The endemic Helicobacter pylori population in Southern Vietnam has both South East Asian and European origins

Abstract Background The burden of Helicobacter pylori-induced gastric cancer varies based on predominant H. pylori population in various geographical regions. Vietnam is a high H. pylori burden country with the highest age-standardized incidence rate of gastric cancer (16.3 cases/100,000 for both sexes) in Southeast Asia, despite this data on the H. pylori population is scanty. We examined the global context of the endemic H. pylori population in Vietnam and present a contextual and comparative genomics analysis of 83 H. pylori isolates from patients in Vietnam. Results There are at least two major H. pylori populations are circulating in symptomatic Vietnamese patients. The majority of the isolates (~ 80%, 66/83) belong to the hspEastAsia and the remaining belong to hpEurope population (~ 20%, 17/83). In total, 66 isolates (66/83) were cagA positive, 64 were hspEastAsia isolates and two were hpEurope isolates. Examination of the second repeat region revealed that most of the cagA genes were ABD type (63/66; 61 were hspEastAsia isolates and two were hpEurope isolates). The remaining three isolates (all from hspEastAsia isolates) were ABC or ABCC types. We also detected that 4.5% (3/66) cagA gene from hspEastAsia isolates contained EPIYA-like sequences, ESIYA at EPIYA-B segments. Analysis of the vacA allelic type revealed 98.8% (82/83) and 41% (34/83) of the strains harboured the s1 and m1 allelic variant, respectively; 34/83 carried both s1m1 alleles. The most frequent genotypes among the cagA positive isolates were vacA s1m1/cagA + and vacA s1m2/cagA + , accounting for 51.5% (34/66) and 48.5% (32/66) of the isolates, respectively. Conclusions There are two predominant lineages of H. pylori circulating in Vietnam; most of the isolates belong to the hspEastAsia population. The hpEurope population is further divided into two smaller clusters.

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Diversity of 3′ variable region of cagA gene in Helicobacter pylori strains isolated from Chinese population

Gut Pathogens ◽

10.1186/s13099-021-00419-3 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Zhijing Xue ◽

Yuanhai You ◽

Lihua He ◽

Yanan Gong ◽

Lu Sun ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Amino Acid ◽

Chinese Population ◽

Statistical Difference ◽

Variable Region ◽

Repeat Region ◽

Geographical Regions ◽

H Pylori ◽

Epiya Motifs

Abstract Background The cytotoxin-associated gene A (cagA) is one of the most important virulence factors of Helicobacter pylori (H. pylori). There is a highly polymorphic Glu-Pro-Ile-Tyr-Ala (EPIYA) repeat region in the C-terminal of CagA protein. This repeat region is thought to play an important role in the pathogenesis of gastrointestinal diseases. The aim of this study was to investigate the diversity of cagA 3′ variable region and the amino acid polymorphisms in the EPIYA segments of the CagA C-terminal region of H. pylori, and their association with gastroduodenal diseases. Methods A total of 515 H. pylori strains from patients in 14 different geographical regions of China were collected. The genomic DNA from each strain was extracted and the cagA 3′ variable region was amplified by polymerase chain reaction (PCR). The PCR products were sequenced and analyzed using MEGA 7.0 software. Results A total of 503 (97.7%) H. pylori strains were cagA-positive and 1,587 EPIYA motifs were identified, including 12 types of EPIYA or EPIYA-like sequences. In addition to the four reported major segments, several rare segments (e.g., B′, B″ and D′) were defined and 20 different sequence types (e.g., ABD, ABC) were found in our study. A total of 481 (95.6%) strains carried the East Asian type CagA, and the ABD subtypes were most prevalent (82.1%). Only 22 strains carried the Western type CagA, which included AC, ABC, ABCC and ABCCCC subtypes. The CagA-ABD subtype had statistical difference in different geographical regions (P = 0.006). There were seven amino acid polymorphisms in the sequences surrounding the EPIYA motifs, among which amino acids 893 and 894 had a statistical difference with gastric cancer (P = 0.004). Conclusions In this study, 503 CagA sequences were studied and analyzed in depth. In Chinese population, most H. pylori strains were of the CagA-ABD subtype and its presence was associated with gastroduodenal diseases. Amino acid polymorphisms at residues 893 and 894 flanking the EPIYA motifs had a statistically significant association with gastric cancer.

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Diversity of 3’ variable region of cagA gene in Helicobacter pylori strains isolated from Chinese population

10.21203/rs.3.rs-127429/v2 ◽

2021 ◽

Author(s):

Zhijing Xue ◽

Yuanhai You ◽

Lihua He ◽

Yanan Gong ◽

Lu Sun ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Amino Acid ◽

Chinese Population ◽

Statistical Difference ◽

Variable Region ◽

Repeat Region ◽

Geographical Regions ◽

H Pylori ◽

Epiya Motifs

Abstract Background: The cytotoxin-associated gene A (cagA) is one of the most important virulence factors of Helicobacter pylori (H. pylori). There is a highly polymorphic Glu-Pro-Ile-Tyr-Ala (EPIYA) repeat region in the C-terminal of CagA protein. This repeat region is thought to play an important role in the pathogenesis of gastrointestinal diseases. The aim of this study was to investigate the diversity of cagA 3’ variable region and the amino acid polymorphisms in the EPIYA segments of the CagA C-terminal region of H. pylori, and their association with gastroduodenal diseases.Methods: A total of 515 H. pylori strains from patients in 14 different geographical regions of China were collected. The genomic DNA from each strain was extracted and the cagA 3’ variable region was amplified by polymerase chain reaction (PCR). The PCR products were sequenced and analyzed using MEGA 7.0 software.Results: A total of 503 (97.7%) H. pylori strains were cagA-positive and 1,587 EPIYA motifs were identified, including 12 types of EPIYA or EPIYA-like sequences. In addition to the four reported major segments, several rare segments (e.g., B’, B’’ and D’) were defined and 20 different sequence types (e.g., ABD, ABC) were found in our study. A total of 481 (95.6%) strains carried the East Asian type CagA, and the ABD subtypes were most prevalent (82.1%). Only 22 strains carried the Western type CagA, which include AC, ABC, ABCC and ABCCCC subtypes. The CagA-ABD subtype had statistical difference in different geographic regions (P = 0.006). There are seven amino acid polymorphisms in the sequences surrounding the EPIYA motifs, among which amino acid residue 893 and 894 had a statistical difference with gastric cancer (P = 0.004).Conclusions: In this study, 503 CagA sequences was studied and analyzed in depth. In Chinese population, most H. pylori strains are of the CagA-ABD subtype and its presence was associated with gastroduodenal diseases. Amino acid polymorphisms at residue 893 and 894 flanking the EPIYA motif had a statistically significant association with gastric cancer.

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Diversity of 3’ Variable Region of cagA Gene in Helicobacter Pylori Strains Isolated from Chinese Population

10.21203/rs.3.rs-127429/v1 ◽

2020 ◽

Author(s):

zhijing Xue ◽

Yuanhai You ◽

Lihua He ◽

Yanan Gong ◽

Lu Sun ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Amino Acid ◽

Chinese Population ◽

Statistical Difference ◽

Variable Region ◽

Repeat Region ◽

Geographical Regions ◽

H Pylori ◽

Epiya Motifs

Abstract Background: CagA is one of the most important virulence factors of Helicobacter pylori (H. pylori). There is a highly polymorphic Glu-Pro-Ile-Tyr-Ala (EPIYA) repeat region in the CagA 3’ variable region. This repeat region is thought to play an important role in the pathogenesis of gastrointestinal diseases. The aim of this study was to investigate the diversity of CagA 3’ variable region and the amino acid polymorphisms in the EPIYA segments, and their association with gastroduodenal diseases.Methods: A total of 515 H. pylori isolates from patients in 14 different geographical regions of China were collected and the genomic DNA was extracted. The 3’ variable region of the cagA was amplified by polymerase chain reaction (PCR) and then followed by DNA sequencing, and the amino acid sequences were analyzed with MEGA 7.0 software.Results: A total of 503 (97.7%) H. pylori isolates were cagA-positive and 1,587 EPIYA motifs were obtained, including 12 types of EPIYA or EPIYA-like sequences. In addition to the four reported major segments, several rare segments (e.g., B’, B’’ and D’) were defined and 20 different sequence types (e.g., ABD, ABC) were found in our study. A total of 481 (95.6%) strains were East Asian type, most of them were ABD subtype (82.1%). Only 22 strains were Western type, including types AC, ABC, ABCC and ABCCCC. The CagA-ABD subtype had statistical difference in different geographic regions (P=0.006). There are seven amino acid polymorphisms in the sequences surrounding the EPIYA motifs, among which amino acid residue 893 and 894 had a statistical difference with gastric cancer (P=0.004).Conclusions: In this study, 503 CagA sequences was studied and analyzed in depth. In Chinese population, most H. pylori isolates are of the CagA-ABD subtype and its presence was associated with gastroduodenal disease. Amino acid polymorphisms at residue 893 and 894 flanking the EPIYA motif had a statistically significant association with gastric cancer.

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Western-Type Helicobacter pylori CagA are the Most Frequent Type in Mongolian Patients

Cancers ◽

10.3390/cancers11050725 ◽

2019 ◽

Vol 11 (5) ◽

pp. 725 ◽

Cited By ~ 2

Author(s):

Tegshee Tserentogtokh ◽

Boldbaatar Gantuya ◽

Phawinee Subsomwong ◽

Khasag Oyuntsetseg ◽

Dashdorj Bolor ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Cancer Patients ◽

East Asian ◽

Virulent Strains ◽

Virulent Type ◽

High Incidence ◽

Caga Status ◽

H Pylori ◽

Gastric Cancer Patients

Helicobacter pylori infection possessing East-Asian-type CagA is associated with carcinogenesis. Mongolia has the highest mortality rate from gastric cancer. Therefore, we evaluated the CagA status in the Mongolian population. High risk and gastric cancer patients were determined using endoscopy and histological examination. H. pylori strains were isolated from different locations in Mongolia. The CagA subtypes (East-Asian-type or Western-type, based on sequencing of Glu-Pro-Ile-Tyr-Ala (EPIYA) segments) and vacA genotypes (s and m regions) were determined using PCR-based sequencing and PCR, respectively. In total, 368 patients were examined (341 gastritis, 10 peptic ulcer, and 17 gastric cancer). Sixty-two (16.8%) strains were cagA-negative and 306 (83.1%) were cagA-positive (293 Western-type, 12 East-Asian-type, and one hybrid type). All cagA-negative strains were isolated from gastritis patients. In the gastritis group, 78.6% (268/341) had Western-type CagA, 2.9% (10/341) had East-Asian-type, and 18.2% (61/341) were cagA-negative. However, all H. pylori from gastric cancer patients possessed Western-type CagA. Histological analyses showed that East-Asian-type CagA was the most virulent strains, followed by Western-type and cagA-negative strains. This finding agreed with the current consensus. CagA-positive strains were the most virulent type. However, the fact that different CagA types can explain the high incidence of gastric cancer might be inapplicable in Mongolia.

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Intrafamilial Infection of Helicobacter Pylori: Abnormal Gastric Epithelial Cells, Pedestal-Rich H. Pylori Adherence, and a Gene Mutation in a Child with Protein-Losing Gastroenteropathy

Medical University ◽

10.2478/medu-2019-0013 ◽

2019 ◽

Vol 2 (3) ◽

pp. 83-99

Author(s):

T.W. Wan ◽

O. Khokhlova ◽

W. Higuchi ◽

I. Protasova ◽

Olga V. Peryanova ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Gastric Mucosa ◽

Epithelial Cells ◽

Gene Mutation ◽

Virulence Factor ◽

East Asian ◽

Gastric Epithelium ◽

Gastric Epithelial Cells ◽

H Pylori

Abstract Helicobacter pylori, one of the most prevalent human pathogens, colonizes the gastric mucosa and is associated with gastric diseases, such as gastritis and peptic ulcers, and is also a bacterial risk factor for gastric cancer. Cytotoxin-associated gene A (CagA) protein, a major virulence factor of H. pylori, is phosphorylated in cells at its Glu-Pro-IIe-Tyr-Ala (EPIYA) motif and is considered to trigger gastric cancer. CagA is classified into two forms, Western CagA with EPIYA-ABC and East Asian CagA with EPIYA-ABD, with the latter associated with a high risk of developing gastric cancer. CagA causes morphological transformation of cells, yielding the “hummingbird” phenotype in AGS cells and possibly membranous pedestals in the gastric epithelium, albeit rarely. H. pylori adherence to the gastric mucosa is not yet fully understood. Here, we describe an intrafamilial infection case of H. pylori, focusing on the gastric epithelium, H. pylori adherence, and a gene mutation in a child with protein-losing gastroenteropathy (characterized by excessive loss of plasma proteins into the gastrointestinal tract). H. pylori, which also infected family members (mother and father), was genetically a single clone with the virulence genes of an East Asian type. The patient’ gastric mucosa exhibited some unique features. Endoscopy revealed the presence of protein plugs on the mucosal surface, which were immunoelectrophoretically similar to serum proteins. Electron microscopy revealed abnormal gastric epithelial cells, totally covered with the secretions or possessing small swollen structures and irregular microvilli. The patient’s H. pylori infection was characterized by frequently occurring thick pedestals, formed along adherent H. pylori. The serum protein level returned to normal and the protein plugs disappeared after the successful eradication of H. pylori, albeit with lag periods for healing. He had a mutation in the OCRL1 gene, associated with Dent disease (asymptomatic proteinuria). Thus, in the patient’s gastric mucosa, we found the abnormal gastric epithelial cells, which may be caused by an OCRL1 mutation or H. pylori, and pedestal-rich H. pylori infection, possibly caused by a higher level of action of CagA in the abnormal epithelial cells. The data suggests a novel H. pylori virulence factor associated with “excessive plasma protein release”.

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Lifestyles, genetics, and future perspectives on gastric cancer in east Asian populations

Journal of Human Genetics ◽

10.1038/s10038-021-00960-8 ◽

2021 ◽

Author(s):

Hiroto Katoh ◽

Shumpei Ishikawa

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Cancer Genomics ◽

State Of The Art ◽

East Asian ◽

Gastric Carcinogenesis ◽

Review Article ◽

Future Perspectives ◽

Asian Populations ◽

H Pylori

AbstractThe prevalence of gastric cancer (GC) differs among regions worldwide, with the highest occurrence in east Asia. Thus, its etiology, with respect to ethnic background, environmental factors, and lifestyles, is also thought to differ essentially. In addition, etiology of GC is speculated to be changing due to the recent decrease in the Helicobacter pylori (H. pylori) infection in Japan. State-of-the-art somatic/germline cancer genomics has clarified the etiologies of gastric carcinogenesis. In this review article, we summarize past and present milestones in our understanding of GC achieved through genomic approaches, including a recent report that revealed higher-than-expected frequencies of GCs attributed to east Asian-specific germline variants in ALDH2 or CDH1 in combination with lifestyles. Based on this updated knowledge, we also discuss the possible impact of and high-risk approaches for GCs in the upcoming “H. pylori-negative era.”

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Genomic differentiation within East Asian Helicobacter pylori

10.1101/2021.06.05.447026 ◽

2021 ◽

Author(s):

Yuanhai You ◽

Kaisa Thorell ◽

Lihua He ◽

Koji Yahara ◽

Yoshio Yamaoka ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Amino Acid ◽

Cancer Incidence ◽

Outer Membrane Proteins ◽

East Asian ◽

Fixation Index ◽

3D Protein Structure ◽

Local Conditions ◽

H Pylori

The East Asian region, including China, Japan and Korea, accounts for half of gastric cancer deaths. However, different areas have contrasting gastric cancer incidence and the population structure of Helicobacter pylori in this ethnically diverse region is yet unknown. We aimed to investigate genomic differences in H. pylori between these areas to identify sequence polymorphisms associated with increased cancer risk. We analysed 381 H. pylori genomes collected from different areas of the three countries using phylogenetic and population genetic tools to characterize population differentiation. The functional consequences of Single Nucleotide Polymorphisms (SNPs) with a highest fixation index (Fst) between subpopulations were examined by mapping amino-acid changes on 3D protein structure, solved or modelled. 329/381 genomes belonged to the previously identified hspEAsia population indicating that import of bacteria from other regions of the world has been uncommon. Seven sub-regional clusters were found within hspEAsia, related to sub-populations with various ethnicities, geographies and gastric cancer risks. Sub-population-specific amino-acid changes were found in multi-drug exporters (hefC), transporters (frpB-4), outer membrane proteins (hopI), and several genes involved in host interaction, such as catalase, involved in H2O2 entrance, and a flagellin site mimicking host glycosylation. Several of the top hits including frpB-4, hefC, alpB/hopB, and hofC. were also differentiated within the Americas, indicating that a handful of genes may be key to local geographic adaptation. H. pylori within East Asia are not homogeneous but have become differentiated geographically at multiple loci that have facilitated adaptation to local conditions and hosts. This has important implications for further evaluation of these changes in relation to the varying gastric cancer incidence between geographical areas in this region.

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Molecular epidemiology of Helicobacter pylori: separation of H. pylori from East Asian and non-Asian countries

Epidemiology and Infection ◽

10.1017/s0950268899003209 ◽

2000 ◽

Vol 124 (1) ◽

pp. 91-96 ◽

Cited By ~ 66

Author(s):

Y. YAMAOKA ◽

M. S. OSATO ◽

A. R. SEPULVEDA ◽

O. GUTIERREZ ◽

N. FIGURA ◽

...

Keyword(s):

Helicobacter Pylori ◽

Hong Kong ◽

East Asia ◽

Genomic Structure ◽

East Asian ◽

Epidemiological Studies ◽

Repeat Region ◽

Asian Countries ◽

Pcr Products ◽

H Pylori

The predominant H. pylori strain circulating among geographic locations differs with regard to the genomic structure. This study determined whether structural subtypes of the cagA 3′ repeat region could be used to identify the population of origin of H. pylori isolates. We examined 600 cagA-positive H. pylori (Colombia, 100; USA, 100; France, 100; Canada, 20; Italy, 20; Korea, 100; Japan, 100; Hong Kong, 20; Taiwan, 20; Vietnam, 20). The cagA 3′ region was amplified by PCR using primers specific to Japanese and Western 3′ cagA gene sequences. PCR using Japanese cagA primers resulted in PCR products in 99·6% of strains from East Asia but no non-Asian strains. Conversely, PCR using Western cagA primers resulted in amplicons in 100% of non-Asian strains, and only one from East Asia. cagA genotyping is useful for molecular epidemiological studies as strains can be completely separated by differences in the cagA 3′ region.

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Prevalence, diversity and disease association of Helicobacter pylori in dyspeptic patients from Pakistan

The Journal of Infection in Developing Countries ◽

10.3855/jidc.2942 ◽

2013 ◽

Vol 7 (03) ◽

pp. 220-228 ◽

Cited By ~ 14

Author(s):

Adnan Khan ◽

Amber Farooqui ◽

Yasir Raza ◽

Faisal Rasheed ◽

Hamid Manzoor ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Disease Burden ◽

Detection Rate ◽

East Asian ◽

Disease Association ◽

Gastric Biopsy ◽

Caga Gene ◽

H Pylori ◽

Type Strains

Introduction: The etiological association of Helicobacter pylori with gastric ulcer (GU), gastric cancer (GC), and duodenal ulcer (DU) is well-known. Understanding the epidemiology of H. pylori facilitates the estimation of disease burden in a certain population. This study presents the diversity of H. pylori genotypes and their association with different clinical outcomes among dyspeptic patients in Pakistan over a period of four years. Methodology: Gastric biopsy samples from a total of 450 dyspeptic individualswere subjected to PCR, genotypingand histology. Results: A total of 201 (45%) cases were found positive for H. pylori. The detection rate was high in GU (91%), DU (86%) and GC (83%) cases compared with those cases who had intact gastric mucosa (18%). Histology revealed the presence of infection in 68% of cases of mild/chronic nonspecific gastritis with others belonging to the GU sequel. cagA gene carriage was observed in 104 (51%) cases or mostly from DU, GU and GC groups, of which 97 were Western type strains while 3 were East-Asian type strains that are rarely observed in South Asia. vacA allelic variant s1am1 was most commonly observed, followed by s1am2, and s1bm1, with direct correlation in diseased cases (gastritis, GU, DU and GC). Prevalent genotypic combinations were s1am1/cagA- in gastritis and s1am1/cagA+ in DU, GU, and GC. Conclusions: Our study indicates the predominant circulation of Western type cagA and vacAs1am1 type H. pylori strains in Pakistan.

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Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations

Molecules ◽

10.3390/molecules26040837 ◽

2021 ◽

Vol 26 (4) ◽

pp. 837

Author(s):

Quan Wang ◽

Wen-Cheng Zhao ◽

Xue-Qi Fu ◽

Qing-Chuan Zheng

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Secondary Structure ◽

Binding Affinity ◽

East Asian ◽

Md Simulations ◽

Sh2 Domain ◽

Regulation Mechanism ◽

H Pylori ◽

Dynamics Simulations

CagA is a major virulence factor of Helicobacter pylori. H. pylori CagA is geographically subclassified into East Asian CagA and Western CagA, which are characterized by the presence of a EPIYA-D or EPIYA-C segment. The East Asian CagA is more closely associated with gastric cancer than the Western CagA. In this study, molecular dynamic (MD) simulations were performed to investigate the binding details of SHP2 and EPIYA segments, and to explore the allosteric regulation mechanism of SHP2. Our results show that the EPIYA-D has a stronger binding affinity to the N-SH2 domain of SHP2 than EPIYA-C. In addition, a single EPIYA-D binding to N-SH2 domain of SHP2 can cause a deflection of the key helix B, and the deflected helix B could squeeze the N-SH2 and PTP domains to break the autoinhibition pocket of SHP2. However, a single EPIYA-C binding to the N-SH2 domain of SHP2 cannot break the autoinhibition of SHP2 because the secondary structure of the key helix B is destroyed. However, the tandem EPIYA-C not only increases its binding affinity to SHP2, but also does not significantly break the secondary structure of the key helix B. Our study can help us better understand the mechanism of gastric cancer caused by Helicobacter pylori infection.

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