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| Year : 2010 | Volume
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| Issue : 1 | Page : 24-27 |
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| CagA status and VacA subtypes of Helicobacter pylori in relation to histopathologic findings in Iranian population |
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Mahsa Molaei1, Forough Foroughi1, Reza Mashayekhi1, Mehrdad Haghazali2, Homayoon Zojaji2, Fereshteh Jafari3, Hossein Dabiri3, Mohammad Reza Zali2
1 Department of Pathology, Research Center for Gastroenterology and Liver Disease, Shaheed Beheshti University, M.C., Tehran, Iran
2 Department of Gastroenterology, Research Center for Gastroenterology and Liver Disease, Shaheed Beheshti University, M.C., Tehran, Iran
3 Department of Microbiology, Research Center for Gastroenterology and Liver Disease, Shaheed Beheshti University, M.C., Tehran, Iran
Click here for correspondence address and email
| Date of Web Publication | 19-Jan-2010 |
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 Abstract | | |
Background/Objective: The aim of this study was to detect dominant cagA/vacA genotypes of Helicobacter Pylori (H. pylori) and determine correlations between different cagA/vacA genotypes and histologic features of chronic gastritis in Iranian patients. Methods: Gastric biopsy was taken from 166 patients with nonulcer dyspepsia. The specimens were processed and DNA from each H. pylori isolate was extracted from multiple colony sweeps for identification of glmM gene. The vacA subtypes and cagA gene were tested by PCR . Histopathological features were recorded and graded according to partial Sydney system. Results: Of the 86 strains, 66 (76.7%) were cagA positive. The proportions of vacA gene subtypes s1, s2, m1 and m2 in the 78 strains isolated were 70.5%, 29.5%, 37.2% and 62.8%, respectively. About 83.3% of the vacA-positive strains had s1 allele. Twenty-six strains (33.3%) were positive for both cagA and m1 allele. Positive cagA status and vacA subtypes were not associated significantly with presence of neutrophil infiltration, intestinal metaplasia or H. pylori density. Only vacA s1 was significantly associated with more severe inflammation (P=0.02). The dominant genotype of H. pylori was vacA plus s1/m2. CagA gene positivity rate was not closely associated with severity of the disease. Conclusion: H. pylori strains showing vacA s1 genotype were associated with more severe gastritis. These findings show that vacA genotyping may have clinical relevance in Iran. Keywords: Helicobecter pylori , cagA status, vacA subtypes
How to cite this article:
Molaei M, Foroughi F, Mashayekhi R, Haghazali M, Zojaji H, Jafari F, Dabiri H, Zali M. CagA status and VacA subtypes of Helicobacter pylori in relation to histopathologic findings in Iranian population. Indian J Pathol Microbiol 2010;53:24-7 |
How to cite this URL:
Molaei M, Foroughi F, Mashayekhi R, Haghazali M, Zojaji H, Jafari F, Dabiri H, Zali M. CagA status and VacA subtypes of Helicobacter pylori in relation to histopathologic findings in Iranian population. Indian J Pathol Microbiol [serial online] 2010 [cited 2023 May 30];53:24-7. Available from: https://www.ijpmonline.org/text.asp?2010/53/1/24/59178 |
| Introduction | |  |
Helicobacter pylori (H. pylori) is a gram-negative rod and has been associated with gastro duodenal disease. It is estimated that H. pylori infects more than 50% of the world's population. In a seroepidemiologic study in different parts of Iran, prevalence of H. pylori infection was found to be about 90% in adults over 35 years. [1] There is evidence for existence of different strains of H. pylori with different degrees of virulence. [2],[3]
Cytotoxin-associated protein (cagA) and vacuolating cytotoxin (vacA) encoded by cagA and vacA genes, respectively, are two major well known virulence factors of H. pylori. Presence of cagA gene has been reported in approximately 60% of H. pylori strains from Western populations as well as over 90% from South East Asian populations. [4],[5],[6],[7]
CagA gene in H. pylori strain is an indicator marker for presence of cag pathogenicity island (cag PAI), which is associated with more virulent H. pylori strains and more severe outcome of the infection. [8] Infection with the cagA positive H. pylori strain has been associated with higher grades of gastric mucosal inflammation and has been suggested to play an important role in the development of gastric carcinoma. [9],[10] The H. pylori vacA gene encodes protein vacA that exhibit a pleiotropic activity on gastric epithelial cells and T lymphocytes. It is present almost in all H. pylori strains. According to the alignment of the vacA nucleotide sequences of toxigenic and nontoxigenic H. pylori strains two distinct families of s1 (s1a; s1b) and s2, with one of the two different vacA alleles in the middle region (m1 and m2) have been described. All combinations of these alleles are possible, with the exception of s2m1, suggesting that re combination may occur in nature between different vacA alleles. [11] Studies conducted in several countries have shown that vacA-type s1 and cagA-positive H. pylori strains are associated with severe H. pylori-induced peptic ulcer disease (PUD). [12],[13],[14]
Thus, existing data is contradictory. Furthermore, it might be useful to know the genetic diversity of H. pylori strains in Iran, a region with a high frequency of H. pylori-induced gastric disease.
This study was designed to investigate the cagA gene and vacA subtypes of H. pylori strains isolated from patients with chronic gastritis and determine local dominant cagA/vacA genotypes of the microbe.
| Material and Methods | | |
Patients
This cross sectional study was conducted on 166 patients with nonulcer dyspepsia (chronic gastritis) who had undergone upper GI-endoscopy during February to December 2006 in a tertiary care hospital, Tehran, Iran.
Patients with peptic ulcer disease, bleeding complications, history of treatment for H. pylori eradication, previous gastric resection, use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), or antibiotics two weeks before the study were excluded from the study.
A questionnaire including clinical data about age, gender, chief complaint, medical history, medication used and family history of gastric polyp/cancer was completed for each patient.
All patients gave informed consent and the study was approved by the Ethical committee of research center for Gastroentrology and liver disease of Shahid Beheshti university of medical sciences.
Histopathology
During endoscopy, two biopsy specimens were taken from the antrum for histologic evaluation. These specimens were fixed in 10% buffered formalin, embedded in paraffin, cut in sequential 4µm sections and stained with hematoxylin and eosin (H and E) and modified Giemsa stain. Multiple high powered fields were examined by two pathologists blinded to the characteristics of H. pylori strains. Severity of gastritis was graded histologically using the partial Sydney classification system criteria. [15] H. pylori density, atrophy, intestinal metaplasia, polymorphonuclear cell infiltration and mononuclear cell infiltration were determined and scored as normal (score is equal to zero), mild (score is equal to one), moderate (score is equal to two and marked (score is equal to three).
Isolation and Identification
Three biopsy specimens were taken from the greater curvature of the antrum; two were used for histological examination and one for H. pylori culture. Specimens for culture were kept in transport medium consisting of thyoglycolate with 1.3 g/L Agar (Merck Co, Humbuerg, Germany) with 3% yeast extract (Oxoid Ltd., Basingstoke,. UK) and brought to the laboratory on the day of endoscopy. The gastric biopsy specimens were cultured on Brusella Agar with seven per cent sheep blood and supplements with different antibiotics, incubated under microaerophilic conditions at 37°C for three to 10 days.
Preparation of Genomic DNA and Polymerase Chain Reaction
H. pylori DNA was extracted from the multiple colony sweeps using QIAamp tissue kit (Qiagen, Hilden, Germany). The genotypes of vacA single sequences (s1 or s2) and middle regions (m1 or m2), the presence of cagA and glmM (phosphoglucosamine mutase) (ureC) were determined by polymerase chain reaction (PCR). Primer sequences are listed in [Table 1]. All PCR mixtures were prepared in a volume of 25 µl, contain 1 PCR buffer, 500 nM of each primer, 1.5 mM MgCl 2 ; 200µM from each dNTP, 1.5U Taq DNA polymerase, and 300ng DNA sample. The mixtures were placed in a thermocycler (Eppendorf AG 22331, Hamburg, Germany). PCR products were visualized by electrophoresis in 1.5% agarose gel, stained with ethidium bromide, and examined under UV illumination.
Data Analysis
Chi Square and Fisher's exact tests were used in data analysis for categorical data. The Mann-Whitney rank sum test was used in assessing differences between ordered categories such as histological grade or cytotoxin production. Sigma Stat for Windows V2.03 (SPSS, Chicago, IL) was applied for data analysis and p values equal or less than 0.05 were considered statistically significant.
| Results | | |
A total of 166 patients including 80 (48.2%) female and 86 (51.8%) male with the mean age of 47.78 (20-82) years were studied. Eighty six of the patients who had positive product for glmM gene were included in this study.
VacA and CagA Status of Isolates
Of the 86 strains, 66 (76.7%) were cagA positive. Complete vacA s and m region genotype was obtained in 78 out of 86 cases (90.7%). Repeated experiments failed to yield PCR product for the other eight patients. Typing of the signal region and middle region of the vacA gene from 78 strains showed that the s1 allele was present in 55 of the 78 isolates (70.5%). Another 23 strains (29.5%) were positive for s2 allele; 83.3% of the cagA-positive strains had s1 allele and 72.2% of the 28 cagA-negative strains had s2 allele (p less than 0.001) [Table 2].
The m1 allele of the middle region was detected in 29 strains (37.2%) while m2 allele was found in 49 strains (62.8%). Twenty-six strains (33.3%) were positive for both cagA and m1 allele while 34 strains (43.6%) were positive for both cagA and m2 allele (p is equal to 0.04).
Intestinal metaplasia was seen in 11 (12.8%) antral specimens. Eight (72%) of the H. pylori isolates obtained from these patients were cagA positive (p is equal to 0.7). No difference was seen between various types of vacA genotypes and intestinal metaplasia.
H. pylori Density and Histopathological Findings
In all 86 patients, chronic gastritis with different severities was confirmed by histopathology. Antral biopsy of seven patients was negative for H. pylori in histopathologic study but they were positive for expression of glmM gene.
The degree of H. pylori density was mild in 24.4%, moderate in 33.7% and severe in 41.9%. The degree of H. pylori colonization was significantly correlated with the degree of gastric neutrophil infiltration (P < 0.001) and the degree of mononuclear cell infiltration (p = to 0.003) but not with the presence of intestinal metaplasia (P = 0.08) or dysplasia (P = 0.34).
H. pylori Density and CagA Status and VacA Subtypes
Fifty of the 65 subjects (76.9%), who had a denser (moderate or severe) H. pylori colonization, were cagA positive. There was no statistically significant association between cagA presence and density of H. pylori (P = 0.94). The degree of H. pylori colonization was independent from vacA signal region type s1 or s2 (P = 0.99), and middle region m1 or m2 (p = 0.85).
CagA Status and Histopathological Findings
Positive cagA status was not associated significantly with presence of neutrophil infiltration, intestinal metaplasia, H. pylori density or degree of mononuclear cell infiltration.
VacA Alleles and Histopathological Findings
The presence of specific vacA signal region type (s1 or s2) or middle region type (m1 or m2) had no significant association with the degree of H. pylori colonization (p = 0.51 and 0.61, respectively), or neutrophil infiltration (p = 0.16 and p = 0.92, respectively). Only vacA s1 was significantly associated with more severe mononuclear cell infiltration (P = 0.02) [Table 3].
| Discussion | | |
H. pylori are one of the most genetically diverse bacterial species; [1] and there are geographic genetic variations among H. pylori strains. Studies in several countries have demonstrated differences in the distribution of vacA alleles and the presence of cagA gene in genotypes of H. pylori strains and their association with gastro duodenal diseases. [16],[17],[18],[19]
In Europe and North America, prevalence of cagA-positive H. pylori varies between 64% and 79% [11],[13] whereas in Asia (e.g. Japan, Korea, China and Turkey), the proportion of cagA positive H. pylori strains is usually over 90%. [13],[20],[21] Few data is available about cagA status in Iran. CagA was present in 44% of the patients according to an investigation by Siavoshi et al. [22] This number was 76.7% in our study; near the European and North American populations. Many studies showed that cagA has a significant association with increased severity of chronic gastritis and presence of atrophic gastritis; although we found no statistically significant differences among strains with or without cagA gene. Associations of cagA status and diseases are not observed in Asian countries; where majority of H. pylori strains are cagA-positive. [13],[14] Surprisingly, the previous study from Iran reported more frequency of positive cagA only among patients with gastric cancer. [22]
The vacA genotypes show considerable geographic variability. Our study showed that the signal sequence of the vacA gene was of the s1 type in 70.5% of isolates, and the midregion of the gene was m2 type in 62.8% of isolates. A recent study reported the same results on the signal sequence in Iranian isolates (78%). [22] This observation is similar to China and Turkey; [20],[21] but in the middle region, results are substantially different from Brazil and Portugal with m1 dominant type. [23],[24] Also, Aydin et al. from Turkey and the large multicenter study of van Doorn et al. reported an equal prevalence of m1 and m2 subtypes. [25],[26]
Similar to other reports, [27] we also found that cagA and vacA s1 were highly significantly associated with each other (p < 0.001) and vacA s2 genotype was more frequent in cagA negative patients (p < 0.001). Also patients with type s1 strains had more severe degree of mononuclear cell infiltration compared to type s2 strains (p = 0.02). Similarly, Martins et al. [23] and Nogueira et al. [24] observed that allele s1 is associated with high degrees of gastric tissue inflammation; although this correlation was in companion with cagA positivity and m1 allele which we found no association. However, the current study does not rule out an association between the expression of vacA or cagA protein and the virulence of H. pylori.
We concluded that, the dominant genotypes of H. pylori in Iranian patients with chronic gastritis may be cagA positive s1/m2. CagA gene expression is probably not closely associated with severity of diseases. The nature of disease complicating chronic infection seems to be determined by the host, environmental, bacterial and perhaps other unknown potent virulence factors which need to be investigated.
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Correspondence Address:
Mahsa Molaei
Department of Pathology, Research Center for Gastroenterology and Liver Disease, Shaheed Beheshti University, M.C. Tehran
Iran
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0377-4929.59178
[Table 1], [Table 2], [Table 3] |
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