J Thromb Thrombolysis DOI 10.1007/s11239-013-1027-4
Hemostasis, cancer, and ABO blood group: the most recent evidence of association Giancarlo Maria Liumbruno • Massimo Franchini
Ó Springer Science+Business Media New York 2013
Abstract Human ABO blood group antigens are expressed on the surface of red blood cells and a variety of human cells and tissues. However, an increasingly number of studies show that the ABO blood group, in addition to its fundamental role in transfusion medicine and in several other disciplines, has a causal role in predisposing to several human diseases, including hemostasis and neoplastic disorders, which will be the focus of this narrative review.
surface of a variety of human cells and tissues several studies have suggested an important role in the development of hemostasis and neoplastic diseases. Therefore, this narrative review will focus on the current knowledge on the association between the ABO blood group system and thrombotic and bleeding disorders as well as cancer.
ABO and hemostasis Hemostasis Cancer ABO blood group Thrombosis Bleeding
Introduction At the beginning of the last century, the results of the studies performed by the Austrian scientist Karl Landsteiner led to the identification of the ABO blood group system, the first genetic polymorphism discovered in humans and the first of the 33 current blood group systems to be identified. The ABO blood group system has a key role in guaranteeing the safety of blood transfusion and cell, tissue, and organ transplantation, but is also fundamental in genetics, forensic medicine, anthropology, and population studies. In addition, as ABO antigens are also highly expressed on the G. M. Liumbruno UOC di Immunoematologia e Medicina Trasfusionale e UOC di Patologia Clinica, San Giovanni Calibita Fatebenefratelli Hospital, Rome, Italy M. Franchini (&) Dipartimento di Medicina Trasfusionale ed Ematologia, Azienda Ospedaliera Carlo Poma, Mantua, Italy e-mail: [email protected]
It has been known since many years that the ABO blood type has a profound influence on hemostasis, being a major determinant of the von Willebrand factor (VWF) and, consequently, of factor VIII (FVIII) plasma levels [1–3]. In particular, VWF levels are approximately 25 % higher in individuals who are blood group other than O [4]. Thus, as high levels of VWF and FVIII are well-established risk factors for thrombosis [5–7], it is reasonable that a number of experimental and clinical studies have assessed so far whether ABO blood type could influence the risk of developing arterial or venous thrombotic events [8–10]. ABO and thrombosis Most of the available published literature data on the association between ABO blood type and thrombosis regard the venous thromboembolism (VTE) [11]. The first observation on this link was made in 1963 by Dick et al. who found a statistically significant predominance of group A in 461 VTE patients [12]. Since then, several studies have analyzed whether the different ABO blood groups carry different risk of developing VTE. For instance, Wautrecht et al. retrospectively analyzed the phenotypic blood group distribution among ambulatory patients with a diagnosis of DVT of the lower extremities over a period of
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14 years [13]. The blood group was available for 369 such patients and compared with that of 49,373 asymptomatic Belgian blood donors. The frequency of DVT patients with non-O blood group was significantly higher than that of the healthy blood donors (70.6 versus 53.9 %; p \ 0.001). To further clarify the interplay of ABO blood group, VWF, and FVIII in the pathogenesis of VTE, Koster et al. planned a population-based case–control study enrolling 301 consecutive patients younger than 70 with a first, objectively diagnosed episode of VTE and 301 healthy, matched controls [5]. Blood group O was confirmed to be less represented among VTE patients than in controls (25 versus 43 %), and subjects carrying blood group O had also lower concentrations of both FVIII and VWF as compared with those carrying non-O blood groups. Overall, the matched, unadjusted odds ratio (OR) for VTE of non-O blood groups versus O blood groups individuals was 2.0 [95 % confidence interval (CI) 1.4–2.9]. After adjustment for FVIII and VWF levels, the VTE risk of non-O blood groups carriers remained significantly higher than that of O blood group (OR 1.5; 95 % CI 1.0–2.2). Similarly, Tirado et al. investigated the role of FVIII, VWF and ABO blood group on thrombotic risk in a case–control study (250 patients with VTE and 250 unrelated controls) [14]. The frequency of group O was higher in controls than in patients with VTE (44 versus 23 %), while that of group A was higher in VTE patients than in controls (59 versus 41 %). The risk of thrombosis was thereby higher in non-O versus O blood individuals, either when expressed as crude OR (2.6; 95 % CI 1.8–3.8) and after adjustment for levels of FVIII and VWF (OR 1.7; 95 % CI 1.1–2.6), respectively. Patients with the A1 allele also showed an increased risk of thrombosis as compared with O blood group individuals (crude OR 3.1; 95 % CI 2.0–4.7; OR adjusted for FVIII and VWF levels 2.0; 95 % CI 1.3–3.3). In 2007, Ohira et al. performed a nested case–control design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort that included 492 participants who subsequently developed VTE and 1,008 participants who remained free of VTE [15]. After analysis of blood group genotypes, they also observed a significant higher risk of VTE among non-O blood type carriers as compared with O-blood type (age-adjusted OR 1.64; 95 % CI 1.32–2.05), which decreased but remained statistically significant after further adjustment for sex, race, body mass index, diabetes mellitus and FVIII levels (OR 1.31; 95 % CI 1.02–1.68). Interestingly, the risk was increased in nonO blood type subjects who were also carriers of factor V Leiden (OR 6.77; 95 % CI 3.65–12.6). In 2008, Wu et al. performed a systematic review and meta-analysis on the association between ABO blood group and vascular disease [16]. The 21 studies included in the VTE analysis gave a pooled OR of 1.79 (95 % CI 1.56–2.05) for non-O status,
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which was confirmed at the genotype analysis where the combination of A1A1/A1B/BB gave an OR of 2.44 (95 % CI 1.79–3.33) and A1O/BO/A2B an OR of 2.11 (95 % CI 1.66–2.68). More recently, we performed a meta-analysis [17] on a larger number of studies and VTE cases (38 studies with 10,305 VTE cases), which replicated the results from Wu et al. [16]. Indeed, we found a prevalence of non-O blood group significantly higher in VTE patients compared to controls with a resulting pooled OR of 2.08 (95 % CI 1.83–2.37; p \ 0.00001). Of note, this association remained when the analysis was restricted to the six studies performed using a genotype analysis (OR of 1.73 [95 % CI 1.47–2.05; p \ 0.00001] for A1O/BO/A2B and OR of 1.87 [95 % CI 1.84–2.44; p \ 0.00001] for A1B/ A1A1/BB). Also the synergic effect on the VTE risk of the association between non-O status and the factor V Leiden mutation (OR 7.60; 95 % CI 3.21–17.99) found in our meta-analysis was in accordance with the previous observations by Wu et al. [16], who calculated a pooled OR of 3.88 (95 % CI 2.51–6.00) in non-O VTE subjects who also carried factor V Leiden. Overall, the literature data clearly document that non-O blood group is associated with an approximately twofold increased risk of VTE and thus it should be considered as one of the most important genetic risk factor for venous thrombosis. As regards the link between ABO blood type and arterial thrombosis, in the previously mentioned systematic review and meta-analysis [16], beside the association with VTE, the authors observed also a consistent relation with peripheral vascular disease (OR 1.45; 95 % CI 1.35–1.56), ischemic stroke (OR 1.14; 95 % CI 1.01–1.27) and coronary heart disease (CHD) (OR 1.25; 95 % CI 1.14–1.36). Recently, He et al. [18] performed a meta-analysis of data from the Health Professionals Follow-up Study (HPFS), Nurses’ Health Study (NHS) and five other prospective cohort studies in which several thousands of participants were enrolled and they concluded that individuals with non-O blood group had an 11 % [relative risk (RR) 1.11; 95 % CI 1.05–1.18; p = 0.001] increased risk of developing CHD as compared with O blood group individuals. These results were replicated by another recent retrospective study carried out by our group where we observed a statistically significant difference of prevalence of O blood group in CHD patients versus healthy controls (40.9 versus 44.5 %; p = 0.01) [19]. Notably, the protective effect of O blood group was maintained in a logistic regression model including possible confounding factors. However, the contrasting results of the study conducted by Jukic et al. [20], who performed ABO genotyping in patients with acute myocardial infarction and controls and did not find a statistically significant difference in the OO/non-OO genotype distribution (OR 1.41; 95 % CI 0.94–2.11), show that the issue of the association between ABO blood group
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am CHD is still unclear and deserves further investigations. Also the literature data on the association between ABO blood group and ischemic stroke are contrasting. Indeed while a Swedish study conducted 600 patients with ischemic stroke and 600 controls did not find an association (OR 0.9; 95 % CI 0.7–1.2) [21], the EuroCLOT study found a significant association between some ABO gene polymorphisms and cardioembolic stroke [22]. ABO and bleeding As plasma VWF levels are 25–35 % lower in subjects with type-O blood group than in non-O individuals [4], the question as to whether the former subjects have an increased bleeding tendency seems reasonable. However, while the positive association between non-O blood group and the risk of developing VTE is well known and has been finally established in two recent meta-analyses [16, 17], the O blood group-related increase in hemorrhagic risk is not so clear. A higher rate of bleeding complications has been reported in O-group patients in a number of older studies [23–26]. Horwich et al. investigated subjects with duodenal ulcers and healthy controls, observing a significant increase of group O in subjects with bleeding duodenal ulcers over the controls [23]. In addition, those with duodenal ulcers who bled had a significantly higher prevalence of blood group O over those with duodenal ulcers that did not. The same results were also found in two subsequent studies [24, 26]. Furthermore, in a series of patients who were admitted to hospital for bleeding duodenal ulcers, Berg et al. found that the mean age of onset for patients carrying blood group O was lower than for those of blood group A [25]. On the other hand, conflicting results have been reported in more recent studies. Reddy et al. [27] analyzed retrospectively 1,261 Caucasian individuals admitted with epistaxis and found that blood group O was over-represented compared with control subjects. Bayan et al. [28] found that group O had a higher frequency in the patients with upper gastrointestinal bleeding than in control group. By contrast, other studies did not confirm the higher bleeding tendency associated with blood group O. For instance, Kuyvenhoven et al. [29] analyzed the interaction between the use of nonsteroidal anti-inflammatory drugs (NSAIDs), Helicobacter pylori (Hp) infection and the ABO blood group system in patients with bleeding peptic ulcer but, among the parameters studied, only NSAID use emerged as a strong predictor for hemorrhage caused by a peptic ulcer. Thus, although the overall data derived from the qualitative analysis of the published literature are rather inconclusive, the results of a quantitative systematic review and metaanalysis conducted by our group, which was performed on 22 studies including 9,468 bleeding cases, evidenced a slight (OR 1.33; 95 % CI 1.25–1.42), but statistically
significant (p \ 0.001) increase in bleeding risk in O blood group patients compared with non-O subjects [30]. Other investigators analyzed the relationship between ABO blood group and bleeding risk in patients with concomitant risk factors for hemorrhage, such as the treatment with vitamin K antagonists (VKA) [31–33]. A Dutch study, which analyzed ABO blood group genotypes using data from the FACTors in ORal anticoagulation Safety (FACTORS) case–control study, showed that the risk for non-fatal major bleeding in non-OO blood group carriers was 30 % lower than that of OO blood group carriers, although the difference was not statistically significant (OR 0.7; 95 % CI 0.4–1.1) [31]. By contrast, Pruissen et al. [32], analyzing 651 patients receiving oral anticoagulant treatment included in the Stroke Prevention In Reversible Ischemia Trial (SPIRIT), found that ABO blood group was not related with the risk of hemorrhage during oral anticoagulant treatment after cerebral ischemia. Interestingly, in a recent case–control study conducted in orally anticoagulated subjects, we found a higher prevalence, although not statistically significant, of O blood group among patients with more severe grade 2 bleeding complications than among patients with less severe grade 1 complications (45.4 versus. 35.3 %), suggesting that O blood group may be involved at least in the degree of severity of bleeding complications [33]. In conclusion, although O blood type seems to confer only a modest increased hemorrhagic risk, it probably plays a more critical role in triggering acute hemorrhagic events as a cofactor in the presence of other concomitant bleeding risk factors, such as the use of VKA.
ABO and cancer Many studies deal with the association between ABO blood group and cancer but a large part of those published before 1950 are not really informative and reliable because they were performed without knowing that ABO frequencies can vary widely also in populations assumed to be ethnically homogeneous and, therefore, included a limited number of patients and inappropriate control groups [34]. Furthermore, many recent studies connecting ABO group to the occurrence of malignant neoplastic disease are still preliminary or controversial, frequently not supported by strong statistical data, and with supposed underlying mechanisms still to be explored or confirmed. This is the case, for example, of the correlation between ABO blood group and nasopharyngeal carcinoma (NPC) that remains controversial after two small-sample size studies carried out almost 50 years apart yielded conflicting results. In fact, the 1964 study by Seow et al. found no association [35] while a multicenter, retrospective, case– control epidemiological study performed in 2011
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highlighted an increased susceptibility to NPC in blood type A patients (OR 2.03; p = 0.002) and a protective effect of O group (OR 0.53; p = 0.009) [36]. Although a very recent large case–control study carried out in a population of Southeast China showed a relatively higher risk for A (OR 1.287; 95 % CI 1.072–1.545; p = 0.007) or AB (OR 1.390; 95 % CI 1.007–1.919; p = 0.045) blood group subjects as compared to blood type O, the aforementioned association still needs to be validated [37]. Similarly, additional replicate studies are needed to confirm the recently found significant higher risk for renal cell cancer (RCC) in non-O blood group women (but not in men) [38] and the statistically significant association of non-O blood type with decreased overall survival after RCC surgery [39]. In addition, data from large prospective cohort studies indicate that the ABO blood group is associated with the risk of developing skin [40], and ovarian [41, 42] cancers, while no association was found with colo-rectum cancer [43] and conflicting results have emerged for lung [44–46] and breast cancers [47, 48]. The most convincing and reliable data concern pancreatic and gastric cancers. Pancreatic cancer Pancreatic cancer is seventh most frequent cancer, is very aggressive, and has mortality rates approaching incidence rates thus leading to 265,000 deaths out of 280,000 new cases in 2008 [49]. The association between ABO blood group and pancreatic cancer can be traced back to the 1960 study of Aird who in 620 patients with pancreatic cancer found ‘‘evidence of some strength that cancer of the pancreas is commoner in persons of group A than in persons of groups O or B’’ [50]. This hypothesis was contradicted only 4 years later by another study that, on the contrary, showed a higher incidence of pancreatic cancer in B blood type as compared to A blood group [51]. These conflicting results were replicated by two studies published in the early ’90. The first one confirmed an increased risk of pancreatic cancer among blood group B patients (OR 1.60; 95 % CI 1.25–2.04, p \ 0.001) [52] while, on the contrary, the second one detected a slight excess risk for pancreatic cancer in blood group A subjects (OR 1.52; 95 % CI 0.87–2.67) [53]. After the aforementioned conflicting results, it took more than 40 years for the association between ABO blood group and risk of pancreatic cancer to receive the right attention that led to establish a definite correlation between the ABO blood group and pancreatic cancer. In fact, in 2009, the result of the cohort study by Wolpin and collaborators showed that patients with non-O blood group had an adjusted hazard ratio (HR) for pancreatic cancer of
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1.44 (95 % CI 1.14–1.82) and were more likely to develop this cancer as compared to O blood group patients [54]. The adjusted HRs were 1.32 (95 % CI 1.02–1.72), 1.51 (95 % CI 1.02–2.23), and 1.72 (95 % CI 1.25–2.38), for blood group A, B, or AB, respectively. The age-adjusted incidence rates for pancreatic cancer per 100,000 personyears were 27 for subjects with blood type O, 36 for those with blood type A, 41 for those with blood type AB, and 46 for those with blood type B, respectively. At the same time, this statistical association observed between ABO and pancreatic cancer was reassessed by the multinational Pancreatic Cancer Cohort Consortium (PanScan) I genome-wide association study (GWAS), which identified pancreatic cancer susceptibility loci in the ABO gene and reported a significant association for rs505922, a singlenucleotide polymorphism, which maps to the first intron of the ABO gene [55]. The aforementioned association was also replicated in an independent sample of 2,457 affected individuals and 2,654 controls from the PanScan II study. A combined analysis of these groups yielded a multiplicative per-allele OR of 1.20 (95 % CI 1.12–1.28), thus confirming earlier epidemiologic evidences that blood group O individuals may have a lower risk of pancreatic cancer than A, B or AB blood group subjects. In addition, an assessment of the influence of specific ABO genotypes on pancreatic cancer risk pointed out that the addition of each non-O allele increased the pancreatic cancer risk [56]. In fact, compared with the OO genotype, individuals with AO and AA genotype had ORs of 1.33 (95 % CI 1.13–1.58) and 1.61 (95 % CI 1.22–2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95 % CI 1.14–1.85) and 2.42 (95 % CI 1.28–4.57). The supposed role of ABO glycosyltransferase activity in pancreatic tumorigenesis was simultaneously confirmed by the evidence that A1 allele (corresponding to increased glycosyltransferase activity) confers greater pancreatic cancer risk than A2 allele [57]. The glycosyltransferases encoded by the ABO gene transfer specific sugar residues to a precursor substance (the H antigen) to produce A and B antigens but glycans (sugars) have also key biological functions in protein maturation and turnover, cell adhesion and trafficking as well as receptor binding and activation [58]. The hypothesis that the association of pancreatic cancer with the A allele is predominantly due to the A1 glycosyltransferase [57], which has higher activity than A2 glycosyltransferase [58], was recently confirmed by a large multicenter study in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium [59]. In fact, this study showed that only carriers of the A allele had increased cancer risk, while carriers of the B allele did not have. These different results could be explained by the fact that PANDoRA subjects were collected from case–control studies, while patients included in other previously
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mentioned studies were drawn from prospective cohort studies [54–57]. Therefore, in A blood group individuals there is a direct connection between the ABO glycosyltransferase activity and the increased pancreatic cancer risk that is mainly due to the A1 allele [57, 59]. The protective effect of O group was also confirmed by a recent meta-analysis (summary RR 0.79; 95 % CI 0.70–0.90) [60] and cohort studies carried out in German (OR for blood group A 2.01; OR for blood group O 0.5) [61] and in Shangai patients (OR for blood group A 1.60; 95 % CI 1.27–2.03) [62]. Finally, a statistically significant association between pancreatic cancer risk and Hp seropositivity was found among individuals with non-O blood type (A, B, and AB) but not among those with O blood type. The association was greatest for non-O individuals colonized by Hp and negative for its cytotoxin-associated gene A (CagA) virulence protein (OR 2.78; 95 % CI 1.49–5.20), while CagA seropositivity was not associated with an increased risk [63]. Interestingly, a recent meta-analysis revealed significant differences in pancreatic cancer risk between CagA-positive-nonendemic and -endemic populations. In fact, group A subjects had increased risk in both CagA-positive-nonendemic and -endemic populations (pooled OR 1.40; 95 % CI 1.32–1.49) [62]. In nonendemic populations, groups B and AB were also associated with higher risk (OR 1.38; 95 % CI 1.16–1.64; and OR 1.52; 95 % CI 1.24–1.85, respectively) but in CagA-positive-endemic populations they were not associated with increased risk. A possible explanation for these differences could involve gastric epithelial expression of A versus B antigens on colonization behaviors of CagA-positive and CagA-negative Hp strains. Gastric cancer Gastric cancer is the fourth most common malignancy in the world and the second leading cause of cancer death in both sexes worldwide (738,000 deaths in 2008, 9.7 % of the total) [64]. The first convincing study proving a link between ABO blood group and gastric cancer can be traced back to 1953 [65]. In this early statistic study on 3,632 patients, Aird et al. highlighted a 20 % increase of carcinoma of the stomach in group A as compared to group O and concluded that it was ‘‘no longer possible to regard blood groups A and O (in adults) as entirely devoid of selective value’’. In 1961, an international combined analysis on gastric cancer cases confirmed this significant positive association between A blood group and the risk of gastric cancer (OR 1.24; 95 % CI 1.18–1-30) [66]. In the 40 years following the study by Aird, over 150 separate sets of patients were
studied (more than 50,000 subjects) and almost all the reports concurred that in gastric cancer the A/O relative incidence is about 1.2 [67]. In 2010, a large prospective population-based study performed within a cohort of Scandinavian blood donors included in the Scandinavian Donations and Transfusions (SCANDAT) database involved more than one million donors who were followed for up to 35 years and confirmed that blood group A is associated with a higher risk of gastric cancer compared to blood group O [68]. The extent of the association was similar to those previously reported and the adjusted incidence rate ratio was 1.20 (95 % CI 1.02–1.42). In 2012, Wang et al. confirmed that the risk of gastric cancer in blood group A was significantly higher than in non-A groups (OR 1.34; 95 % CI 1.25–1.44) and that it was lower in blood group O subjects (OR 0.80; 95 % CI 0.72–0.88) [69]. The authors also carried out a meta-analysis (15,843 gastric cancer cases and 1,421,740 controls) that produced similar findings: (i) OR of group A individuals 1.11; 95 % CI 1.07–1.15; (ii) OR of group O individuals 0.91; 95 % CI 0.89–0.94. In addition, they also found that the ratio of Hp infection in blood group A patients was significantly higher than in non-A blood group subjects (OR 1.42; 95 % CI 0.12–1.38). The link between blood type allele, Hp infection status, and the risk of advanced gastric precancerous lesions has recently been confirmed [70]. In fact, according to the results of a very recent study ABO blood group is a risk factor for progression towards gastric cancer in patients with Hp infection but the association is highly dependent on Hp CagA status, which is responsible for the secretion of the CagA virulence protein that is injected in the host cell cytosol and plays a relevant role in the precancerous lesion development. Only one study has identified a statistically significant association between ABO genotype and gastric cancer, atrophic gastritis, and Hp infection. The OR of gastric cancer was 0.70 (95 % CI 0.50–0.99) for OO and 0.53 (95 % CI 0.36–0.77) for BO as compared to AA genotype. An increased gastric cancer risk was observed with addition of the A allele, and a decreased risk with that of the B allele and ABO gene locus was also able to influence atrophic gastritis prevalence and Hp infection [71]. However, according to a recent large-scale case–control study gastric cancer risk may differ according to sex and histological type. In fact, the ABO genotypes AA (OR 1.56; 95 % CI 1.08–2.26) and AO (OR 1.57; 95 % CI 1.21–2.03) were significantly associated with gastric cancer only in females and only for diffuse-type gastric cancer [72]. Despite the indisputable evidence supporting the link between ABO blood group and gastric cancer a recently carried out case–control analysis of data of the European
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Institute of Oncology (Milan, Italy) did not confirm the aforementioned relationship because the study was not adequately statistically powered [60].
Conclusions Increasing evidence support a key role of ABO blood group in bleeding and thrombotic disorders as well as in neoplastic diseases. In the near future the GWAS studies that have already confirmed the link between ABO blood group and pancreatic cancer will play a key role in the thorough reassessment of all the other associations observed between ABO and diseases. Conflict of interest G M. Liumbruno and M. Franchini declare that there is no conflict of interests regarding the publication of this article.
References 1. Preston AE, Barr A (1964) The plasma concentration of factor VIII in the normal population. Br J Haematol 10:238–245 2. Moeller A, Weippert-Kretschmer M, Prinz H, Kretschmer V (2001) Influence of ABO blood groups on primary hemostasis. Transfusion 2001:56–60 3. O’Donnell JS, Lasffan MA (2001) The relationship between ABO histo-blood group, factor VIII and von Willebrand factor. Transfus Med 11:343–351 4. Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR (1987) The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 69:1691–1695 5. Koster T, Blann AD, Brie¨t E, Vandenbroucke JP, Rosendaal FR (1995) Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 345:152–155 6. Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE (1997) Prospective study of hemostatic factors and incidence of coronary heart disease: the atherosclerosis risk in communities (ARIC) Study. Circulation 96:1102–1108 7. Whincup PH, Danesh J, Walker M et al (2002) Von Willebrand factor and coronary heart disease: prospective study and metaanalysis. Eur Heart J 23:1764–1770 8. Franchini M, Capra F, Targher G, Montagnana M, Lippi G (2007) Relationship between ABO blood group and von Willebrand factor levels: from biology to clinical implications. Thromb J 5:14 9. Franchini M, Favaloro EJ, Targher G, Lippi G (2012) ABO blood group, hypercoagulability, and cardiovascular and cancer risk. Crit Rev Clin Lab Sci 49:137–149 10. Franchini M, Liumbruno GM (2013) ABO blood group: old dogma, new perspectives. Clin Chem Lab Med 51:1545–1553 11. Franchini M, Makris M (2013) Non-O blood group: an important genetic risk factor for venous thromboembolism. Blood Transfus 11:164–165 12. Dick W, Schneider W, Brockmuller K, Mayer W (1963) Interrelations of thrombo-embolic diseases and blood group distribution. Thromb Diath Haemorrh 9:472–474 13. Wautrecht JC, Galle C, Motte S, Dereume JP, Dramaix M (1998) The role of ABO blood groups in the incidence of deep vein thrombosis. Thromb Haemost 79:688–689
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14. Tirado I, Mateo J, Soria JM et al (2005) The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism. Thromb Haemost 93:468–474 15. Ohira T, Cushman M, Tsai YM et al (2007) ABO blood group, other risk factors and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE). J Thromb Haemost 5:1455–1461 16. Wu O, Bayoumi N, Vickers MA, Clark P (2008) ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 6:62–69 17. Dentali F, Sironi AP, Ageno W et al (2012) Non-O blood type is the commonest genetic risk factor for VTE: results from a metaanalysis of the literature. Semin Thromb Hemost 38:535–548 18. He M, Wolpin B, Rexrode K et al (2012) ABO blood group and risk of coronary heart disease in two prospective cohort studies. Arterioscler Thromb Vasc Biol 32:2314–2320 19. Franchini M, Rossi C, Mengoli C et al (2013) ABO blood group and the risk of coronary artery disease. J Thromb Thrombolysis 36:286–287 20. Jukic I, Bingulac-Popovic J, Dogic V et al (2013) Evaluation of ABO blood groups as a risk factor for myocardial infarction. Blood Transfus 11:464–465 21. Hanson E, Karlsson S, Jood K, Nilsson S, Blomstrand C, Jern C (2012) No evidence for an association between ABO blood group and overall ischemic stroke or any of the major etiologic subtypes. Thromb Res 130:339–342 22. Williams FM, Carter AM, Hysi PG et al (2013) Ischemic stroke is associated with the ABO locus: the EuroCLOT study. Ann Neurol 73:16–31 23. Horwich L, Evans D, McConnell R, Donohoe W (1966) ABO blood groups in gastric bleeding. Gut 7:680–685 24. Evans D, Horwich L, McConnell R, Bullen M (1968) Influence of the ABO blood groups and secretor status on bleeding and on perforation of duodenal ulcer. Gut 9:319–322 25. Berg M (1969) Influence of age and ABO blood groups in the precipitation of bleeding peptic ulcers. Gut 10:1029–1030 26. Viskum K (1972) Long-term survival of patients with gastrointestinal hemorrhage with special reference to the ABO blood Groups. Scand J Gastroenterol 7:55–63 27. Reddy VM, Daniel M, Bright E, Broad SR, Moir AA (2008) Is there an association between blood group O and epistaxis? J Laryngol Otol 22:366–368 28. Bayan K, Tuzun Y, Yilmaz S, Dursun M, Canoruc F (2009) Clarifying the relationship between ABO/Rhesus blood group antigens and upper gastrointestinal bleeding. Dig Dis Sci 54:1029–1034 29. Kuyvenhoven JP, Veenendaal RA, Vanderbroucke JP (1999) Peptic ulcer bleeding: interaction between non-steroidal antiinflammatory drugs, Helicobacter pylori infection and the ABO blood group system. Scand J Gastroenterol 34:1082–1086 30. Dentali F, Sironi AP, Ageno W et al (2013) Relationship between ABO blood group and hemorrhage: a systematic literature review and meta-analysis. Semin Thromb Hemost 39:72–82 31. Garcia AA, van der Heijden JF, Meijers JCM et al (2006) The relationship between ABO blood group and the risk of bleeding during vitamin K antagonist treatment. J Thromb Haemost 4:1418–1420 32. Pruissen DMO, Rosendaal FR, Gorter JW, Garcia AA, Kappelle LJ, Algra A (2007) Haemostatic genetic variants, ABO blood group and bleeding risk during oral anticoagulant treatment after cerebral ischaemia of arterial origin. J Neurol 254:1660–1665 33. Franchini M, Crestani S, Frattini F, Mengoli C, Bonfanti C (2012) Relationship between ABO blood group and bleeding complications in orally anticoagulated patients. J Thromb Haemost 10:1688–1691
Hemostasis, cancer, and ABO blood group 34. Garratty G (2000) Blood groups and disease: a historical perspective. Transfus Med Rev 14:291–301 35. Seow LJ, Kwa SB, Teoh CK (1964) A preliminary survey of ABO blood group frequency in nasopharyngeal carcinoma in Chinese patients. Singapore Med J 4:93–95 36. Turkoz FP, Celenkoglu G, Dogu GG (2011) Risk factors of nasopharyngeal carcinoma in Turkey—an epidemiological survey of the Anatolian Society of Medical Oncology. Asian Pac J Cancer Prev 12:3017–3021 37. Sheng L, Sun X, Zhang L, Su D (2013) ABO blood group and nasopharyngeal carcinoma risk in a population of Southeast China. Int J Cancer 133:893–897 38. Joh HK, Cho E, Choueiri TK (2012) ABO blood group and risk of renal cell cancer. Cancer Epidemiol 36:528–532 39. Kaffenberger SD, Morgan TM, Stratton KL (2012) ABO blood group is a predictor of survival in patients undergoing surgery for renal cell carcinoma. BJU Int 110:E641–E646 40. Xie J, Qureshi AA, Li Y, Han J (2010) ABO blood group and incidence of skin cancer. PLoS ONE 5:e11972 41. Gates MA, Wolpin BM, Cramer DW, Hankinson SE, Tworoger SS (2011) ABO blood group and incidence of epithelial ovarian cancer. Int J Cancer 128:482–486 42. Yuzhalin AE, Kutikhin AG (2012) ABO and Rh blood groups in relation to ovarian, endometrial and cervical cancer risk among the population of South-East Siberia. Asian Pac J Cancer Prev 13:5091–5096 43. Khalili H, Wolpin BM, Huang ES et al (2011) ABO blood group and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 20:1017–1029 44. Lee JS, Ro JY, Sahin AA et al (1991) Expression of blood-group antigen A—a favorable prognostic factor in non-small-cell lung cancer. N Engl J Med 324:1084–1090 45. Oguz A, Unal D, Tasdemir A et al (2013) Lack of any association between blood groups and lung cancer, independent of histology. Asian Pac J Cancer Prev 14:453–456 46. Urun Y, Utkan GA, Cangir K et al (2013) Association of ABO Blood Group and Risk of Lung Cancer in a Multicenter Study in Turkey. Asian Pac J Cancer Prev 14:2801–2803 47. Gates MA, Xu M, Chen WY, Kraft P, Hankinson SE, Wolpin BM (2012) ABO blood group and breast cancer incidence and survival. Int J Cancer 130:2129–2137 48. Miao SY, Zhou W, Chen L, Wang S, Liu SA (2013) Influence of ABO blood group and Rhesus factor on breast cancer risk: a meta-analysis of 9665 breast cancer patients and 244768 controls. Asia Pac J Clin Oncol. doi:10.1111/ajco.12083 49. Bosetti C, Bertuccio P, Negri E, La Vecchia C, Zeegers MP, Boffetta B (2012) Pancreatic cancer: overview of descriptive epidemiology. Mol Carcinog 51:3–13 50. Aird I, Lee DR, Roberts IA (1960) ABO blood groups and cancer of oesophagus, cancer of pancreas, and pituitary adenoma. Br Med J 1:1163–1166 51. Macafee AL (1964) ABO blood groups and carcinoma of pancreas. Ulster Med J 33:129–131 52. Annese V, Minervini M, Gabbrielli A, Gambassi G, Manna R (1990) ABO blood groups and cancer of the pancreas. Int J Pancreatol 6:81–88 53. Vioque J, Walker AM (1991) Pancreatic cancer and ABO blood types: a study of cases and controls. Med Clı´n 96:761–764
54. Wolpin BM, Chan AT, Hartge P et al (2009) ABO blood group and the risk of pancreatic cancer. J Natl Cancer Inst 101:424–431 55. Amundadottir L, Kraft P, Stolzenberg-Solomon RZ et al (2009) Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 41:986–990 56. Wolpin BM, Kraft P, Gross M et al (2010) Pancreatic cancer risk and ABO blood group alleles: results from the pancreatic cancer cohort consortium. Cancer Res 70:1015–1023 57. Wolpin BM, Kraft P, Xu M et al (2010) Variant ABO blood group alleles, secretor status, and risk of pancreatic cancer: results from the pancreatic cancer cohort consortium. Cancer Epidemiol Biomarkers Prev 19:3140–3149 58. Moran AP, Gupta A, Joshi L (2011) Sweet-talk: role of host glycosylation in bacterial pathogenesis of the gastrointestinal tract. Gut 60:1412–1425 59. Rizzato D, Campa D, Pezzilli R et al (2013) ABO blood groups and pancreatic cancer risk and survival: results from the PANcreatic Disease ReseArch (PANDoRA) consortium. Oncol Rep 29:637–644 60. Iodice S, Maisonneu P, Botteri E, Sandri MT, Lowenfels AB (2010) ABO blood group and cancer. Eur J Cancer 46:3345–3350 61. Pelzer U, Klein F, Bahra M et al (2013) Blood group determinates incidence for pancreatic cancer in Germany. Front Physiol 24:118 62. Risch HA, Lu L, Wang J et al (2013) ABO blood group and risk of pancreatic cancer: a study in Shanghai and meta-analysis. Am J Epidemiol 177:1326–1337 63. Risch HA, Yu H, Lu L, Kidd MS (2010) ABO blood group, Helicobacter pylori seropositivity, and risk of pancreatic cancer: a case–control study. J Natl Cancer Inst 102:502–505 64. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90 65. Aird I, Bentall HH, Fraser Roberts JA (1953) A relationship between cancer of stomach and the ABO blood groups. Br Med J 1:799–801 66. Clarke CA (1961) Blood group and disease. In: Steiberg AG (ed) Progress in medical genetics. Grune and Stratton, New York, pp 81–119 67. Garratty G (1994) Do blood groups have a biological role? In: Garratty G (ed) Immunobiology of transfusion medicine. Marcel Dekker, Inc., New York, pp 201–255 68. Edgren G, Hjalgrim H, Rostgaard K et al (2010) Risk of gastric cancer and peptic ulcers in relation to ABO blood type: a cohort study. Am J Epidemiol 172:1280–1285 69. Wang Z, Liu L, Ji J et al (2012) ABO blood group system and gastric cancer: a case–control study and meta-analysis. Int J Mol Sci 13:13308–13321 70. Rizzato C, Kato I, Plummer M et al (2013) Risk of advanced gastric precancerous lesions in Helicobacter pylori infected subjects is influenced by ABO blood group and cagA status. Int J Cancer 133:315–322 71. Nakao M, Matsuo K, Ito H et al (2011) ABO genotype and the risk of gastric cancer, atrophic gastritis, and Helicobacter pylori infection. Cancer Epidemiol Biomarkers Prev 20:1665–1672 72. Song HR, Shin MH, Kim HN et al (2013) Sex-specific differences in the association between ABO genotype and gastric cancer risk in a Korean population. Gastric Cancer 16:254–260
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Hemostasis, cancer, and ABO blood group: the most recent evidence of association Giancarlo Maria Liumbruno • Massimo Franchini
Ó Springer Science+Business Media New York 2013
Abstract Human ABO blood group antigens are expressed on the surface of red blood cells and a variety of human cells and tissues. However, an increasingly number of studies show that the ABO blood group, in addition to its fundamental role in transfusion medicine and in several other disciplines, has a causal role in predisposing to several human diseases, including hemostasis and neoplastic disorders, which will be the focus of this narrative review.
surface of a variety of human cells and tissues several studies have suggested an important role in the development of hemostasis and neoplastic diseases. Therefore, this narrative review will focus on the current knowledge on the association between the ABO blood group system and thrombotic and bleeding disorders as well as cancer.
ABO and hemostasis Hemostasis Cancer ABO blood group Thrombosis Bleeding
Introduction At the beginning of the last century, the results of the studies performed by the Austrian scientist Karl Landsteiner led to the identification of the ABO blood group system, the first genetic polymorphism discovered in humans and the first of the 33 current blood group systems to be identified. The ABO blood group system has a key role in guaranteeing the safety of blood transfusion and cell, tissue, and organ transplantation, but is also fundamental in genetics, forensic medicine, anthropology, and population studies. In addition, as ABO antigens are also highly expressed on the G. M. Liumbruno UOC di Immunoematologia e Medicina Trasfusionale e UOC di Patologia Clinica, San Giovanni Calibita Fatebenefratelli Hospital, Rome, Italy M. Franchini (&) Dipartimento di Medicina Trasfusionale ed Ematologia, Azienda Ospedaliera Carlo Poma, Mantua, Italy e-mail: [email protected]
It has been known since many years that the ABO blood type has a profound influence on hemostasis, being a major determinant of the von Willebrand factor (VWF) and, consequently, of factor VIII (FVIII) plasma levels [1–3]. In particular, VWF levels are approximately 25 % higher in individuals who are blood group other than O [4]. Thus, as high levels of VWF and FVIII are well-established risk factors for thrombosis [5–7], it is reasonable that a number of experimental and clinical studies have assessed so far whether ABO blood type could influence the risk of developing arterial or venous thrombotic events [8–10]. ABO and thrombosis Most of the available published literature data on the association between ABO blood type and thrombosis regard the venous thromboembolism (VTE) [11]. The first observation on this link was made in 1963 by Dick et al. who found a statistically significant predominance of group A in 461 VTE patients [12]. Since then, several studies have analyzed whether the different ABO blood groups carry different risk of developing VTE. For instance, Wautrecht et al. retrospectively analyzed the phenotypic blood group distribution among ambulatory patients with a diagnosis of DVT of the lower extremities over a period of
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14 years [13]. The blood group was available for 369 such patients and compared with that of 49,373 asymptomatic Belgian blood donors. The frequency of DVT patients with non-O blood group was significantly higher than that of the healthy blood donors (70.6 versus 53.9 %; p \ 0.001). To further clarify the interplay of ABO blood group, VWF, and FVIII in the pathogenesis of VTE, Koster et al. planned a population-based case–control study enrolling 301 consecutive patients younger than 70 with a first, objectively diagnosed episode of VTE and 301 healthy, matched controls [5]. Blood group O was confirmed to be less represented among VTE patients than in controls (25 versus 43 %), and subjects carrying blood group O had also lower concentrations of both FVIII and VWF as compared with those carrying non-O blood groups. Overall, the matched, unadjusted odds ratio (OR) for VTE of non-O blood groups versus O blood groups individuals was 2.0 [95 % confidence interval (CI) 1.4–2.9]. After adjustment for FVIII and VWF levels, the VTE risk of non-O blood groups carriers remained significantly higher than that of O blood group (OR 1.5; 95 % CI 1.0–2.2). Similarly, Tirado et al. investigated the role of FVIII, VWF and ABO blood group on thrombotic risk in a case–control study (250 patients with VTE and 250 unrelated controls) [14]. The frequency of group O was higher in controls than in patients with VTE (44 versus 23 %), while that of group A was higher in VTE patients than in controls (59 versus 41 %). The risk of thrombosis was thereby higher in non-O versus O blood individuals, either when expressed as crude OR (2.6; 95 % CI 1.8–3.8) and after adjustment for levels of FVIII and VWF (OR 1.7; 95 % CI 1.1–2.6), respectively. Patients with the A1 allele also showed an increased risk of thrombosis as compared with O blood group individuals (crude OR 3.1; 95 % CI 2.0–4.7; OR adjusted for FVIII and VWF levels 2.0; 95 % CI 1.3–3.3). In 2007, Ohira et al. performed a nested case–control design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort that included 492 participants who subsequently developed VTE and 1,008 participants who remained free of VTE [15]. After analysis of blood group genotypes, they also observed a significant higher risk of VTE among non-O blood type carriers as compared with O-blood type (age-adjusted OR 1.64; 95 % CI 1.32–2.05), which decreased but remained statistically significant after further adjustment for sex, race, body mass index, diabetes mellitus and FVIII levels (OR 1.31; 95 % CI 1.02–1.68). Interestingly, the risk was increased in nonO blood type subjects who were also carriers of factor V Leiden (OR 6.77; 95 % CI 3.65–12.6). In 2008, Wu et al. performed a systematic review and meta-analysis on the association between ABO blood group and vascular disease [16]. The 21 studies included in the VTE analysis gave a pooled OR of 1.79 (95 % CI 1.56–2.05) for non-O status,
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which was confirmed at the genotype analysis where the combination of A1A1/A1B/BB gave an OR of 2.44 (95 % CI 1.79–3.33) and A1O/BO/A2B an OR of 2.11 (95 % CI 1.66–2.68). More recently, we performed a meta-analysis [17] on a larger number of studies and VTE cases (38 studies with 10,305 VTE cases), which replicated the results from Wu et al. [16]. Indeed, we found a prevalence of non-O blood group significantly higher in VTE patients compared to controls with a resulting pooled OR of 2.08 (95 % CI 1.83–2.37; p \ 0.00001). Of note, this association remained when the analysis was restricted to the six studies performed using a genotype analysis (OR of 1.73 [95 % CI 1.47–2.05; p \ 0.00001] for A1O/BO/A2B and OR of 1.87 [95 % CI 1.84–2.44; p \ 0.00001] for A1B/ A1A1/BB). Also the synergic effect on the VTE risk of the association between non-O status and the factor V Leiden mutation (OR 7.60; 95 % CI 3.21–17.99) found in our meta-analysis was in accordance with the previous observations by Wu et al. [16], who calculated a pooled OR of 3.88 (95 % CI 2.51–6.00) in non-O VTE subjects who also carried factor V Leiden. Overall, the literature data clearly document that non-O blood group is associated with an approximately twofold increased risk of VTE and thus it should be considered as one of the most important genetic risk factor for venous thrombosis. As regards the link between ABO blood type and arterial thrombosis, in the previously mentioned systematic review and meta-analysis [16], beside the association with VTE, the authors observed also a consistent relation with peripheral vascular disease (OR 1.45; 95 % CI 1.35–1.56), ischemic stroke (OR 1.14; 95 % CI 1.01–1.27) and coronary heart disease (CHD) (OR 1.25; 95 % CI 1.14–1.36). Recently, He et al. [18] performed a meta-analysis of data from the Health Professionals Follow-up Study (HPFS), Nurses’ Health Study (NHS) and five other prospective cohort studies in which several thousands of participants were enrolled and they concluded that individuals with non-O blood group had an 11 % [relative risk (RR) 1.11; 95 % CI 1.05–1.18; p = 0.001] increased risk of developing CHD as compared with O blood group individuals. These results were replicated by another recent retrospective study carried out by our group where we observed a statistically significant difference of prevalence of O blood group in CHD patients versus healthy controls (40.9 versus 44.5 %; p = 0.01) [19]. Notably, the protective effect of O blood group was maintained in a logistic regression model including possible confounding factors. However, the contrasting results of the study conducted by Jukic et al. [20], who performed ABO genotyping in patients with acute myocardial infarction and controls and did not find a statistically significant difference in the OO/non-OO genotype distribution (OR 1.41; 95 % CI 0.94–2.11), show that the issue of the association between ABO blood group
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am CHD is still unclear and deserves further investigations. Also the literature data on the association between ABO blood group and ischemic stroke are contrasting. Indeed while a Swedish study conducted 600 patients with ischemic stroke and 600 controls did not find an association (OR 0.9; 95 % CI 0.7–1.2) [21], the EuroCLOT study found a significant association between some ABO gene polymorphisms and cardioembolic stroke [22]. ABO and bleeding As plasma VWF levels are 25–35 % lower in subjects with type-O blood group than in non-O individuals [4], the question as to whether the former subjects have an increased bleeding tendency seems reasonable. However, while the positive association between non-O blood group and the risk of developing VTE is well known and has been finally established in two recent meta-analyses [16, 17], the O blood group-related increase in hemorrhagic risk is not so clear. A higher rate of bleeding complications has been reported in O-group patients in a number of older studies [23–26]. Horwich et al. investigated subjects with duodenal ulcers and healthy controls, observing a significant increase of group O in subjects with bleeding duodenal ulcers over the controls [23]. In addition, those with duodenal ulcers who bled had a significantly higher prevalence of blood group O over those with duodenal ulcers that did not. The same results were also found in two subsequent studies [24, 26]. Furthermore, in a series of patients who were admitted to hospital for bleeding duodenal ulcers, Berg et al. found that the mean age of onset for patients carrying blood group O was lower than for those of blood group A [25]. On the other hand, conflicting results have been reported in more recent studies. Reddy et al. [27] analyzed retrospectively 1,261 Caucasian individuals admitted with epistaxis and found that blood group O was over-represented compared with control subjects. Bayan et al. [28] found that group O had a higher frequency in the patients with upper gastrointestinal bleeding than in control group. By contrast, other studies did not confirm the higher bleeding tendency associated with blood group O. For instance, Kuyvenhoven et al. [29] analyzed the interaction between the use of nonsteroidal anti-inflammatory drugs (NSAIDs), Helicobacter pylori (Hp) infection and the ABO blood group system in patients with bleeding peptic ulcer but, among the parameters studied, only NSAID use emerged as a strong predictor for hemorrhage caused by a peptic ulcer. Thus, although the overall data derived from the qualitative analysis of the published literature are rather inconclusive, the results of a quantitative systematic review and metaanalysis conducted by our group, which was performed on 22 studies including 9,468 bleeding cases, evidenced a slight (OR 1.33; 95 % CI 1.25–1.42), but statistically
significant (p \ 0.001) increase in bleeding risk in O blood group patients compared with non-O subjects [30]. Other investigators analyzed the relationship between ABO blood group and bleeding risk in patients with concomitant risk factors for hemorrhage, such as the treatment with vitamin K antagonists (VKA) [31–33]. A Dutch study, which analyzed ABO blood group genotypes using data from the FACTors in ORal anticoagulation Safety (FACTORS) case–control study, showed that the risk for non-fatal major bleeding in non-OO blood group carriers was 30 % lower than that of OO blood group carriers, although the difference was not statistically significant (OR 0.7; 95 % CI 0.4–1.1) [31]. By contrast, Pruissen et al. [32], analyzing 651 patients receiving oral anticoagulant treatment included in the Stroke Prevention In Reversible Ischemia Trial (SPIRIT), found that ABO blood group was not related with the risk of hemorrhage during oral anticoagulant treatment after cerebral ischemia. Interestingly, in a recent case–control study conducted in orally anticoagulated subjects, we found a higher prevalence, although not statistically significant, of O blood group among patients with more severe grade 2 bleeding complications than among patients with less severe grade 1 complications (45.4 versus. 35.3 %), suggesting that O blood group may be involved at least in the degree of severity of bleeding complications [33]. In conclusion, although O blood type seems to confer only a modest increased hemorrhagic risk, it probably plays a more critical role in triggering acute hemorrhagic events as a cofactor in the presence of other concomitant bleeding risk factors, such as the use of VKA.
ABO and cancer Many studies deal with the association between ABO blood group and cancer but a large part of those published before 1950 are not really informative and reliable because they were performed without knowing that ABO frequencies can vary widely also in populations assumed to be ethnically homogeneous and, therefore, included a limited number of patients and inappropriate control groups [34]. Furthermore, many recent studies connecting ABO group to the occurrence of malignant neoplastic disease are still preliminary or controversial, frequently not supported by strong statistical data, and with supposed underlying mechanisms still to be explored or confirmed. This is the case, for example, of the correlation between ABO blood group and nasopharyngeal carcinoma (NPC) that remains controversial after two small-sample size studies carried out almost 50 years apart yielded conflicting results. In fact, the 1964 study by Seow et al. found no association [35] while a multicenter, retrospective, case– control epidemiological study performed in 2011
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highlighted an increased susceptibility to NPC in blood type A patients (OR 2.03; p = 0.002) and a protective effect of O group (OR 0.53; p = 0.009) [36]. Although a very recent large case–control study carried out in a population of Southeast China showed a relatively higher risk for A (OR 1.287; 95 % CI 1.072–1.545; p = 0.007) or AB (OR 1.390; 95 % CI 1.007–1.919; p = 0.045) blood group subjects as compared to blood type O, the aforementioned association still needs to be validated [37]. Similarly, additional replicate studies are needed to confirm the recently found significant higher risk for renal cell cancer (RCC) in non-O blood group women (but not in men) [38] and the statistically significant association of non-O blood type with decreased overall survival after RCC surgery [39]. In addition, data from large prospective cohort studies indicate that the ABO blood group is associated with the risk of developing skin [40], and ovarian [41, 42] cancers, while no association was found with colo-rectum cancer [43] and conflicting results have emerged for lung [44–46] and breast cancers [47, 48]. The most convincing and reliable data concern pancreatic and gastric cancers. Pancreatic cancer Pancreatic cancer is seventh most frequent cancer, is very aggressive, and has mortality rates approaching incidence rates thus leading to 265,000 deaths out of 280,000 new cases in 2008 [49]. The association between ABO blood group and pancreatic cancer can be traced back to the 1960 study of Aird who in 620 patients with pancreatic cancer found ‘‘evidence of some strength that cancer of the pancreas is commoner in persons of group A than in persons of groups O or B’’ [50]. This hypothesis was contradicted only 4 years later by another study that, on the contrary, showed a higher incidence of pancreatic cancer in B blood type as compared to A blood group [51]. These conflicting results were replicated by two studies published in the early ’90. The first one confirmed an increased risk of pancreatic cancer among blood group B patients (OR 1.60; 95 % CI 1.25–2.04, p \ 0.001) [52] while, on the contrary, the second one detected a slight excess risk for pancreatic cancer in blood group A subjects (OR 1.52; 95 % CI 0.87–2.67) [53]. After the aforementioned conflicting results, it took more than 40 years for the association between ABO blood group and risk of pancreatic cancer to receive the right attention that led to establish a definite correlation between the ABO blood group and pancreatic cancer. In fact, in 2009, the result of the cohort study by Wolpin and collaborators showed that patients with non-O blood group had an adjusted hazard ratio (HR) for pancreatic cancer of
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1.44 (95 % CI 1.14–1.82) and were more likely to develop this cancer as compared to O blood group patients [54]. The adjusted HRs were 1.32 (95 % CI 1.02–1.72), 1.51 (95 % CI 1.02–2.23), and 1.72 (95 % CI 1.25–2.38), for blood group A, B, or AB, respectively. The age-adjusted incidence rates for pancreatic cancer per 100,000 personyears were 27 for subjects with blood type O, 36 for those with blood type A, 41 for those with blood type AB, and 46 for those with blood type B, respectively. At the same time, this statistical association observed between ABO and pancreatic cancer was reassessed by the multinational Pancreatic Cancer Cohort Consortium (PanScan) I genome-wide association study (GWAS), which identified pancreatic cancer susceptibility loci in the ABO gene and reported a significant association for rs505922, a singlenucleotide polymorphism, which maps to the first intron of the ABO gene [55]. The aforementioned association was also replicated in an independent sample of 2,457 affected individuals and 2,654 controls from the PanScan II study. A combined analysis of these groups yielded a multiplicative per-allele OR of 1.20 (95 % CI 1.12–1.28), thus confirming earlier epidemiologic evidences that blood group O individuals may have a lower risk of pancreatic cancer than A, B or AB blood group subjects. In addition, an assessment of the influence of specific ABO genotypes on pancreatic cancer risk pointed out that the addition of each non-O allele increased the pancreatic cancer risk [56]. In fact, compared with the OO genotype, individuals with AO and AA genotype had ORs of 1.33 (95 % CI 1.13–1.58) and 1.61 (95 % CI 1.22–2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95 % CI 1.14–1.85) and 2.42 (95 % CI 1.28–4.57). The supposed role of ABO glycosyltransferase activity in pancreatic tumorigenesis was simultaneously confirmed by the evidence that A1 allele (corresponding to increased glycosyltransferase activity) confers greater pancreatic cancer risk than A2 allele [57]. The glycosyltransferases encoded by the ABO gene transfer specific sugar residues to a precursor substance (the H antigen) to produce A and B antigens but glycans (sugars) have also key biological functions in protein maturation and turnover, cell adhesion and trafficking as well as receptor binding and activation [58]. The hypothesis that the association of pancreatic cancer with the A allele is predominantly due to the A1 glycosyltransferase [57], which has higher activity than A2 glycosyltransferase [58], was recently confirmed by a large multicenter study in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium [59]. In fact, this study showed that only carriers of the A allele had increased cancer risk, while carriers of the B allele did not have. These different results could be explained by the fact that PANDoRA subjects were collected from case–control studies, while patients included in other previously
Hemostasis, cancer, and ABO blood group
mentioned studies were drawn from prospective cohort studies [54–57]. Therefore, in A blood group individuals there is a direct connection between the ABO glycosyltransferase activity and the increased pancreatic cancer risk that is mainly due to the A1 allele [57, 59]. The protective effect of O group was also confirmed by a recent meta-analysis (summary RR 0.79; 95 % CI 0.70–0.90) [60] and cohort studies carried out in German (OR for blood group A 2.01; OR for blood group O 0.5) [61] and in Shangai patients (OR for blood group A 1.60; 95 % CI 1.27–2.03) [62]. Finally, a statistically significant association between pancreatic cancer risk and Hp seropositivity was found among individuals with non-O blood type (A, B, and AB) but not among those with O blood type. The association was greatest for non-O individuals colonized by Hp and negative for its cytotoxin-associated gene A (CagA) virulence protein (OR 2.78; 95 % CI 1.49–5.20), while CagA seropositivity was not associated with an increased risk [63]. Interestingly, a recent meta-analysis revealed significant differences in pancreatic cancer risk between CagA-positive-nonendemic and -endemic populations. In fact, group A subjects had increased risk in both CagA-positive-nonendemic and -endemic populations (pooled OR 1.40; 95 % CI 1.32–1.49) [62]. In nonendemic populations, groups B and AB were also associated with higher risk (OR 1.38; 95 % CI 1.16–1.64; and OR 1.52; 95 % CI 1.24–1.85, respectively) but in CagA-positive-endemic populations they were not associated with increased risk. A possible explanation for these differences could involve gastric epithelial expression of A versus B antigens on colonization behaviors of CagA-positive and CagA-negative Hp strains. Gastric cancer Gastric cancer is the fourth most common malignancy in the world and the second leading cause of cancer death in both sexes worldwide (738,000 deaths in 2008, 9.7 % of the total) [64]. The first convincing study proving a link between ABO blood group and gastric cancer can be traced back to 1953 [65]. In this early statistic study on 3,632 patients, Aird et al. highlighted a 20 % increase of carcinoma of the stomach in group A as compared to group O and concluded that it was ‘‘no longer possible to regard blood groups A and O (in adults) as entirely devoid of selective value’’. In 1961, an international combined analysis on gastric cancer cases confirmed this significant positive association between A blood group and the risk of gastric cancer (OR 1.24; 95 % CI 1.18–1-30) [66]. In the 40 years following the study by Aird, over 150 separate sets of patients were
studied (more than 50,000 subjects) and almost all the reports concurred that in gastric cancer the A/O relative incidence is about 1.2 [67]. In 2010, a large prospective population-based study performed within a cohort of Scandinavian blood donors included in the Scandinavian Donations and Transfusions (SCANDAT) database involved more than one million donors who were followed for up to 35 years and confirmed that blood group A is associated with a higher risk of gastric cancer compared to blood group O [68]. The extent of the association was similar to those previously reported and the adjusted incidence rate ratio was 1.20 (95 % CI 1.02–1.42). In 2012, Wang et al. confirmed that the risk of gastric cancer in blood group A was significantly higher than in non-A groups (OR 1.34; 95 % CI 1.25–1.44) and that it was lower in blood group O subjects (OR 0.80; 95 % CI 0.72–0.88) [69]. The authors also carried out a meta-analysis (15,843 gastric cancer cases and 1,421,740 controls) that produced similar findings: (i) OR of group A individuals 1.11; 95 % CI 1.07–1.15; (ii) OR of group O individuals 0.91; 95 % CI 0.89–0.94. In addition, they also found that the ratio of Hp infection in blood group A patients was significantly higher than in non-A blood group subjects (OR 1.42; 95 % CI 0.12–1.38). The link between blood type allele, Hp infection status, and the risk of advanced gastric precancerous lesions has recently been confirmed [70]. In fact, according to the results of a very recent study ABO blood group is a risk factor for progression towards gastric cancer in patients with Hp infection but the association is highly dependent on Hp CagA status, which is responsible for the secretion of the CagA virulence protein that is injected in the host cell cytosol and plays a relevant role in the precancerous lesion development. Only one study has identified a statistically significant association between ABO genotype and gastric cancer, atrophic gastritis, and Hp infection. The OR of gastric cancer was 0.70 (95 % CI 0.50–0.99) for OO and 0.53 (95 % CI 0.36–0.77) for BO as compared to AA genotype. An increased gastric cancer risk was observed with addition of the A allele, and a decreased risk with that of the B allele and ABO gene locus was also able to influence atrophic gastritis prevalence and Hp infection [71]. However, according to a recent large-scale case–control study gastric cancer risk may differ according to sex and histological type. In fact, the ABO genotypes AA (OR 1.56; 95 % CI 1.08–2.26) and AO (OR 1.57; 95 % CI 1.21–2.03) were significantly associated with gastric cancer only in females and only for diffuse-type gastric cancer [72]. Despite the indisputable evidence supporting the link between ABO blood group and gastric cancer a recently carried out case–control analysis of data of the European
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Institute of Oncology (Milan, Italy) did not confirm the aforementioned relationship because the study was not adequately statistically powered [60].
Conclusions Increasing evidence support a key role of ABO blood group in bleeding and thrombotic disorders as well as in neoplastic diseases. In the near future the GWAS studies that have already confirmed the link between ABO blood group and pancreatic cancer will play a key role in the thorough reassessment of all the other associations observed between ABO and diseases. Conflict of interest G M. Liumbruno and M. Franchini declare that there is no conflict of interests regarding the publication of this article.
References 1. Preston AE, Barr A (1964) The plasma concentration of factor VIII in the normal population. Br J Haematol 10:238–245 2. Moeller A, Weippert-Kretschmer M, Prinz H, Kretschmer V (2001) Influence of ABO blood groups on primary hemostasis. Transfusion 2001:56–60 3. O’Donnell JS, Lasffan MA (2001) The relationship between ABO histo-blood group, factor VIII and von Willebrand factor. Transfus Med 11:343–351 4. Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR (1987) The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 69:1691–1695 5. Koster T, Blann AD, Brie¨t E, Vandenbroucke JP, Rosendaal FR (1995) Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 345:152–155 6. Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE (1997) Prospective study of hemostatic factors and incidence of coronary heart disease: the atherosclerosis risk in communities (ARIC) Study. Circulation 96:1102–1108 7. Whincup PH, Danesh J, Walker M et al (2002) Von Willebrand factor and coronary heart disease: prospective study and metaanalysis. Eur Heart J 23:1764–1770 8. Franchini M, Capra F, Targher G, Montagnana M, Lippi G (2007) Relationship between ABO blood group and von Willebrand factor levels: from biology to clinical implications. Thromb J 5:14 9. Franchini M, Favaloro EJ, Targher G, Lippi G (2012) ABO blood group, hypercoagulability, and cardiovascular and cancer risk. Crit Rev Clin Lab Sci 49:137–149 10. Franchini M, Liumbruno GM (2013) ABO blood group: old dogma, new perspectives. Clin Chem Lab Med 51:1545–1553 11. Franchini M, Makris M (2013) Non-O blood group: an important genetic risk factor for venous thromboembolism. Blood Transfus 11:164–165 12. Dick W, Schneider W, Brockmuller K, Mayer W (1963) Interrelations of thrombo-embolic diseases and blood group distribution. Thromb Diath Haemorrh 9:472–474 13. Wautrecht JC, Galle C, Motte S, Dereume JP, Dramaix M (1998) The role of ABO blood groups in the incidence of deep vein thrombosis. Thromb Haemost 79:688–689
123
14. Tirado I, Mateo J, Soria JM et al (2005) The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism. Thromb Haemost 93:468–474 15. Ohira T, Cushman M, Tsai YM et al (2007) ABO blood group, other risk factors and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE). J Thromb Haemost 5:1455–1461 16. Wu O, Bayoumi N, Vickers MA, Clark P (2008) ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 6:62–69 17. Dentali F, Sironi AP, Ageno W et al (2012) Non-O blood type is the commonest genetic risk factor for VTE: results from a metaanalysis of the literature. Semin Thromb Hemost 38:535–548 18. He M, Wolpin B, Rexrode K et al (2012) ABO blood group and risk of coronary heart disease in two prospective cohort studies. Arterioscler Thromb Vasc Biol 32:2314–2320 19. Franchini M, Rossi C, Mengoli C et al (2013) ABO blood group and the risk of coronary artery disease. J Thromb Thrombolysis 36:286–287 20. Jukic I, Bingulac-Popovic J, Dogic V et al (2013) Evaluation of ABO blood groups as a risk factor for myocardial infarction. Blood Transfus 11:464–465 21. Hanson E, Karlsson S, Jood K, Nilsson S, Blomstrand C, Jern C (2012) No evidence for an association between ABO blood group and overall ischemic stroke or any of the major etiologic subtypes. Thromb Res 130:339–342 22. Williams FM, Carter AM, Hysi PG et al (2013) Ischemic stroke is associated with the ABO locus: the EuroCLOT study. Ann Neurol 73:16–31 23. Horwich L, Evans D, McConnell R, Donohoe W (1966) ABO blood groups in gastric bleeding. Gut 7:680–685 24. Evans D, Horwich L, McConnell R, Bullen M (1968) Influence of the ABO blood groups and secretor status on bleeding and on perforation of duodenal ulcer. Gut 9:319–322 25. Berg M (1969) Influence of age and ABO blood groups in the precipitation of bleeding peptic ulcers. Gut 10:1029–1030 26. Viskum K (1972) Long-term survival of patients with gastrointestinal hemorrhage with special reference to the ABO blood Groups. Scand J Gastroenterol 7:55–63 27. Reddy VM, Daniel M, Bright E, Broad SR, Moir AA (2008) Is there an association between blood group O and epistaxis? J Laryngol Otol 22:366–368 28. Bayan K, Tuzun Y, Yilmaz S, Dursun M, Canoruc F (2009) Clarifying the relationship between ABO/Rhesus blood group antigens and upper gastrointestinal bleeding. Dig Dis Sci 54:1029–1034 29. Kuyvenhoven JP, Veenendaal RA, Vanderbroucke JP (1999) Peptic ulcer bleeding: interaction between non-steroidal antiinflammatory drugs, Helicobacter pylori infection and the ABO blood group system. Scand J Gastroenterol 34:1082–1086 30. Dentali F, Sironi AP, Ageno W et al (2013) Relationship between ABO blood group and hemorrhage: a systematic literature review and meta-analysis. Semin Thromb Hemost 39:72–82 31. Garcia AA, van der Heijden JF, Meijers JCM et al (2006) The relationship between ABO blood group and the risk of bleeding during vitamin K antagonist treatment. J Thromb Haemost 4:1418–1420 32. Pruissen DMO, Rosendaal FR, Gorter JW, Garcia AA, Kappelle LJ, Algra A (2007) Haemostatic genetic variants, ABO blood group and bleeding risk during oral anticoagulant treatment after cerebral ischaemia of arterial origin. J Neurol 254:1660–1665 33. Franchini M, Crestani S, Frattini F, Mengoli C, Bonfanti C (2012) Relationship between ABO blood group and bleeding complications in orally anticoagulated patients. J Thromb Haemost 10:1688–1691
Hemostasis, cancer, and ABO blood group 34. Garratty G (2000) Blood groups and disease: a historical perspective. Transfus Med Rev 14:291–301 35. Seow LJ, Kwa SB, Teoh CK (1964) A preliminary survey of ABO blood group frequency in nasopharyngeal carcinoma in Chinese patients. Singapore Med J 4:93–95 36. Turkoz FP, Celenkoglu G, Dogu GG (2011) Risk factors of nasopharyngeal carcinoma in Turkey—an epidemiological survey of the Anatolian Society of Medical Oncology. Asian Pac J Cancer Prev 12:3017–3021 37. Sheng L, Sun X, Zhang L, Su D (2013) ABO blood group and nasopharyngeal carcinoma risk in a population of Southeast China. Int J Cancer 133:893–897 38. Joh HK, Cho E, Choueiri TK (2012) ABO blood group and risk of renal cell cancer. Cancer Epidemiol 36:528–532 39. Kaffenberger SD, Morgan TM, Stratton KL (2012) ABO blood group is a predictor of survival in patients undergoing surgery for renal cell carcinoma. BJU Int 110:E641–E646 40. Xie J, Qureshi AA, Li Y, Han J (2010) ABO blood group and incidence of skin cancer. PLoS ONE 5:e11972 41. Gates MA, Wolpin BM, Cramer DW, Hankinson SE, Tworoger SS (2011) ABO blood group and incidence of epithelial ovarian cancer. Int J Cancer 128:482–486 42. Yuzhalin AE, Kutikhin AG (2012) ABO and Rh blood groups in relation to ovarian, endometrial and cervical cancer risk among the population of South-East Siberia. Asian Pac J Cancer Prev 13:5091–5096 43. Khalili H, Wolpin BM, Huang ES et al (2011) ABO blood group and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 20:1017–1029 44. Lee JS, Ro JY, Sahin AA et al (1991) Expression of blood-group antigen A—a favorable prognostic factor in non-small-cell lung cancer. N Engl J Med 324:1084–1090 45. Oguz A, Unal D, Tasdemir A et al (2013) Lack of any association between blood groups and lung cancer, independent of histology. Asian Pac J Cancer Prev 14:453–456 46. Urun Y, Utkan GA, Cangir K et al (2013) Association of ABO Blood Group and Risk of Lung Cancer in a Multicenter Study in Turkey. Asian Pac J Cancer Prev 14:2801–2803 47. Gates MA, Xu M, Chen WY, Kraft P, Hankinson SE, Wolpin BM (2012) ABO blood group and breast cancer incidence and survival. Int J Cancer 130:2129–2137 48. Miao SY, Zhou W, Chen L, Wang S, Liu SA (2013) Influence of ABO blood group and Rhesus factor on breast cancer risk: a meta-analysis of 9665 breast cancer patients and 244768 controls. Asia Pac J Clin Oncol. doi:10.1111/ajco.12083 49. Bosetti C, Bertuccio P, Negri E, La Vecchia C, Zeegers MP, Boffetta B (2012) Pancreatic cancer: overview of descriptive epidemiology. Mol Carcinog 51:3–13 50. Aird I, Lee DR, Roberts IA (1960) ABO blood groups and cancer of oesophagus, cancer of pancreas, and pituitary adenoma. Br Med J 1:1163–1166 51. Macafee AL (1964) ABO blood groups and carcinoma of pancreas. Ulster Med J 33:129–131 52. Annese V, Minervini M, Gabbrielli A, Gambassi G, Manna R (1990) ABO blood groups and cancer of the pancreas. Int J Pancreatol 6:81–88 53. Vioque J, Walker AM (1991) Pancreatic cancer and ABO blood types: a study of cases and controls. Med Clı´n 96:761–764
54. Wolpin BM, Chan AT, Hartge P et al (2009) ABO blood group and the risk of pancreatic cancer. J Natl Cancer Inst 101:424–431 55. Amundadottir L, Kraft P, Stolzenberg-Solomon RZ et al (2009) Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 41:986–990 56. Wolpin BM, Kraft P, Gross M et al (2010) Pancreatic cancer risk and ABO blood group alleles: results from the pancreatic cancer cohort consortium. Cancer Res 70:1015–1023 57. Wolpin BM, Kraft P, Xu M et al (2010) Variant ABO blood group alleles, secretor status, and risk of pancreatic cancer: results from the pancreatic cancer cohort consortium. Cancer Epidemiol Biomarkers Prev 19:3140–3149 58. Moran AP, Gupta A, Joshi L (2011) Sweet-talk: role of host glycosylation in bacterial pathogenesis of the gastrointestinal tract. Gut 60:1412–1425 59. Rizzato D, Campa D, Pezzilli R et al (2013) ABO blood groups and pancreatic cancer risk and survival: results from the PANcreatic Disease ReseArch (PANDoRA) consortium. Oncol Rep 29:637–644 60. Iodice S, Maisonneu P, Botteri E, Sandri MT, Lowenfels AB (2010) ABO blood group and cancer. Eur J Cancer 46:3345–3350 61. Pelzer U, Klein F, Bahra M et al (2013) Blood group determinates incidence for pancreatic cancer in Germany. Front Physiol 24:118 62. Risch HA, Lu L, Wang J et al (2013) ABO blood group and risk of pancreatic cancer: a study in Shanghai and meta-analysis. Am J Epidemiol 177:1326–1337 63. Risch HA, Yu H, Lu L, Kidd MS (2010) ABO blood group, Helicobacter pylori seropositivity, and risk of pancreatic cancer: a case–control study. J Natl Cancer Inst 102:502–505 64. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90 65. Aird I, Bentall HH, Fraser Roberts JA (1953) A relationship between cancer of stomach and the ABO blood groups. Br Med J 1:799–801 66. Clarke CA (1961) Blood group and disease. In: Steiberg AG (ed) Progress in medical genetics. Grune and Stratton, New York, pp 81–119 67. Garratty G (1994) Do blood groups have a biological role? In: Garratty G (ed) Immunobiology of transfusion medicine. Marcel Dekker, Inc., New York, pp 201–255 68. Edgren G, Hjalgrim H, Rostgaard K et al (2010) Risk of gastric cancer and peptic ulcers in relation to ABO blood type: a cohort study. Am J Epidemiol 172:1280–1285 69. Wang Z, Liu L, Ji J et al (2012) ABO blood group system and gastric cancer: a case–control study and meta-analysis. Int J Mol Sci 13:13308–13321 70. Rizzato C, Kato I, Plummer M et al (2013) Risk of advanced gastric precancerous lesions in Helicobacter pylori infected subjects is influenced by ABO blood group and cagA status. Int J Cancer 133:315–322 71. Nakao M, Matsuo K, Ito H et al (2011) ABO genotype and the risk of gastric cancer, atrophic gastritis, and Helicobacter pylori infection. Cancer Epidemiol Biomarkers Prev 20:1665–1672 72. Song HR, Shin MH, Kim HN et al (2013) Sex-specific differences in the association between ABO genotype and gastric cancer risk in a Korean population. Gastric Cancer 16:254–260
123
