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1.  Evaluation of the Association of Nine Helicobacter pylori Virulence Factors with Strains Involved in Low-Grade Gastric Mucosa-Associated Lymphoid Tissue Lymphoma  
Infection and Immunity  2004;72(2):880-888.
Helicobacter pylori has been associated with the development of two malignant diseases: gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although the cag pathogenicity island, especially the cagA gene, has been linked with adenocarcinoma, few data concerning H. pylori pathogenic factors involved in low-grade gastric MALT lymphoma are available. The goal of this study was to analyze the prevalence of and correlation between genes coding for seven H. pylori virulence factors (cagA, cagE, vacA, iceA, babA, hopQ, and oipA) and two novel adhesins (sabA and hopZ) by comparing a collection of 43 H. pylori strains isolated from patients with low-grade gastric MALT lymphoma to 39 strains isolated from age-matched patients with gastritis only. Our results show that taken individually, none of the nine genes tested can be considered associated with MALT strains and allow us to conclude that MALT pathogenesis is not linked with more proinflammatory H. pylori strains. We demonstrated that in patients infected with strains harboring the iceA1 allele, sabA functional status, and hopZ “off” status, the odds of developing a MALT lymphoma were 10 times higher. However, the low prevalence of such strains (10 of 43 MALT strains) renders this triple association a low-sensitivity marker for MALT strains. Our data confirmed that H. pylori virulence factors are correlated with one another. If the involvement of H. pylori in MALT lymphoma is well established, the pathomechanism by which gastric lymphoma occurs remains to be identified.
doi:10.1128/IAI.72.2.880-888.2004
PMCID: PMC321584  PMID: 14742532
2.  Relationship between Helicobacter pylori iceA, cagA, and vacA Status and Clinical Outcome: Studies in Four Different Countries 
Journal of Clinical Microbiology  1999;37(7):2274-2279.
There is continuing interest in identifying Helicobacter pylori virulence factors that might predict the risk for symptomatic clinical outcomes. It has been proposed that iceA and cagA genes are such markers and can identify patients with peptic ulcers. We compared H. pylori isolates from four countries, looking at the cagA and vacA genotypes, iceA alleles, and presentation of the infection. We used PCR to examine iceA, vacA, and cagA status of 424 H. pylori isolates obtained from patients with different clinical presentations (peptic ulcer, gastric cancer, and atrophic gastritis). The H. pylori isolates examined included 107 strains from Bogota, Colombia, 70 from Houston, Tex., 135 from Seoul, Korea, and 112 from Kyoto, Japan. The predominant genotype differed among countries: the cagA-positive iceA1 vacA s1c-m1 genotype was predominant in Japan and Korea, the cagA-positive iceA2 vacA s1b-m1 genotype was predominant in the United States, and the cagA-positive iceA2 vacA s1a-m1 genotype was predominant in Colombia. There was no association between the iceA, vacA, or cagA status and clinical outcome in patients in the countries studied. iceA status shows considerable geographic differences, and neither iceA nor combinations of iceA, vacA, and cagA were helpful in predicting the clinical presentation of an H. pylori infection.
PMCID: PMC85136  PMID: 10364597
3.  Analysis of iceA genotypes in South African Helicobacter pylori strains and relationship to clinically significant disease 
Gut  2001;49(5):629-635.
BACKGROUND—South African Helicobacter pylori isolates are characterised by the universal presence of cagA but have differences in vacuolating cytotoxin gene (vacA) alleles which correlate with clinically significant disease. However, the candidate virulence marker gene iceA has not been investigated.
AIM—To characterise the genetic organisation and heterogeneity of iceA genotypes in different South African clinical isolates.
PATIENTS AND METHODS—We studied H pylori strains isolated from 86 dyspeptic patients (30 with peptic ulcer disease (PUD), 19 with distal gastric adenocarcinoma (GC), and 37 with non-erosive gastritis) for the presence of iceA1 or iceA2 genes, and for differences in the genetic organisation of iceA2 by polymerase chain reaction, Southern hybridisation analysis, and sequencing.
RESULTS—Genetic analysis of iceA1 demonstrated significant homology (92-95%) with the USA type strain 26695 and probably functions as a transcriptional regulator, while a novel variant (iceA2D') of iceA2 and marked differences in predicted protein secondary structure of the iceA2 protein were defined. iceA1 was detected in 68% and iceA2 in 80% of all clinical isolates. Although approximately 40% of patients had both strains, a higher prevalence (p< 0.01) of GC patients were infected with iceA1 isolates which were invariably vacA s1/iceA1 (p< 0.005 v gastritis). Isolates from PUD patients were distinguished by the structurally altered iceA2D variant (53%; p<0.03 v gastritis) while the iceA2C variant distinguished isolates from patients with gastritis alone (67%; p< 0.005 v PUD).
CONCLUSION—In this study, an association between iceA1 and GC was noted while differences in variants of iceA2 differentiated between PUD and gastritis alone. Combination analyses of iceA genotypes and vacA alleles supported these associations.


Keywords: adenocarcinoma; gastritis; Helicobacter pylori; iceA; peptic ulceration; protein prediction; sequencing; South Africa
doi:10.1136/gut.49.5.629
PMCID: PMC1728508  PMID: 11600464
4.  Investigation of the association between clinical outcome and the cag pathogenicity-island and other virulence genes of Helicobacter pylori isolates from patients with dyspepsia in Eastern Turkey 
Brazilian Journal of Microbiology  2014;44(4):1267-1274.
The aims of our work were to determine the presence of the cag pathogenicity-island (cag PAI) and other virulence genes of Helicobacter pylori recovered from patients with gastritis and peptic ulcer, and to investigate the correlation of these virulence genes with clinical outcome. The presence of the cagA, the promoter regions of cagA, cagE, cagT, and the left end of cag-PAI (LEC), cag right junction (cagRJ), the plasticity region open reading frames (ORFs), vacA and oipA genes among 69 H. pylori isolates were determined by polymerase chain reaction. Intact cag PAI was detected in only one (1.4%) isolate. The cagA gene was identified in 52.1% and 76.2% of isolates from patients with dyspepsia (gastritis and peptic ulcer), respectively. The plasticity region ORFs i.e. JHP912 and JHP931 were predominantly detected in isolates from peptic ulcer. Less than 25% of the isolates carried other ORFs. Types I, II and III were the most commonly found among the isolates. None of the isolates possessed type Ib, 1c, IIIb, IV and V motifs. The most commonly vacA genotypes were s1am1a and s1m2 in isolates with peptic ulcer and gastritis, respectively. The results confirmed that the prevalence of oipA (Hp0638) gene was 75% and 85.7% in patients with gastritis and peptic ulcer, respectively. Furthermore, vacA s1am1a positivity was significantly related to peptic ulcer (p < 0.05).
PMCID: PMC3958197  PMID: 24688521
Helicobacter pylori; gastritis; peptic ulcer; cag pathogenicity-island; polymerase chain reaction
5.  Genotyping CagA, VacA subtype, IceA1, and BabA of Helicobacter pylori isolates from Korean patients, and their association with gastroduodenal diseases. 
Journal of Korean Medical Science  2001;16(5):579-584.
The genetic status of cagA, vacA subtype, iceA1, and babA, and the relationship to gastroduodenal diseases were assessed in Helicobacter pylori isolates in Korea. Seventy-six strains of H. pylori were isolated from the antrum and the corpus of 41 adult patients (22 with peptic ulcer and 19 with gastritis). The cagA, iceA1, and babA genes were assessed by polymerase chain reaction and the vacA subtypes were determined by reverse hybridization-line probe assay. The positive rates of 349-bp cagA, 208-bp cagA, iceA1, and babA genes were 97.4%, 96.1%, 84.2%, and 36.1%, respectively. The vacA s1a, s1b, s1c, and s2 variants were detected in 11.8%, 3.9%, 80.4%, and 1.3%, respectively. m1 (78.9%) is more prevalent than m2 (5.3%). The most common vacA genotype was s1c/m1 (61.9%), and 14 isolates (18.4%) contained mixed vacA genotypes from a single biopsy specimen. Twenty-one (60%) of 35 patients were infected with more than two strains of different cagA, iceA1, babA, and vacA genotypes. None of cagA, iceA1, babA, and vacA s1/m1 were associated with peptic ulcer. In conclusion, most H. pylori isolates in Korea carry cagA, iceA1, and vacA s1c/m1 genes, and reside with multiple strains. These genes do not correlate with the peptic ulcer in the Korean patients.
PMCID: PMC3057590  PMID: 11641526
6.  Diversity of Helicobacter pylori vacA and cagA Genes and Relationship to VacA and CagA Protein Expression, Cytotoxin Production, and Associated Diseases 
Journal of Clinical Microbiology  1998;36(4):944-948.
The vacuolating cytotoxin and the cytotoxin-associated protein, encoded by vacA and cagA, respectively, are important virulence determinants of Helicobacter pylori. Sixty-five H. pylori strains were isolated from dyspeptic patients (19 with peptic ulcer disease, 43 with chronic gastritis, and 3 with gastric cancer) and studied for differences in the vacA and cagA genes and their relationship to VacA and CagA expression, cytotoxin activity, and the clinical outcome of infection. By PCR, fifty-four (83.1%) of 65 strains had the vacA signal sequence genotype s1 and only 10 (15.4%) had the type s2. After primer modification, the vacA middle-region types m1 and m2 were detected in 24 (36.9%) and 41 (63.1%) strains, respectively. The combinations s1-m2 (31 [47.7%]) and s1-m1 (23 [35.4%]) occurred more frequently than s2-m2 (10 [15.4%]) (P = 0.01). No strain with the combination s2-m1 was found. All 19 patients with peptic ulcers harbored type s1 strains, in contrast to 32 (74.4%) of 43 patients with gastritis (P = 0.02). The vacA genotype s1 was associated with the presence of cagA (P < 0.0001), VacA expression (P < 0.0001), and cytotoxin activity (P = 0.003). The cagA gene was detectable in 48 (73.8%) of 65 isolates and present in 16 (84.2%) of 19 ulcer patients and 29 (67.4%) of 43 patients with gastritis (P = 0.17). The vacA genotypes of German H. pylori isolates are identical to those previously reported. H. pylori strains of vacA type s1 are associated with the occurrence of peptic ulceration and the presence of cagA, cytotoxin activity, and VacA expression.
PMCID: PMC104665  PMID: 9542913
7.  The significance of virulence factors in Helicobacter pylori 
Journal of digestive diseases  2013;14(7):341-349.
Helicobacter pylori (H. pylori) infection is linked to various gastroduodenal diseases; however, only a small fraction of these patients develop associated diseases. Despite the high prevalence of H. pylori infection in Africa and South Asia, the incidence of gastric cancer in these areas is much lower than those in other countries. The incidence of gastric cancer tends to decrease from north to south in East Asia. Such geographic differences in the pathology can be explained, at least in part, by the presence of different types of H. pylori virulence factors in addition to the host and environmental factors. Virulence factors of H. pylori, such as cagA, vacA, dupA, iceA, oipA and babA, have been demonstrated to be predictors of severe clinical outcomes. Interestingly, meta-analysis showed that CagA seropositivity was associated with gastric cancer compared with gastritis even in East Asian countries where almost of the strains possessing cagA. Meta-analysis also confirmed the significance of vacA, dupA and iceA. However, there remains the possibility that additional important pathogenic genes can be existed because H. pylori consists of approximately 1 600 genes. Despite advances in our understanding of the development of H. pylori-related diseases, further work is required to clarify the roles of H. pylori virulence factors.
doi:10.1111/1751-2980.12054
PMCID: PMC3721066  PMID: 23452293
Helicobacter pylori; virulence factors; stomach neoplasms
8.  Association of peptic ulcer with increased expression of Lewis antigens but not cagA, iceA, and vacA in Helicobacter pylori isolates in an Asian population 
Gut  2000;47(1):18-22.
BACKGROUND—Studies in Western populations suggest that cagA, iceA, and vacA gene status in Helicobacter pylori isolates is associated with increased virulence and peptic ulcer disease.
AIM—To investigate the relationship between peptic ulcer and expression of Lewis (Le) antigens as well as cagA, iceA, and vacA in H pylori isolates in Singapore.
METHODS—Expression of Le antigens in H pylori isolates obtained from patients with dyspepsia was measured by enzyme linked immunosorbent assay. The cagA, iceA, and vacA status was determined by polymerase chain reaction.
RESULTS—Of 108 H pylori isolates, 103 (95.4%) expressed Lex and/or Ley, while Lea and Leb were expressed in 23 (21.3%) and 47 (43.5%) isolates, respectively. Expression of two or more Le antigens (Lex, Ley, Lea, or Leb) was significantly higher in H pylori isolated from ulcer patients than in non-ulcer patients (89.6% v 73.2%, p=0.035). There were no significant differences in the prevalence of cagA or iceA1 in H pylori isolates from peptic ulcer and non-ulcer patients (86.6% v 90.2% for cagA; 70.1% v 68.3% for iceA1), and no association of peptic ulcer with any specific vacA genotype.
CONCLUSIONS—The present study indicates that peptic ulcer disease is associated with increased expression of Lewis antigens but not cagA, iceA, or vacA genotype in H pylori isolates in our population. This suggests that cagA, iceA, and vacA are not universal virulence markers, and that host-pathogen interactions are important in determining clinical outcome.


Keywords: Lewis blood group antigens; cagA; iceA; vacA; Helicobacter pylori; peptic ulcer
doi:10.1136/gut.47.1.18
PMCID: PMC1727977  PMID: 10861258
9.  Clinical Relevance of the vacA, iceA, cagA, and flaA Genes of Helicobacter pylori Strains Isolated in Eastern Taiwan 
Journal of Clinical Microbiology  2005;43(6):2913-2915.
The genotypes of Helicobacter pylori flaA, cagA, vacA, and iceA were determined for DNA isolated from patients with chronic gastritis or peptic ulcer in eastern Taiwan. The vacA gene encoding the s1a subtype was found to predominate in peptic ulcer patients, and the iceA1 genotype was associated with chronic gastritis. cagA and flaA genes were not found to be associated with these types of disease.
doi:10.1128/JCM.43.6.2913-2915.2005
PMCID: PMC1151873  PMID: 15956417
10.  Distribution of Helicobacter pylori cagA, cagE, oipA and vacA in different major ethnic groups in Tehran, Iran 
Background and Aim
There are geographical variations in Helicobacter pylori virulence genes; cagA, cagE, vacA and oipA. The present study compared the distribution of these genotypes in major ethnic groups residing in Tehran, Iran and their association with clinical outcomes.
Methods
A total of 124 H. pylori-positive patients living in Tehran were enrolled in this study. The ethnic distribution was 74 Persians, 33 Turks and 17 other ethnics including Kurds, Lurs, Afghanis and Arabs. The presence of the cagA, cagE and oipA genes and vacA alleles (signal [s] and middle [m] region) were determined by polymerase chain reaction (PCR) from H. pylori DNA.
Results
The cagA-positive status was predominant in all three ethnic groups (e.g. 65% in Persians and 73% in Turks). In contrast, the cagE-positive status was less than half in Persians (47%) and Turks (30%), whereas it was 77% in other ethnicities (P = 0.008). The predominant vacA genotypes were s1 and m1 in all three ethnic groups (e.g. 68% in Persians and 70% in Turks were s1). There was no significant association between cagA and cagE status or vacA genotypes and clinical outcomes. The oipA-positive strains were more common in non-ulcer dyspepsia (NUD) (63%) than in peptic ulcer patients (15%) (P = 0.001) in Persians, but the association was not observed in other ethnic groups.
Conclusion
There are some differences in the H. pylori genotypes among the ethnic groups in Iran. However, none of these markers seemed to be clinically helpful in predicting the clinical presentation of a H. pylori infection in Iran.
doi:10.1111/j.1440-1746.2009.05876.x
PMCID: PMC3128249  PMID: 19702906
clinical outcome; ethnic; Helicobacter pylori genotype; Iran; virulence factor
11.  Clinical and histological associations of cagA and vacA genotypes in Helicobacter pylori gastritis. 
Journal of Clinical Pathology  1998;51(1):55-61.
AIMS: To determine the relation among the cytotoxin associated gene (cagA) and vacuolating cytotoxin gene (vacA) status of Helicobacter pylori isolates, the associated clinical diseases, and the severity and pattern of chronic gastritis. METHODS: Helicobacter pylori was cultured from gastric biopsies obtained from dyspeptic patients. DNA was extracted from the isolates and the cagA and vacA status determined by the polymerase chain reaction (PCR). The prevalence of the different cagA and vacA genotypes in three clinical groups, duodenal ulcer, gastric ulcer, and non-ulcer dyspepsia was compared. The histological features in sections from two antral and two corpus biopsies were graded by one blinded observer. The grades were compared with age and sex matched groups with different cagA and vacA genotypes, and with duodenal ulcers, or non-ulcer dyspepsia. RESULTS: Isolates from 161 patients were included. One hundred and nine (68%) harboured a cagA+ strain and 143 (89%) harboured a vacA s1 strain. The prevalence of cagA+ strains in duodenal ulcer patients (94%) was highly significantly greater than in those with non-ulcer dyspepsia (56%). However, of the patients infected with a cagA+ strain, almost equal numbers had non-ulcer dyspepsia or peptic ulceration. Chronic inflammation, polymorph activity, surface epithelial degeneration, atrophy, and intestinal metaplasia were all significantly more severe in the cagA+ than in the cagA- group, whereas only corpus epithelial degeneration was significantly more severe in the vacA s1 group compared with the vacA s2 group. Patients infected with cagA+ strains were almost four times more likely to have antral intestinal metaplasia than cagA- patients. An antral predominant gastritis was present in duodenal ulcer patients compared with matched non-ulcer dyspepsia patients, but this was not attributable to cagA or vacA status. CONCLUSIONS: Helicobacter pylori strains showing cagA positively and the vacA s1 genotype are associated with more severe gastritis but these virulence factors do not appear to determine the overall pattern. The pattern is closely linked to clinical disease. Therefore, it is likely that the nature of the disease complicating chronic infection is determined by host and environmental factors, while bacterial factors determine the magnitude of the risk of developing such disease.
Images
PMCID: PMC500433  PMID: 9577374
12.  DNA-Level Characterization of Helicobacter pylori Strains from Patients with Overt Disease and with Benign Infections in Bangladesh 
Journal of Clinical Microbiology  2003;41(5):2008-2014.
The complex relation between the genotype of Helicobacter pylori and its association with clinical outcome is not well understood. Studies in the West have showed that strains expressing certain virulence factors (vacAs1, vacAm1, and cagA) are associated with duodenal ulcer disease. However, the H. pylori genotype is known to vary with geographic region. In the present study, we compared several virulence markers (cagA, vacA, and iceA) and neutral markers (IS605, IS606, and IS608) in H. pylori strains isolated from 65 adult patients with peptic ulcer (PU) and 50 patients with nonulcer dyspepsia (NUD). PCR tests indicated that cagA is present in 75% of the strains from patients with PU compared to 55% in patients with NUD, and 80% of the isolates from patients with PU carried potentially toxigenic vacAs1 alleles of the vacuolating cytotoxin gene (vacA) compared to 60% in isolates from patients with NUD. However, no significant difference in any other virulence marker was observed in isolates from both groups. Phylogenetic analysis of the vacA middle region and the 5′ end of the cagA gene indicates that Bangladeshi isolates are more closely related to H. pylori isolates from India and are different from isolates from East Asia.
doi:10.1128/JCM.41.5.2008-2014.2003
PMCID: PMC154730  PMID: 12734242
13.  Frequency of vacA, cagA and babA2 virulence markers in Helicobacter pylori strains isolated from Mexican patients with chronic gastritis 
Background
Helicobacter pylori has been strongly associated with chronic gastritis, peptic and duodenal ulcers, and it is a risk factor for gastric cancer. Three major virulence factors of H. pylori have been described: the vacuolating toxin (VacA), the cytotoxin-associated gene product (CagA) and the adhesion protein BabA2. Since considerable geographic diversity in the prevalence of H. pylori virulence factors has been reported, the aim of this work was to establish the H. pylori and vacA, cagA and babA2 gene status in 238 adult patients, from a marginal urban area of Mexico, with chronic gastritis.
Methods
H. pylori was identified in cultures of gastric biopsies by nested PCR. vacA and cagA genes were detected by multiplex PCR, whereas babA2 gene was identified by conventional PCR.
Results
H. pylori-positive biopsies were 143 (60.1%). All H. pylori strains were vacA+; 39.2% were cagA+; 13.3% were cagA+ babA2+ and 8.4% were babA2+. Mexican strains examined possessed the vacA s1, m1 (43.4%), s1, m2 (24.5%), s2, m1 (20.3%) and s2, m2 (11.9%) genotypes.
Conclusion
These results show that the Mexican patients suffering chronic gastritis we have studied had a high incidence of infection by H. pylori. Forty four percent (63/143) of the H. pylori strains analyzed in this work may be considered as highly virulent since they possessed two or three of the virulence markers analyzed: vacA s1 cagA babA2 (9.8%, 14/143), vacA s1 babA2 (4.9%, 7/143), and vacA s1 cagA (29.4%, 42/143). However, a statistically significant correlation was not observed between vacAs1, cagA and babA2 virulence markers (χ2 test; P > 0.05).
doi:10.1186/1476-0711-8-14
PMCID: PMC2683802  PMID: 19405980
14.  Regulation of Gastric Carcinogenesis by Helicobacter pylori Virulence Factors 
Cancer research  2008;68(2):379-387.
Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, and strains that possess the cag secretion system, which translocates the bacterial effector CagA into host cells, augment cancer risk. H. pylori strains that express the vacuolating cytotoxin or the outer membrane protein OipA are similarly associated with severe pathologic outcomes. We previously reported that an in vivo adapted H. pylori strain, 7.13, induces gastric adenocarcinoma in rodent models of gastritis. In the current study, we used carcinogenic strain 7.13 as a prototype to define the role of virulence constituents in H. pylori–mediated carcinogenesis. Mongolian gerbils were infected with wild-type strain 7.13 or cagA−, vacA−, or oipA− mutants for 12 to 52 weeks. All infected gerbils developed gastritis; however, inflammation was significantly attenuated in animals infected with the cagA− but not the vacA− or oipA− strains. Gastric dysplasia and cancer developed in >50% of gerbils infected with either the wild-type or vacA− strain but in none of the animals infected with the cagA− strain. Inactivation of oipA decreased β-catenin nuclear localization in vitro and reduced the incidence of cancer in gerbils. OipA expression was detected significantly more frequently among H. pylori strains isolated from human subjects with gastric cancer precursor lesions versus persons with gastritis alone. These results indicate that loss of CagA prevents the development of cancer in this model. Inactivation of oipA attenuates β-catenin nuclear translocation and also decreases the incidence of carcinoma. In addition to defining factors that mediate H. pylori–induced cancer, these results provide insight into mechanisms that may regulate the development of other malignancies arising within the context of inflammatory states.
doi:10.1158/0008-5472.CAN-07-0824
PMCID: PMC3114460  PMID: 18199531
15.  Helicobacter pylori babA2, cagA, and s1 vacA genes work synergistically in causing intestinal metaplasia 
Journal of Clinical Pathology  2003;56(4):287-291.
Aims: To determine any associations between the Helicobacter pylori genes babA2, oipA, cagA and the s and m alleles of vacA. In addition, to verify whether these genes work synergistically or independently in causing gastritis, peptic ulcer, and intestinal metaplasia.
Methods: One hundred and sixty seven H pylori positive patients were studied (52 antral gastritis, 41 diffuse gastritis, 41 peptic ulcer, and 33 duodenitis). Helicobacter pylori virulence genes were amplified by means of the polymerase chain reaction.
Results: Significant associations were found between babA2 and the other H pylori genes studied. When considered singly, all the genes were associated with disease diagnosis, inflammation, and intestinal metaplasia. Four H pylori groups were defined. Group A: cagA−, s2m2, babA2−; group B: cagA+, s1m1, babA2+; group C: cagA+, s1m2, babA2+; group D: cagA+, s1m2, babA2−. Group A infecting strains were associated with less severe endoscopic and inflammatory conditions, whereas group B strains were associated with the worst endoscopic and inflammatory findings. Intestinal metaplasia was a rare finding in group A infected patients (< 10%), whereas it was frequent in those infected with group B strains (48%).
Conclusions: The H pylori genes cagA, oipA “on”, s1 and m1 vacA, and babA2 are associated with each other, possibly as a result of shared selective pressure. When coexpressed by the same H pylori strain, cagA, s1 and m1 vacA, and babA2 work synergistically in worsening inflammation. Infections caused by strains coexpressing cagA, s1m1 vacA, and babA2 are those at higher risk for intestinal metaplasia.
PMCID: PMC1769933  PMID: 12663641
babA2; intestinal metaplasia; cagA; vacA
16.  Conservation of the cag pathogenicity island is associated with vacA alleles and gastroduodenal disease in South African Helicobacter pylori isolates 
Gut  2001;49(1):11-17.
BACKGROUND—The development of clinically significant disease in South Africa is associated with the vacuolating cytotoxin gene (vacA) s1 genotype but not with the presence of the cytotoxin associated gene cagA. cagA occurs in >95% of South African isolates and is a variable marker for the entire cag pathogenicity island (PAI).
AIM—To characterise the cagPAI in South African isolates and to investigate if structural variants of this multigene locus were associated with variations in vacA status and clinical outcome.
PATIENTS AND METHODS—We studied 109 Helicobacter pylori strains (36 from patients with peptic ulceration, 26 with gastric adenocarcinoma, and 47 with no pathology other than gastritis) for differences in selected genes of the cagPAI and alleles of vacA by polymerase chain reaction.
RESULTS—All strains were cagA+. Sixty five (60%) strains had an intact contiguous cagPAI; 78% of peptic ulcer isolates, 73% of gastric adenocarcinoma isolates, but only 40% of gastritis alone isolates (p< 0.01). The entire cagII region was undetectable in 23% of gastritis alone isolates but in only 8% of peptic ulceration isolates (p<0.05). The vacA signal sequence and mid region demonstrated a strong relationship between the virulence associated vacA s1 (p<0.005) and vacA m1 (p=0.05) alleles and an intact cagPAI.
CONCLUSION—Although a complete cagPAI was a feature of most infected individuals, deletions in the 5' region of this genetic locus were associated with gastritis alone and with the non-cytotoxic s2/m2 vacA genotype.


Keywords: cagA; gastric cancer; Helicobacter pylori; pathogenicity; peptic ulcer; vacuolating cytotoxin
doi:10.1136/gut.49.1.11
PMCID: PMC1728366  PMID: 11413104
17.  Comparative genomics of Helicobacter pylori isolates recovered from ulcer disease patients in England 
BMC Microbiology  2005;5:32.
Background
Genomic diversity of H. pylori from many different human populations is largely unknown. We compared genomes of 65 H. pylori strains from Nottingham, England. Molecular analysis was carried out to identify rearrangements within and outside the cag-pathogenicity-island (cag PAI) and DNA sequence divergence in candidate genes. Phylogenetic analysis was carried out based on various high-resolution genotyping techniques.
Results
Analyses of virulence genes (cagT, cagE, cagA, vacA, iceA, oipA and babB) revealed that H. pylori strains from England are genetically distinct from strains obtained from other countries. The toxigenic vacA s1m1 genotype was found to be less common and the plasticity region cluster was found to be disrupted in all the isolates. English isolates showed a predominance of iceA1 alleles and a functional proinflammatory oipA gene. The English H. pylori gene pool revealed several Asian/oriental features. This included the predominance of cagA – glr (cagA right junction) motif types III and II (up to 42%), presence of vacA m1c alleles and phylogenetic affinity towards East Asian / Amerindian gene pools based on fluorescent amplified fragment length polymorphism (FAFLP) analysis and glmM sequence analysis.
Conclusion
Overall, our results demonstrated genetic affinities of H. pylori in England with both European and the Asian gene pools and some distinctive genetic features of virulence genes that may have evolved in this important European population.
doi:10.1186/1471-2180-5-32
PMCID: PMC1180443  PMID: 15916705
18.  cagA and vacA in strains of Helicobacter pylori from ulcer and non-ulcerative dyspepsia patients 
BMC Gastroenterology  2002;2:20.
Background
The cytotoxin associated gene A (cagA), and the vacuolating cytotoxin gene A (vacA) of Helicobacter pylori have been associated to phenotypic characteristics of virulence. The objectives of this study were to detect the presence of cagA and to characterize the allelic variants of vacA in 63 strains of H. pylori isolated from colonized individuals with different clinical outcomes.
Methods
38 strains were isolated from patients with non-ulcerative dyspepsia (NUD) and 25 were isolated from colonized individuals with peptic ulcers. The genotypic characterization was carried out utilizing PCR methodology. The presence of the cagA gene was detected using two set of primers from the middle conservative region of the cagA, and primers for the signal and middle region were used for the genotyping of vacA
Results
The presence of cagA showed similar rates in strains from peptic ulcers (60%) and NUD patients (55%). Also similar was the prevalence of the allelic form s1 of vacA between the strains obtained from ulcers or NUD patients. However, the combination cagA+/vacA s1m1 was found more frequently among the H. pylori strains from peptic ulcer patients (52%) than among strains isolated from NUD patients (26%), this difference was statistically significant (p = 0.035).
Conclusions
The presence of either cagA or the allelic variant s1 vacA alone do not have a predictive value as as a risk markers of severe gastric pathologies in the Chilean population. However, being infected by a H. pylori strain with the genotype cagA+/vacA s1m1 may be associated to an increased risk of acquiring a peptic ulcer disease.
doi:10.1186/1471-230X-2-20
PMCID: PMC128829  PMID: 12223115
19.  Relationship between Helicobacter pylori Virulence Genes and Clinical Outcomes in Saudi Patients 
Journal of Korean Medical Science  2012;27(2):190-193.
Helicobacter pylori has been strongly associated with gastritis, gastric and duodenal ulcers, and it is a risk factor for gastric cancer. Two major virulence factors of H. pylori have been described: the cytotoxin-associated gene product (cagA) and the vacuolating toxin (vacA). Since considerable geographic diversity in the prevalence of H. pylori virulence factors has been reported, the aim of this work was to determine if there is a significant correlation between different H. pylori virulence genes (cagA and vacA) in 68 patients, from Saudi Arabia, and gastric clinical outcomes. H. pylor was recognized in cultures of gastric biopsies. vacA and cagA genes were detected by polymerase chain reaction (PCR). The cagA gene was obtained with 42 isolates (61.8%). The vacA s- and m- region genotypes were determined in all strains studied. Three genotypes were found: s1/m1 (28%), s1/m2 (40%) and s2/m2 (26%). The s2/m1 genotype was not found in this study. The relation of the presence of cagA and the development of cases to gastritis and ulcer was statistically significant (P < 0.05). The study showed a significant correlation between the vacA s1/m2 genotype and gastritis cases, and a significant correlation between vacA s1/m1 genotype and peptic ulcer cases. The results of this study might be used for the identification of high-risk patients who are infected by vacA s1/m1 genotype of H. pylori strains. In conclusion, H. pylori strains of vacA type s1 and the combination of s1/m1 were associated with peptic ulceration and the presence of cagA gene.
doi:10.3346/jkms.2012.27.2.190
PMCID: PMC3271293  PMID: 22323867
Helicobacter pylori; cagA; vacA; Gastritis; Peptic Ulcer
20.  Prevalence of Helicobacter pylori vacA, cagA and iceA genotypes and correlation with clinical outcome 
The aim of this study was to assess the genetic status of cagA, vacA subtype and iceA genotypes of Helicobacter pylori and the relationship with upper gastrointestinal diseases in Northeast China. Gastric biopsies were obtained from 378 patients with upper gastrointestinal diseases and 197 samples were used. The cagA, vacA alleles and iceA genotypes were determined by polymerase chain reaction. CagA was present in 176 (89.3%) of 197 patients. Of the 197 cases, 186 (94.4%) had vacA signal sequence s1c allele, 6 (3%) had s1a and 5 (2.5%) had s1b. The vacA s2 genotype was not detected in our study. VacA middle region sequences, m1 and m2, were found in 20 (10.2%) and 150 (76.1%), respectively. The allelic variant iceA1 (70.1%) was more prevalent than iceA2 (23.4%). The vacA allele s1am2 had a significant relationship with the presence of gastric cancer (p<0.05) and the iceA1 genotype was also associated with gastric cancer (p<0.05). These may be useful risk factors for upper gastrointestinal diseases.
doi:10.3892/etm.2012.704
PMCID: PMC3494117  PMID: 23226771
Helicobacter pylori; prevalence; genotype; Northeast China
21.  Comparing Genomes of Helicobacter pylori Strains from the High-Altitude Desert of Ladakh, India 
Journal of Clinical Microbiology  2005;43(4):1538-1545.
The genomic diversity of Helicobacter pylori from the vast Indian subcontinent is largely unknown. We compared the genomes of 10 H. pylori strains from Ladakh, North India. Molecular analysis was carried out to identify rearrangements within and outside the cag pathogenicity island (cag PAI) and DNA sequence divergence in candidate genes. Analyses of virulence genes (such as the cag PAI as a whole, cagA, vacA, iceA, oipA, babB, and the plasticity cluster) revealed that H. pylori strains from Ladakh are genetically distinct and possibly less virulent than the isolates from East Asian countries, such as China and Japan. Phylogenetic analyses based on the cagA-glr motifs, enterobacterial repetitive intergenic consensus patterns, repetitive extragenic palindromic signatures, the glmM gene mutations, and several genomic markers representing fluorescent amplified fragment length polymorphisms revealed that Ladakhi strains share features of the Indo-European, as well as the East Asian, gene pools. However, the contribution of genetic features from the Indo-European gene pool was more prominent.
doi:10.1128/JCM.43.4.1538-1545.2005
PMCID: PMC1081395  PMID: 15814963
22.  Helicobacter pylori Virulence Factor Genotypes in Children in the United States: Clues about Genotype and Outcome Relationships▿  
Journal of Clinical Microbiology  2010;48(7):2550-2551.
The most common Helicobacter pylori genotype among 37 U.S. children was cagA positive, vacA s1m1, and oipA “on” (n = 17, 45.9%), followed by cagA negative, vacA s2m2, and oipA “off” (n = 8, 21.6%), similar to the pattern in adults. cagA positivity was more common in blacks than in whites (i.e., 100% versus 56.5%, P = 0.032).
doi:10.1128/JCM.00114-10
PMCID: PMC2897538  PMID: 20421443
23.  Association between cagA and vacA genotypes and pathogenesis in a Helicobacter pylori infected population from South-eastern Sweden 
BMC Microbiology  2012;12:129.
Background
Chronic gastritis, peptic ulcer disease, and gastric cancer have been shown to be related to infection with Helicobacter pylori (H. pylori). Two major virulence factors of H. pylori, CagA and VacA, have been associated with these sequelae of the infection. In this study, total DNA was isolated from gastric biopsy specimens to assess the cagA and vacA genotypes.
Results
Variations in H. pylori cagA EPIYA motifs and the mosaic structure of vacA s/m/i/d regions were analysed in 155 H. pylori-positive gastric biopsies from 71 individuals using PCR and sequencing. Analysis of a possible association between cagA and vacA genotypes and gastroduodenal pathogenesis was made by logistic regression analysis. We found that H. pylori strains with variation in the number of cagA EPIYA motif variants present in the same biopsy correlated with peptic ulcer, while occurrence of two or more EPIYA-C motifs was associated with atrophy in the gastric mucosa. No statistically significant relation between vacA genotypes and gastroduodenal pathogenesis was observed.
Conclusions
The results of this study indicate that cagA genotypes may be important determinants in the development of gastroduodenal sequelae of H. pylori infection. In contrast to other studies, vacA genotypes were not related to disease progression or outcome. In order to fully understand the relations between cagA, vacA and gastroduodenal pathogenesis, the mechanisms by which CagA and VacA act and interact need to be further investigated.
doi:10.1186/1471-2180-12-129
PMCID: PMC3520705  PMID: 22747681
Chronic gastritis; Atrophy; Intestinal metaplasia; Peptic ulcer; Duodenal ulcer; CagA EPIYA motif; VacA mosaic structure
24.  Prevalence of genotypes in Helicobacter pyloriisolates from patients in eastern Turkey and the association of these genotypes with clinical outcome 
Brazilian Journal of Microbiology  2012;43(4):1332-1339.
There is not much information available regarding the prevalence of the genotypes of Helicobacter pylori isolates in Turkey, particularly in eastern Turkey. The aims of this study were to detect the prevalence of different genotypes of H. pylori in Turkish patients with gastrointestinal complaints and to determine the relationship of these genotypes with clinical outcome and sex. One hundred forty H. pylori isolates were examined for the presence of its genotypes by the PCR. We found that the prevalence of vacAs1,vacAs2, cagA, cagE, iceA1, iceA2 and babA2 genes were 88.6%, 11.4%, 71.4%, 35.7%, 41.4%, 58.6%, and 62.1%, respectively. The most predominant vacA subtype was s1a (81.4%). The most vacA allelic combination detected were vacAs1m1 (65.2%) and s1m2 (53.9%) in patients with peptic ulcer and gastritis, respectively. The only vacAs1 isolate was significantly associated with gastritis and peptic ulcer (p<0.05). The vacAs1a, ml, slml and babA2 genes were significantly associated with peptic ulcer (p<0.05), whereas m2 gene was significantly associated with only gastritis (p<0.05). The difference between sex and genotypes was statistically significant among the cagA,vacAs1, iceA2 and babA2 genes. This study reported for the first time the prevalence of H. pylori genotypes in patients with gastrointestinal complaints in eastern Turkey. Further studies are needed to understand epidemiological importance of the genotypes of H. pylori isolates in this region and the association between the virulence genes and clinical outcome in different regions.
doi:10.1590/S1517-838220120004000014
PMCID: PMC3769024  PMID: 24031961
Helicobacter pylori; prevalence; patient; genotypes; PCR
25.  Analysis of antimicrobial susceptibility and virulence factors in Helicobacter pylori clinical isolates 
BMC Gastroenterology  2003;3:20.
Background
In this study, we evaluated the prevalence of primary resistance of Brazilian H. pylori isolates to metronidazole, clarithromycin, amoxicillin, tetracycline, and furazolidone. In addition, the vacA, iceA, cagA and cagE genotypes of strains isolated from Brazilian patients were determined and associated with clinical data in an effort to correlate these four virulence markers and antibiotic resistance.
Methods
H. pylori was cultured in 155 H. pylori-positive patients and MICs for metronidazole, clarithromycin, amoxicillin, tetracycline, and furazolidone were determined by the agar dilution method. Genomic DNA was extracted, and allelic variants of vacA, iceA, cagA and cagE were identified by the polymerase chain reaction.
Results
There was a strong association between the vacA s1/cagA -positive genotype and peptic ulcer disease (OR = 5.42, 95% CI 2.6–11.3, p = 0.0006). Additionally, infection by more virulent strains may protect against GERD, since logistic regression showed a negative association between the more virulent strain, vacA s1/cagA-positive genotype and GERD (OR = 0.26, 95% CI 0.08–0.8, p = 0.03). Resistance to metronidazole was detected in 75 patients (55%), to amoxicillin in 54 individuals (38%), to clarithromycin in 23 patients (16%), to tetracycline in 13 patients (9%), and to furazolidone in 19 individuals (13%). No significant correlation between pathogenicity and resistance or susceptibility was detected when MIC values for each antibiotic were compared with different vacA, iceA, cagA and cagE genotypes.
Conclusion
The analysis of virulence genes revealed a specific association between H. pylori strains and clinical outcome, furthermore, no significant association was detected among pathogenicity and resistance or susceptibility.
doi:10.1186/1471-230X-3-20
PMCID: PMC194586  PMID: 12911839

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