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. Author manuscript; available in PMC: 2014 Jul 15.
Published in final edited form as: Int J Cancer. 2013 Feb 12;133(2):315–322. doi: 10.1002/ijc.28019

Risk of advanced gastric precancerous lesions in Helicobacter pylori infected subjects is influenced by ABO blood group and cagA status

Cosmeri Rizzato 1, Ikuko Kato 2, Martyn Plummer 3, Nubia Muñoz 4, Angelika Stein 1, Leen Jan van Doorn 5, Silvia Franceschi 3, Federico Canzian 1
PMCID: PMC3656130  NIHMSID: NIHMS435334  PMID: 23319424

Abstract

A higher incidence of stomach cancer in ABO blood type A individuals than in those with blood type O has been known for a long time. We studied this association in relation to Helicobacter pylori (Hp) of different cagA status.

For this study we used baseline gastric histopathology data and DNAs from frozen gastric biopsies of 2077 subjects enrolled in a chemoprevention trial for gastric precancerous lesions in Venezuela. We analyzed 6 single nucleotide polymorphisms in the ABO gene and we assessed the presence of the Hp cagA gene. Odds ratios for risk of advanced precancerous gastric lesions were calculated using individuals with normal gastric epithelium or non-atrophic gastritis as a reference.

Among individuals carrying a cagA negative Hp infection or no Hp infection, those with blood type A had a lower risk of intestinal metaplasia and dysplasia than those with blood type O (OR=0.60; 95% CI 0.38-0.94). In carriers of cagA positive Hp strains, individuals with blood type A had a higher risk of intestinal metaplasia or dysplasia than those with blood type O (OR=1.42, 95% CI 1.09-1.86) and a higher risk if compared with subjects carrying cagA− strain and non-A blood group (OR=3.82, 95%CI=2.80-5.20). The interaction between Hp cagA status and blood type was statistically significant (P=0.0006).

We showed that SNPs in the ABO gene, predictive of ABO blood groups, are associated with risk of advanced precancerous gastric lesions in individuals infected with Hp, but the assessment of the risk is strictly dependent on cagA status.

Keywords: Helicobacter pylori, ABO blood groups, risk of preneoplastic gastric lesions

Introduction

Helicobacter pylori (Hp) is one of the most common chronic bacterial infections in humans and it has been acknowledged to be a causative factor for gastric adenocarcinoma. To colonize mucosal surfaces and invade the epithelium, microbes, including Hp, commonly interact with glycan structures of the host glycocalyx. In particular, the adherence of Hp to the human gastric epithelial lining can be mediated by the blood-group antigen-binding adhesin (BabA) that targets human fucosylated blood group antigens H type I (type O substance) and Lewis b (Leb) 1, 2. Secure attachment is crucial for bacteria to transfer their virulence molecules, such as the CagA protein, to host cells. The cagA gene resides within the cytotoxin-associated gene pathogenicity island (cagPAI) of the Hp genome, and is responsible for most of the Hp-associated malignant phenotypes: it triggers IL-8 secretion priming an inflammatory response, promotes cell proliferation, scattering and migration through phosphorylation-dependent and independent mechanisms 3, 4.

A higher proportion of ABO blood type A in gastric cancer patients than in control individuals was noticed as early as in the 1950s 5.

The ABO gene encodes enzymes known as glycosyltransferases which transfer specific sugar residues to a precursor substance (the H antigen) to produce the A and B antigens. Glycosylation is one of the most prevalent modifications mediated by complex enzymatic machinery, whereby glycans (sugars) are covalently attached to specific amino acid sites of proteins. Glycans have important biological functions in protein maturation and turnover, cell adhesion and trafficking, and receptor binding and activation 6.

There are three major alleles at the ABO locus on chromosome 9q34: A, B and O, defined by single base deletions and substitutions (SNP) occurring in exons 6 and 7. The A allele encodes α1→3 N-acetylgalactosaminyltransferase, which adds N-acetylgalactosamine (GalNAc) to the H antigen to form the A antigen. The B allele encodes α1→3 galactosyltransferase which transfers galactose to the H antigen to construct the B antigen 7. The O allele does not produce an active enzyme 7. Four SNPs at nucleotides (nt) 526, 703, 796 and 803 resulting in amino acid substitutions (Arg176Gly, Gly235Ser, Leu266Met and Gly268Ala) explain all the differences in the activity and the nucleotide-sugar donor specificity of the A and B transferases. In addition, a base substitution (rs1053878) at nt 467, resulting in an amino acid substitution (Pro156Leu), distinguishes the A1 from A2 subtypes. A2 is present in approximately 20% of subjects with A blood group among Caucasians and shows an intermediate phenotype, between the “full” enzymatic activity defined by the A1 allele and the nonfunctioning enzyme defined by the O allele 8.

Although the association between ABO blood groups and risk of gastric cancer is well established, very little is known about the possible relation between ABO blood groups and preneoplastic gastric lesions, in particular advanced ones such as intestinal metaplasia and dysplasia. Here, we conducted a study to assess the impact of ABO genotype on the risk of advanced precancerous lesions in a Venezuelan population in relation with the infection with different strains of Hp. In particular we tested the relevance of the presence of the cagA gene which is known to increase the risk of more severe gastric lesions 9.

Materials and Method

Study population

The randomized trial that provided the infrastructure for this study has been described previously 10. Briefly, eligible subjects were participants in the gastric cancer control program of Tachira State, Venezuela, between 35 and 69 years of age. After they gave written informed consent, all subjects underwent gastroscopic examination with collection of gastric biopsies, blood, and urine specimens, and they were administered a questionnaire on sociodemographic and lifestyle variables by a trained interviewer. During the study recruitment period from July 1991 to February 1995, there were 4349 eligible subjects, of whom 2272 were invited to participate in the trial. Of these, 72 refused to participate. All participants signed an informed written consent. The study was approved by the ethical review boards of the institutions responsible for subject recruitment in each of the recruitment centres.

Ethical clearance for the study was obtained from the International Agency for Research on Cancer (IARC) Ethical Committee in Lyon, France, and the Cancer Control Center in San Cristobal, Venezuela.

The presence of the cagA gene in gastric biopsies from the study subjects was previously assessed by reverse hybridization using a line probe assay or a DNA enzyme immunoassay at Delft Diagnostic Laboratory as described 11. Basic characteristics of this study population are presented in Table 1.

Table 1.

Characteristics of study population.

Characteristics No.a (%)
Gender Male 971 47.1%
Female 1091 52.9%
Age ≤39 479 23.2%
40-49 753 36.5%
50-59 532 25.8%
≥60 298 14.5%
Years of schooling 0-5 688 33.4%
6-8 701 34.0%
9+ 672 32.6%
Years of refrigerator use 0-9 276 13.4%
10-19 348 16.9%
20-29 615 29.8%
30+ 823 39.9%
Cigarette smoking Never 1459 70.8%
Ever 603 29.2%
Family history of gastric cancer No 1767 85.7%
Yes 294 14.3%
Hp status No Hp 181 8.8%
cagA− Hp 567 27.5%
cagA+ Hp 1314 63.7%
Histological diagnosis Normal 10 0.5%
Superficial gastritis 78 3.8%
Chronic gastritis 979 47.5%
Atrophic gastritis 323 15.7%
Intestinal metaplasia 560 27.2%
Dysplasia 112 5.4%
Blood groups O 1202 58.3%
A 690 33.5%
B 141 6.8%
AB 29 1.4%
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a

2200 subjects accepted to participate in the study. For 138 subjects the DNA from biopsies was not available anymore or the quality was insufficient for genotyping, leaving thus a total of 2062 subjects who were included in statistical analyses.

Genotyping

Total DNA was extracted from gastric biopsy specimens after digestion with Proteinase K. Briefly, biopsies were incubated in 250 μL of a solution of 10 mM Tris – HCl (pH 8.0), 5 mM EDTA, 0.1% sodium dodecyl sulfate, and 0.1 mg/mL Proteinase K for at least 2 hours at 55°C. Proteinase K was inactivated by incubation at 95°C for 10 minutes.

In this study we examined 6 single nucleotide polymorphisms (SNPs) on the ABO gene: rs505922 (tagging rs8176719 12), rs1053878, rs8176720, rs8176741, rs8176746 (tagging rs7853989, rs8176743 and rs8176749), and rs8176747. They account for all the variability in the functional polymorphisms and predict the ABO blood groups, as shown in Table 2.

Table 2.

ABO gene SNP selection.

Blood groups
cDNAa aab SNP Tagc O A1 A2 B
aa aa aa
261 87 rs8176719 rs5059221 del (frame shift)
293 99 rs8176720 gly gly gly
467 156 rs1053878 pro leu pro
526 176 rs7853989 rs8176746 arg arg gly
657 219 rs8176741 his his his
703 235 rs8176743 rs8176746 gly gly ser
796 266 rs8176746 leu leu met
803 268 rs8176747 gly gly ala
930 268 rs8176749 rs8176746 leu leu leu
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a

Position (nucleotide number) within the ABO cDNA

b

Position (aminoacid/codon number) within the ABO protein

c

SNP that can be used as surrogate because of complete linkage disequilibrium(r2=1 in HapMap CEU subjects)

Genotyping was performed at the German Cancer Research Center (Heidelberg, Germany) using an allele-specific PCR-based KASPar SNP genotyping system (KBiosciences, Hoddesdon, UK). Thermocycling was performed according to the manufacturer’s instructions. Detection was performed using an ABI PRISM 7900 HT sequence detection system with SDS 2.4 software (Applied Biosystems, Foster City, CA, USA).

Haplotype blocks were constructed from genotyping data using Phase software 13 and SNP tool (http://www.dkfz.de/de/molgen_epidemiology/tools/SNPtool.html)14.

In addition, we typed two SNPs in the cagA gene in position 154 (cagA154_GA) and 858 (cagA858_CT), by allele-specific PCR-based KASPar SNP genotyping system. The presence of the two polymorphic sites has been assessed by sequencing in a small subset of the same population 15. The results obtained with the KASPar assays were compared with the sequencing results with 100% concordance. A sample was defined as cagA positive when it showed a signal in at least two out of three PCRs (i.e. the reverse hybridization/DNA enzyme immunoassay and the two SNP assays).

Statistical analysis

After excluding 138 subjects whose DNA samples were unavailable or failed in ABO genotyping assays, 2062 subjects were left for statistical analysis.

The response variable in this study was histological diagnosis, which was divided into 6 groups: dysplasia, intestinal metaplasia (IM), atrophic gastritis, chronic gastritis, superficial gastritis and normal epithelium. The last three groups were combined to create the control group in this study because the combined frequency of normal epithelium and superficial gastritis in this population was less than 5%. Multinomial logistic regression analysis was employed, using the SAS CATMOD procedure, to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associated with ABO SNPs for atrophic gastritis, IM and dysplasia, in comparison with controls. All ORs were adjusted for basic demographic variables (sex, age and educational levels), and other environmental risk factors reported previously (family history of gastric cancer, cigarette smoking, quintile levels of fruit and starchy vegetable intakes, and duration of refrigerator use) 16. In addition we calculated the ORs for the association between cagA+ HP infection and ABO genotypes in the control group by unconditional logistic regression model including the same covariates.

Results

Basic characteristics of the population included in this study are presented in Table 1. Genotype success was >95%. Blinded duplicate samples (16.7%) included for quality control showed >99% genotype concordance. The genotype frequencies for all SNPs in controls were in accordance with Hardy–Weinberg equilibrium and any deviation from the expected was not statistically significant (data not shown).

We reconstructed the ABO blood groups of the study subjects by using their genotypes at the 6 SNPs we genotyped, as shown in Table 2. The concordance between blood groups assessed by use of genotyping data and serology-obtained blood group data collected at baseline was 96% (data not shown).

We assessed the risk for gastric precancerous lesions, in comparisons with normal epithelium and non-atrophic gastritis, according to blood types and cagA status (Table 3).

Table 3.

Associations between ABO blood types determined by 6 ABO SNPs and risk of gastric precancerous lesions, in comparison with normal epithelium or non-atrophic gastritis

Normal/non-
atrophic
gastritis		 Atrophic gastritis Intestinal metaplasia Dysplasia Intestinal metaplasia +
Dysplasia
Hp cagA
status		 Blood
genotypes		 No. No ORa (95% CI) No. ORa (95% CI) No. ORa (95% CI) No. ORa (95% CI)
Negative O 285 59 1 76 1 16 1 92 1
B/AB 44 16 1.69 (0.88-3.26) 14 1.18 (0.60-2.33) 1 - 15 1.05 (0.54-2.02)
A 172 30 0.83 (0.51-1.36) 33 0.68 (0.43-1.08) 2 - 35 0.60 (0.38-0.94)
 AO 155 27 0.83 (0.50-1.38) 31 0.70 (0.43-1.12) 1 - 32 0.60 (0.38-0.95)
 AA 17 3 0.89 (0.24-3.20) 2 0.48 (0.11-2.17) 1 - 3 0.63 (0.18-2.26)
 A1b 132 24 0.84 (0.49-1.42) 25 0.65 (0.39-1.07) 1 - 26 0.56 (0.34-0.91)
 A2c 40 6 0.81 (0.32-2.04) 8 0.80 (0.33-1.82) 1 - 9 0.78 (0.36-1.71)
Positive O 348 127 1 244 1 47 1 291 1
B/AB 46 19 1.12 (0.63-2.00) 26 0.88 (0.52-1.48) 4 0.69 (0.23-2.04) 30 0.85 (0.51-1.41)
A 172 72 1.14 (0.80-1.61) 167 1.36 (1.03-1.79) 42 1.78 (1.11-2.85) 209 1.42 (1.09-1.86)
 AO 156 63 1.11 (0.77-1.59) 152 1.38 (1.04-1.84) 38 1.78 (1.09-2.89) 190 1.44 (1.10-1.90)
 AA 16 9 1.38 (0.59-3.26) 15 1.16 (0.55-2.45) 4 1.77 (0.55-5.76) 19 1.25 (0.62-2.54)
 A1b 122 46 1.02 (0.69-1.53) 118 1.34 (0.98-1.83) 32 1.88 (1.13-3.15) 150 1.42 (1.06-1.92)
 A2c 50 26 1.40 (0.83-2.36) 49 1.40 (0.90-2.17) 10 1.50 (0.69-3.23) 59 1.42 (0.93-2.17)
Pinteractiond 0.189 0.006 0.0006
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a

Odd ratios were adjusted for age, gender, family history of gastric cancer, smoking status, length of refrigerator use, educational level, fruit and starchy vegetable intakes. Analyses adjusted only for age and gender showed essentially the same results (data not shown). Values in bold are statistically significant (p<0.05). Statistical analysis was not performed for the dysplasia group among cagA negative subjects because of the very small numbers.

b

A1 includes homozygotes A1/A1 and heterozygotes A1/O

c

A2 includes heterozygotes A2/A1, heterozygotes A2/O and homozygotes A2/A2

d

P-value of interaction between Hp cagA status and blood type A

In individuals carrying cagA negative strains or not infected with Hp (748 cases) we found no associations between blood types and risk of atrophic gastritis (105 cases). Individuals with A blood type showed a lower risk of intestinal metaplasia (123 cases) and dysplasia (19 cases) with an OR of 0.60 (95% CI 0.38-0.94) than individuals with blood type O. The association is shown in heterozygous AO subjects with an OR=0.60 (95% CI 0.38-0.95) but not in the homozygotes, due to the small number (3 cases).

In carriers of cagA positive Hp strains (1314 subjects) we detected a higher risk of IM (437 cases) and dysplasia (93 cases) in individuals with blood type A compared with blood type O, with an OR of 1.42 (95%CI 1.09-1.86). Due to the larger numbers in the the cagA positive stratum, it was possible to estimate separate odds ratios for IM (OR=1.36, 95% CI 1.03-1.79), and dysplasia (OR=1.78, 95% CI 1.11-2.85).

We observed a statistically significant interaction between Hp cagA status and blood type, with a P=0.0006 for the combined group of subjects with IM or dysplasia (Table 3).

SNPs in the ABO gene were not associated with risk of cagA positive Hp infection in the subjects without advanced precancerous lesions (normal epithelium to non-atrophic gastritis; data not shown).

Furthermore, we assessed the risk for advanced gastric precancerous lesions, in comparison with normal epithelium and non-atrophic gastritis, combining blood types and cagA status (Figure 1). For this analysis we used subjects with normal epithelium or non-atrophic gastritis carrying cagA negative strains as reference group. This analysis confirmed a decreased risk of IM or dysplasia in subjects with blood group A and carriers of cagA negative strain (OR=0.60, 95%CI 0.38-0.93). Infection with cagA positive strains showed an increased risk of atrophic gastritis and IM or dysplasia in all subjects, but in particular among subjects with blood group A (OR=2.10; 95%CI 1.41-3.13 for atrophic gastritis and OR=3.84; 95%CI 2.78-5.31 for IM or dysplasia).

Figure 1.

Figure 1

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Risk of gastric lesions in subjects infected with different strains of Helicobacter pylori according to cagA status and blood group. Subjects with normal epithelium or non-atrophic gastritis carrying cagA negative strains were considered the reference group (* p<0.05; ***p<0.001)

We also tested if there was an association between individual SNPs and risk of preoneoplastic lesions (Table 4). We found an association with SNP rs505922, which discriminates the O phenotype from A or B: the T allele of the SNP is associated with a increased risk of dysplasia (OR=1.57; 95% CI 1.00-2.48) in carriers of cagA positive strains.

Table 4.

Associations between individual ABO SNPs and risk of gastric precancerous lesions, in comparison with normal epithelium or non-atrophic gastritis.

ABO SNPs Comparison Normal/n
on
atrophic
gastritis		 Atrophic gastritis Intestinal metaplasia Dysplasia Intestinal metaplasia + Dysplasia
No* No* ORa (95% CI) No* ORa (95% CI) No* ORa (95% CI) No* ORa (95%CI)
CagA negative
rs505922 (CT+CC)/TT 216/283 46/58 1.02 (0.66-1.58) 46/72 0.80 (0.53-1.22) 3/16 - 49/88 0.70 (0.47-1.05)
rs8176720 (AG+AA)/GG 361/133 75/29 1.01 (0.62-1.64) 88/33 1.01 (0.64-1.60) 12/7 - 100/40 0.95 (0.62-1.46)
rs8176746 (AC+AA)/CC 46/453 16/88 1.72 (0.92-3.24) 14/108 1.28 (0.67-2.46) 1/18 - 15/126 1.17 (0.62-2.21)
rs8176747 (CG+CC)/GG 46/455 16/89 1.71 (0.91-3.21) 14/109 1.28 (0.66-2.46) 1/18 - 15/127 1.16 (0.61-2.21)
rs1053878 (TC+TT)/CC 52/440 9/92 0.95 (0.44-2.03) 9/109 0.71 (0.35-1.58) 2/17 - 11/126 0.82 (0.41-1.65)
rs8176741 (TC+TT)/CC 45/448 16/88 1.72 (0.91-3.23) 14/105 1.32 (0.68-2.54) 1/18 - 15/123 1.19 (0.63-2.27)
Caga positive
rs505922 (CT+CC)/TT 216/345 89/124 1.14 (0.82-1.57) 189/24
3		 1.25 (0.96-1.62) 46/47 1.57 (1.00-
2.48) 		235/290 1.30 (1.01-1.67)
rs8176720 (AG+AA)/GG 430/133 163/54 0.92 (0.63-1.32) 329/10
4		 0.98 (0.72-1.34) 73/20 1.16 (0.67-2.02) 402/124 1.01 (0.75-1.36)
rs8176746 (AC+AA)/CC 48/518 19/198 1.02 (0.58-1.79) 26/411 0.74 (0.44-1.24) 4/89 0.52 (0.18-1.50) 30/500 0.70 (0.43-1.15)
rs8176747 (CG+CC)/GG 48/518 19/199 1.01 (0.58-1.78) 26/411 0.74 (0.44-1.24) 4/89 0.51 (0.18-1.50) 30/500 0.70 (0.43-1.15)
rs1053878 (TC+TT)/CC 69/493 33/183 1.29 (0.82-2.04) 55/381 1.02 (0.69-1.51) 10/83 0.85 (0.41-1.75) 65/464 1.00 (0.68-1.45)
rs8176741 (TC+TT)/CC 48/502 17/186 0.94 (0.52-1.69) 28/391 0.82 (0.50-1.36) 4/84 0.55 (0.18-1.60) 32/475 0.79 (0.48-1.26)
Open in a new tab
a

Odd ratios were adjusted for age, gender, family history of gastric cancer, smoking status, length of refrigerator use, educational level, fruit and starchy vegetable intakes. Analyses adjusted only for age and gender showed essentially the same results (data not shown). Values in bold are statistically significant (p<0.05). SNPs were analyzed according to a dominant model. Statistical analysis was not performed for the dysplasia group among cagA negative subjects because of the very small numbers.

None of the other SNPs showed any statistically significant association with the risk of preneoplastic lesions, either in cagA positive carriers or in cagA negative subjects.

Discussion

ABO genotype has been investigated as a risk factor for a number of different cancer sites. A recent genome-wide association study (GWAS) has revealed associations between variants in the ABO locus, predicting blood groups, and susceptibility to pancreatic cancer 17. The association has been confirmed in other recent studies 8, 12, 18. Studies of other cancer sites that have tested ABO blood groups by genotyping have shown mixed results: they have not confirmed old epidemiological evidence for an association with breast cancer risk and survival 19, 20, nor with risk for colorectal cancer 21, while the B blood group was positively associated with ovarian cancer incidence 22.

The results of the present study suggest that the A allele exerts its biological effects in gastric carcinogenesis in the presence of the bacterial cagA gene. This may account for inconsistent associations between blood type A and gastric cancer observed in earlier studies that did not take into account the prevalence of Hp infection in the study population.

Glycoconjugates, such as the ABO antigen, are important mediators of intercellular adhesion and membrane signaling, which are both critical to the progression and spread of malignant cells 23. Altered expression of ABO blood group antigen has been described in colorectal adenocarcinomas, lung carcinoma and urinary bladder cancer 24. Moreover, as cell surface molecules they are also recognized by the host immune response and may influence immunosurveillance for malignant cells 25.

Studies have found that ABO antigens including H antigen can be present on epidermal growth factor receptor (EGFR), integrins, cadherins, and CD-44 (a cell-surface glycoprotein), which are involved in cell proliferation, cell-cell interaction, cell adhesion and motility, as well as angiogenicity 26, 27.

In addition to gastric cancer, ABO blood types and secretor phenotypes have been associated with various kinds of infection including norovirus, cholera and malaria 28.

Furthermore, recent GWASs suggest that SNPs of the ABO gene are associated with several serum markers of inflammation and cell adhesion: TNF-α, soluble intercellular adhesion molecule-1 (ICAM-1), soluble E-selectin, and soluble P-selectin 29-32. These findings support the possibility that ABO blood group alleles might correlate with systemic inflammatory state and immune cell recruitment, and thereby influence the risk of several cancers 8.

In the gastric epithelium, the ABO blood group antigens and their related carbohydrate structures, such as the Lewis b antigens, are one of the major functional receptors for Hp 8. The observed association between ABO blood groups and risk of Hp-induced gastric cancer can thus be explained by differential binding of the bacterium to the blood group antigens. In particular, on the bacterial side, the binding is mediated by the outer-membrane protein BabA, encoded by the gene baba2 8. baba2-positive Hp strains are associated with an increased risk of gastric adenocarcinoma 1. The binding between BabA and Lewis b antigen is important not only for Hp to adhere to the stomach surface but also to anchor the bacterial secretion system (T4SS) to the host cell surface so that bacterial factors, including the CagA protein, can be effectively injected into the host cell cytosol. This interaction plays an important role in potentiating T4SS-mediated secretion, resulting in inflammation and intestinal metaplasia 33, although we cannot address how specifically blood group type A affects HP attachment to gastric epithelial cells. The presence of babA2 is correlated with the presence of cagA and vacA s1; strains positive for the three genes carry the highest risk of gastric cancer 1.

Some South American (Amerindian) strains use exclusively blood group O antigen for attachment to gastric epithelial cells 34 and Amerindian strains are known to carry distinct genetic structures from Western and Eastern strains. While attenuated virulence of CagA protein from those strains has been reported35, sequence variations in the other regions of the genome 36 may account for reduced risk of advanced precursor lesion with type A compared with type O in CagA-negative patients.

The association between ABO blood groups and Hp infection is still unclear because of discordant results. In particular, nine studies have tested the association between ABO blood group and Hp infection in healthy subjects; two of them have found a statistically significant association between the infection and A blood type (in Bangladeshi young children 37 and Estonian blood donors 38). In other studies no association was detected, either in children 39, 40 or adults 41-44. Other studies that focused on gastric preneoplastic or gastric cancer cases (two of them in the Japanese population 18, 45) showed an increased risk for atrophic gastritis in individuals with blood group A. Nevertheless other studies in different populations on gastritis or gastric cancer patients did not confirm the association 46-48.

We realize that our study has some limitations. First, although the overall study is rather large, the sample sizes for some gastric histologies are rather small. Furthermore another possible limitation with the cross-sectional study design is difficulty in inferring causal relationship for the observed associations because temporal relations between exposures and outcomes are not clear. Yet, the cross-sectional analysis has an advantage in accumulating histological changes developing over several decades as Hp is generally acquired in the childhood in high-risk populations 49. Finally, our study was limited to a Venezuelan population and the results cannot necessarily be extrapolated to other populations.

In summary, our cross sectional study in a Venezuelan population showed that SNPs at the ABO gene, predictive of ABO blood groups, were associated with the risk of more severe gastric preneoplastic lesion depending on cagA status. In particular, in carriers of cagA positive Hp strains, we detected a significantly increased risk of IM and dysplasia associated with blood group A. On the contrary, among individuals carrying cagA negative strains or not infected with Hp, presence of the A blood type showed a strong decrease of risk of dysplasia. These findings suggest that ABO blood group can be considered a risk factor for progression towards gastric cancer in individuals infected with Hp, but the association is highly dependent on Hp cagA status.

Novelty and impact.

We have studied the impact on the risk of advanced precancerous gastric lesions of ABO blood groups and the presence of cagA in a population characterized by high prevalence of Helicobacter pylori (Hp) infection and high rates of gastric cancer.

Our findings suggest that ABO blood groups are associated with risk of advanced precancerous gastric lesions in Hp-infected individuals, but the assessment of the risk is strictly dependent on cagA status.

Acknowledgments

This work was supported by the European Community (CT90-0555 to I.K.) and the US National Cancer Institute (CA 98309 to I.K.).

Footnotes

All the authors report no conflicts of interest

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