of pepticulcer, a disease that can be ef caciously treated by eradicating thebacterium with antibiotics and acid secretion inhibitors. In 1993,Boren and colleagues demonstrated that H. pylori binds to blood group

O Lewis b (Leb ) but not A Le b , thus providing a reasonable backgroundfor explaining the greater susceptibility of group O secretors to thisinfectious agent [25]. Although subsequent studies demonstrated thatnot all strains are speci c for O Leb , it can be generally assumed thatH. pylori has an approximately 5-fold increased binding af nity for OLeb compared with A Le b [26] . It is now clear that the ABO/Le b bloodgroup antigens represent one of the major functional receptors forH. pylori in the gastric epithelium, and the blood group antigen-

binding adhesin (BabA) has been identi ed as the leading mediator of this binding [27]. The interaction is important not only for H. pylori ad-hesion to the stomach surface, but also to anchor the bacterial secretionsystem to the host cell surface, so that bacterial virulence factors,namelythe cytotoxinassociated gene (CagA),can be effectively injectedinto the host cell cytosol [27].

Susceptibility to norovirus infection, which is responsible for thevast majority of cases of acute gastroenteritis in humans, is also closelyassociated with expression of ABH and Le antigens in the gastrointesti-nal tract [28,29] . The early study published by Hutson and colleagues in2002 showed that individuals with an O phenotype were more likely tobe infected with norovirus (odds ratio [OR]: 11.8; 95% CI: 1.3 – 103),whereassubjects with a B blood groupantigen had a reduced risk of in-fection (OR: 0.096; 95% CI: 0.016 – 0.56) and symptomatic disease (OR:0; 95% CI: 0– 0.999) [30]. Further studies have disclosed that norovirusGI-1 (Norwalk virus) binds preferably to O secretor cells, whereasGII-3 and GII-4 strains bind preferably to A secretor cells [31,32] , thussuggesting that the association of ABO blood group antigens withsusceptibility to norovirus infection could be strain-dependent ratherthan genogroup-dependent.

Association between ABO blood group antigens and other entericpathogens has also been described. Harris and colleagues showed thatthe phenotype group O confers a greater likelihood of severe infectionfrom Vibrio cholerae than non-O blood group phenotypes [33]. Accord-ingly, Glass and colleagues suggested that the low prevalence of groupO and the high prevalence of B blood group observed in the GangesDelta in Bangladesh could be directly related to selective pressurefrom this infectious disease, which is reportedly endemic in that area[34]. Similarly, in an outbreak of gastrointestinal infections caused byEscherichia coli O157 in Scotland in 1996, 87.5% (14/16) of patientswho died were from group O [35].

2.2. ABO and cancers

Another area that has been extensively studied over the last vedecades is that of the association between the ABO blood group typesand cancer, with and the most consistent relationship being observedfor pancreatic and gastric cancers [36]. In the Nurses' Health Studyand Health Professionals Follow-up Study, Wolpin and colleagues [37]found that participants with blood groups A, AB or B were more likelyto develop pancreatic cancer compared to those with blood group O(adjusted hazard ratio [aHR] 1.44; 95% CI: 1.14 – 1.82). Further studiescon rmedthe protectiveeffect of O group and showed that theA1 allele

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

Category Disease ABO association References

Infectious diseases – Plasmodium falciparum malaria O blood type protects against severe malar ia [14– 23]– Helicobacter pylori -associated peptic ulcer O Le b is associated with H. pylori infection [24– 27]– Norovirus-associated acute gastroenteritis O blood type is associated with norovirus infection [28– 32]– Vibrio cholerae in fection O blood type is associated with severe infection [33,34]– Escherichia coli infection O blood type is associated with severe infection [35]

Cancers – Pancreatic cancer O blood type has a protective effect against pancreatic cancer [37,38]– Gastric cance r A blood type is associated wi th an increased risk o f gastric cancer [39,40]

Cardiovascular diseases – VTE Non-O blood type is associated with an increased VTE risk [50,51,56,57]– MI, IS and PAD O blood type has a protective effect against MI, IS, and PAD risks [53– 55]

Other diseases – Parkinson's disease B blood g roup is associated with Parkinson's disease [65]– Incident cognitive impairment AB blood group is associated with incident cognitive impairment [67]

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

67M. Franchini, C. Bonfanti / Clinica Chimica Acta 444 (2015) 66 –71


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(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 inpatients withcarcinoma of thestomach historically observed by severalstudies [36] has been recently con rmed in a large prospectivepopulation-based study involving more than one million of Scandina-vian blood donors, who were followed for up to 35 years (OR 1.20;95% CI: 1.02– 1.42) [39]. A similar nding emerged also in the recently

published Golestan Cohort Study, which analyzed the associationbetween the ABO blood groups, overall and cause-speci c mortality inover 50,000 people recruited between the 2004 and 2008 [40].

Although the underlying mechanisms linking the ABO blood groupsystem andcancer are still largelyunknown,oneplausible hypothesis in-volves theABOblood group-drivenregulation of circulating levels of sev-eral in ammatory adhesion molecules (i.e., soluble E-selectin, P-selectinandintercellular adhesionmolecule-1), whichmay play a keyrole in theprocess of tumorigenesis [36]. Moreover, the recent discovery that vonWillebrand factor (VWF), which carries the ABO blood group determi-nants, is an important modulator of angiogenesis and apoptosis offersan alternative, particularly intriguing pathogenetic hypothesis [41].

2.3. ABO and cardiovascular disease

The ABO blood group system exerts a profound in uence on hemo-stasis, particularlyon VWFand, consequently, on factor VIII (FVIII) plas-ma levels, which areboth importantprothrombotic risk factors [42] .Itiswell known, indeed, that individuals of non-O blood group status haveVWF and FVIII plasma levels that are approximately 25% higher thanthe O blood group subjects [43]. The molecular basis of this phenome-non is consistent with the presence of ABH antigenic structures oncirculating VWF, which are hence capable to modulate VWF activitythrough different degrees of glycosylation [44]. Indeed, the addition of A and B antigens generated by A and B glycosyltransferase enzymeson the existing VWF H oligosaccharides has been found to positivelymodulate VWF levels and activity [44] . With this background, it thisnot surprising that a number of studies were planned to investigatethe existence of an association between the ABO blood type and cardio-vascular disease over the last 50 years [44,45] . In this chapter, we focuson the contribution of our group to this eld. To assess the hypothesis

that ABO subtypes carry different thrombotic risks (see Fig. 1), we rstperformed three systematic reviews and meta-analysis to analyze theexisting literature on the association between the ABO blood groupand hemostasis abnormalities [46 – 48] . In the rst meta-analysis, in-cluding 38 studies with 10,305 VTE cases of venous thromboembolism(VTE),we concluded that a non-O blood group phenotypecarries an ap-proximately 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 signi -

cant, association was found between the non-O blood type and arterialthrombosis (OR of 1.28 [95% CI: 1.17 – 1.40; P b 0.001] for myocardial in-farction and 1.17 [95% CI: 1.01 – 1.35; P = 0.03] for ischemic stroke) inanother more recent systematic review conducted on 28 studies enroll-ing 12,231 patients with myocardial infarction or ischemic stroke [47].Thefact that theassociation between thenon-O blood group andthear-terial vascular risk seems to lower than that between the non-O bloodgroup and VTE is particularly intriguing, also considering that higherVWF and FVIII levels are predictors of an increased venous, ratherthan arterial, risk [49]. If these two meta-analyses highlighted the im-portant role of the non-O blood type in the pathogenesis of thrombosis,in another meta-analysis evaluating 22 studies with 9468 bleeding pa-tients, we demonstrated that the O blood group was associated withVWF levels 25 – 35% lower than the non-O blood groups, as well aswith a moderately increased hemorrhagic risk (pooled OR 1.33; 95%CI: 1.25– 1.42; P b 0.001) [48]. Following these three meta-analyses, re-sults were validated in our clinical experience. In a case – control studycomparing the ABO blood group distribution in 77 consecutive patientswith cerebral vein thrombosis (CVT) and 4272 blood donors, we ob-served a higher prevalence of the non-O blood type in CVT patients(75% versus 55%) [50] . Therefore, carriers of the non-O blood groupwere found to have a 2.4-fold increase of risk of CVT (OR 2.44; 95% CI:1.42 – 4.26; P = 0.0008). Even more impressive results emerged fromanother study which analyzed the relationship between the ABOblood group and the occurrence of residual vein obstruction (RVO) in268 patients with a rst episode of deep vein thrombosis [51]. Surpris-ingly, the non-O blood type was independently associated with analmost 4-fold increased risk of RVO persistence (OR 3.71; 95% CI:1.61 – 8.56; P b 0.01). Another eld of our investigation was that of theassociation between the ABO blood type and arterial thrombosis, inwhich the evidence of the literature was less robust than that regarding

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

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the non-O blood group and venous thrombosis [52]. In a retrospectivecase – control study, we observed a statistically signi cant difference of the prevalence of the O blood group in patients with coronary heartdisease versus healthy controls (40.9% versus 44.5%; P = 0.01) [53] .Therefore, theO blood group wasfound to confera 10%protective effectagainst the risk of developing coronary artery disease, which wasmaintained also in a logistic regression model including possibleconfounding factors. A similar protective effect for the O group was

also observed for the risk of developing peripheral arterial thrombosisin patients with atrial brillation [54]. Thanks to our research and thatof otherinvestigators [55– 57], theABOblood type has now beeninclud-ed in a number of scores evaluating the thrombotic risk. For instance,Yang and colleagues assessed the association of blood groups with theNational Institute of Health Stroke Scale (NIHSS) score in young strokepatients, and identi ed the AB subtype as a major predictor of strokeseverity [58]. In addition, Gong and colleagues investigated the relationof the ABO blood type and the severity of coronary atherosclerosisassessed by Gensini score, and concluded that blood group A wasan in-dependent risk factor (OR1.44; 95% CI: 1.16 – 1.80; P = 0.001), whereasgroup 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 riskassociated with the O blood type [48], another interesting eld of re-search is to investigate whether or not the O group could be implicatedin the development of hemorrhagic adverse events in patients withother concomitant bleeding risk factors. To address this issue, weestablished the relationship existing between the ABO blood groupand 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 devel-oping VKA-related bleeding complications, we observed a higher prev-alence, although not statistically signi cant, of subjects with theO bloodgroup among patients with more severe hemorrhages. This evidencesuggests that the O blood group could be involved in the degree of se-verity of bleeding complications. To further elucidate this hypothesis,we conducted a retrospective cohort study on 676 patients with majorhemorrhagic events, 99 of whom were undergoing VKA therapy [61].Notably, we found a signi cantly higher prevalence of the O bloodtype in orally anti-coagulated patients with gastrointestinal hemor-rhage than in those with cerebral hemorrhage (60% versus 33%, P =0.01), thus showing that the O blood group (which has the lowestVWF levels among the ABO blood groups) is an important risk factorfor severe mucosal hemorrhage in patients with other concomitantrisk factors for bleeding. This nding is not particularly surprising if one considers that the hemostatic role of VWF is particularly critical atmucosal sites. Indeed, patients with congenital von Willebrand diseaseexperience a bleeding diathesis predominantly at mucosal sites, ratherthan soft tissue bleeding, intracranial hemorrhage and hemarthroseswhich are, however, more frequent in patients with severe congenitalhemophilia [62].

2.4. Other diseases

Among the various areas of research in this setting, there is a partic-ular interest toward the association between the ABO blood type andneurological disorders, also considering that the ABO groups play akey role in neurogenesis [4]. A few studies have addressed this issue,and con icting results were generated. The most consisting data regardpatients with Parkinson's disease. Although no signi cant difference

was found in the ABO blood group distribution in Parkinson's diseasepatients compared with controls in two studies conducted by Strang[63] and by Chia and Liu [64], in another study published by Kak andGordon an excess of blood group B was described [65] . No signi cantassociation with the ABO blood groups was reported by Renvoize inpatients with Alzheimer's disease [66], while in a recent study theblood group AB andhigherFVIIIwereassociated with incident cognitiveimpairment [67] . This latter nding is very interesting, and is seeminglyin agreement with previous observations of an involvement of acoagulation system in the pathogenesis of some neurodegenerativedisorders [68].

3. ABO blood group and evolution

TheABO blood group polymorphismrepresents an admirableexam-ple of evolutionary adaptation. An effective means to study thisphenomenon is that of investigating the association between the ABOandvariousdiseases. Another importantissue to be addressedis wheth-er the ABOblood groups may contribute or not to favor individuals' life-extensionby eluding most serious diseases.For instance, thehypothesisthat the non-O blood types could confer a survival advantage to earlyhumans by protecting them from hemorrhages is particularly intrigu-ing. A similar argument has been raised for the occurrence of the gain-of-function prothrombotic mutations factor V Leiden and prothrombin20210GA, which emerged approximately 20,000 – 25,000 years agoand have been signi cantly associated with a lower bleeding-relatedrisk 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 possiblefactors contributing to extreme longevity [72]. A signi cant increase of the A blood type was observed by Murray in a study conducted morethan half a century ago in healthy elderly males from the UK, althoughvery few subjects were over 100 years of age [73] . In a study carriedout on a small sample of very long-lived Turkish population, no similarassociation was found [74]. Likewise, in a more recent study conductedin Sicilian centenarians, the ABO blood groups did not appear to affectlongevity [75] . In a survey of 269 Japanese centenarians, B allele wasfound to be associated with longevity [76]. By contrast, in a furtherstudy conducted in the US by Brecher and Hay [77], the authors retro-spectively reviewed the blood group distribution in a cohort of patientsstrati ed by a decade of death, and found that the group B patients had

Table 2Main studies on the association between ABO blood groups and longevity.

First author, year Country Study population Main results Ref.

Murray, 1961 United Kingdom 633 persons aged over 64 years/1482 blood donors An excess of group A was observed in healthy elderly males [73]Sturgeon et al ., 1969 Turkey 50 persons aged 90 – 140 years/110 controls No association was found between ABO blood groups and longevity [74]Shimizu et al., 2004 Japan 269 centenarians/7153 controls B blood type was more frequent among centenarians than among

controls (29.4% versus 21.9%, P = 0.04)[76]

Vasto et a l. , 2011 I taly 38 centenarians/59 controls No association was found between ABO blood groups and longevi ty [75]Brecher and Hay, 2011 U SA 772 patients died The percentage of patients with group B declined with age (P b 0.01) [77]Mengoli, 2014 Italy 28,129 subjects aged 0 – 103 years The percentage of subject with group B declined with age (P b 0.001) [78]Coppola, 2003 Italy 74 centenarians/110 controls No statistical signi cant difference was found in O blood type distribution

between centenarians and controls (43% versus 35%,P = NS). a VWF levelswere signi cantly higher in centenarians than in controls regardless of theABO blood type

[80]

a

Chi square analysis.



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an overall decreased survival. This latter nding is in keeping withresults of another recent study, with a similar design, published by ourgroup. In brief, a negative association between the B blood group andlife-expectancy was found in a large cohort (n = 28,129) of Italiansubjects [78] . An explanation for this occurrence could be brought asan association between the B blood type and some aging-associatedconditions, including degenerative neurological and neoplastic disor-ders, 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 diseasesthrough its effect on VWF levels in several studies and meta-analyses.This speci c issue was analyzed by Coppola and colleagues [80] in acase – control study comparing the VWF levels and ABO blood groupdistribution in 74 centenarians and 110 controls. Surprisingly, the anti-genicandfunctional (ristocetin cofactor)plasma levelsof theVWF weresigni cantly higher in centenarians than in controls without signi cantdifference between the blood group O or non-O, thus suggestingthe existence of mechanisms other than those playing a key role insuccessful aging. Indeed, a series of genome-wide association studiesdemonstrated that the ABO locus is a main determinant of the serumlevels of soluble intercellular adhesion molecule-1 (sICAM-1), P-selectin,S-selectin and interleukin-6 (IL-6) [81 – 85]. Since these in ammatorybiomarkers are involved in several diseases, including cardiovasculardisorders, 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 abletoin uence the individuals' predisposition to several disorders throughtheir capacity of modulating the hemostatic system and the in amma-tory response. In particular, the different prevalence of the ABO groupgenotypes among populations in various geographical areas wasfound to be driven by some pathogens, most notably P. falciparum andVibrio cholera . Other consistent data involve an association betweenthe non-O blood type and cardiovascular disease, especially VTE, so

that the addition of the ABO phenotype to the current thrombotic riskscores will probably allow the more accurate calculation of the throm-botic risk of each patient, in order to better tailor primary or secondaryantithrombotic prophylaxis.

The possibility that theABO gene may be implied in longevity is stilla matter of debate. The studies on the ABO phenotype in centenarians,the best example of successful aging, are largely inconclusive. The nd-ings from Brecher and Hay [77] and our [78] studies that the B allele is amarker for earlier death rather than for longevity are particular intrigu-ing, but need to be supported by further evidences from larger studies.

In conclusion, the issue of longevity is particularly challenging. Ac-cording to the current knowledge,thebiological explanationis seeminglymultifactorial, being the results of several inherited (i.e., polymorphismsin the ABO, HLA [human leukocyte antigen] and in ammatory response

regulating genes) and environmental factors (i.e., dietary, physical,mental and social activity, air quality) that interplay to cope with theaging process [86].

Con icts of interest

The authors declare that they have no con icts of interest regardingthis manuscript.

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