Skip to main content

Genetic variation in the cag pathogenicity island of Helicobacter pylori strains detected from gastroduodenal patients in Thailand

Brazilian Journal of Microbiology volume 51, pages 1093–1101 (2020)Cite this article

Abstract

There is a lack of evidence of genetic variation in the Helicobacter pylori cag-PAI in Thailand, a region with the low incidence of gastric cancer. To clarify this issue, variation in the H. pylori cag-PAI in strains detected in Thailand was characterized and simultaneously compared with strains isolated from a high-risk population in Korea. The presence of ten gene clusters within cag-PAI (cagA, cagE, cagG, cagH, cagL, cagM, cagT, orf13, virB11, and orf10) and IS605 was characterized in H. pylori strains detected from these two countries. The cagA genotypes and EPIYA motifs were analyzed by DNA sequencing. The overall proportion of the ten cag-PAI genes that were detected ranged between 66 and 79%; additionally, approximately 48% of the strains from Thai patients contained an intact cag-PAI structure, while a significantly higher proportion (80%) of the strains from Korean patients had an intact cag-PAI. A significantly higher proportion of IS605 was detected in strains from Thai patients (55%). Analysis of cagA genotypes and EPIYA motifs revealed a higher frequency of Western-type cagA in Thai patients (87%) relative to Korean patients (8%) who were predominately associated with the East Asian-type cagA (92%). Variations in the Western-type cagA in the Thai population, such as EPIYA-BC patterns and EPIYA-like sequences (EPIYT), were mainly detected as compared with the Korean population (p < 0.05). In summary, H. pylori strains that colonize the Thai population tend to be associated with low virulence due to distinctive cag-PAI variation, which may partially explain the Asian paradox phenomenon in Thailand.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

  1. Dunn BE, Cohen H, Blaser MJ (1997) Helicobacter pylori. Clin Microbiol Rev 10(4):720–741

    CAS  Article  Google Scholar 

  2. Fock KM, Ang TL (2010) Epidemiology of Helicobacter pylori infection and gastric cancer in Asia. J Gastroenterol Hepatol 25(3):479–486. https://doi.org/10.1111/j.1440-1746.2009.06188.x

    CAS  Article  Google Scholar 

  3. Sahara S, Sugimoto M, Vilaichone RK, Mahachai V, Miyajima H, Furuta T, Yamaoka Y (2012) Role of Helicobacter pylori cagA EPIYA motif and vacA genotypes for the development of gastrointestinal diseases in southeast Asian countries: a meta-analysis. BMC Infect Dis 12:223. https://doi.org/10.1186/1471-2334-12-223

    Article  PubMed  PubMed Central  Google Scholar 

  4. Myint T, Miftahussurur M, Vilaichone RK, Ni N, Aye TT, Subsomwong P, Uchida T, Mahachai V, Yamaoka Y (2018) Characterizing Helicobacter pylori cagA in Myanmar. Gut Liver 12(1):51–57. https://doi.org/10.5009/gnl17053

    CAS  Article  Google Scholar 

  5. Zaidi SF (2016) Helicobacter pylori associated Asian enigma: does diet deserve distinction? World J Gastrointest Oncol 8(4):341–350. https://doi.org/10.4251/wjgo.v8.i4.341

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chen SY, Zhang RG, Duan GC (2016) Pathogenic mechanisms of the oncoprotein CagA in H. pylori-induced gastric cancer (review). Oncol Rep 36(6):3087–3094. https://doi.org/10.3892/or.2016.5145

    CAS  Article  Google Scholar 

  7. Costa AC, Figueiredo C, Touati E (2009) Pathogenesis of Helicobacter pylori infection. Helicobacter 14(Suppl 1):15–20. https://doi.org/10.1111/j.1523-5378.2009.00702.x

    CAS  Article  Google Scholar 

  8. Censini S, Lange C, Xiang Z, Crabtree JE, Ghiara P, Borodovsky M, Rappuoli R, Covacci A (1996) cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci U S A 93(25):14648–14653. https://doi.org/10.1073/pnas.93.25.14648

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Covacci A, Rappuoli R (2000) Tyrosine-phosphorylated bacterial proteins: Trojan horses for the host cell. J Exp Med 191(4):587–592. https://doi.org/10.1084/jem.191.4.587

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Yamaoka Y, Orito E, Mizokami M, Gutierrez O, Saitou N, Kodama T, Osato MS, Kim JG, Ramirez FC, Mahachai V, Graham DY (2002) Helicobacter pylori in North and South America before Columbus. FEBS Lett 517(1–3):180–184. https://doi.org/10.1016/s0014-5793(02)02617-0

    CAS  Article  Google Scholar 

  11. Yamaoka Y, El-Zimaity HM, Gutierrez O, Figura N, Kim JG, Kodama T, Kashima K, Graham DY (1999) Relationship between the cagA 3′ repeat region of Helicobacter pylori, gastric histology, and susceptibility to low pH. Gastroenterology 117(2):342–349. https://doi.org/10.1053/gast.1999.0029900342

    CAS  Article  Google Scholar 

  12. Yuan XY, Yan JJ, Yang YC, Wu CM, Hu Y, Geng JL (2017) Helicobacter pylori with East Asian-type cagPAI genes is more virulent than strains with Western-type in some cagPAI genes. Braz J Microbiol 48(2):218–224. https://doi.org/10.1016/j.bjm.2016.12.004

    CAS  Article  Google Scholar 

  13. Go MF, Kapur V, Graham DY, Musser JM (1996) Population genetic analysis of Helicobacter pylori by multilocus enzyme electrophoresis: extensive allelic diversity and recombinational population structure. J Bacteriol 178(13):3934–3938

    CAS  Article  Google Scholar 

  14. Hsu PI, Hwang IR, Cittelly D, Lai KH, El-Zimaity HM, Gutierrez O, Kim JG, Osato MS, Graham DY, Yamaoka Y (2002) Clinical presentation in relation to diversity within the Helicobacter pylori cag pathogenicity island. Am J Gastroenterol 97(9):2231–2238. https://doi.org/10.1111/j.1572-0241.2002.05977.x

    CAS  Article  Google Scholar 

  15. Chomvarin C, Namwat W, Chaicumpar K, Mairiang P, Sangchan A, Sripa B, Tor-Udom S, Vilaichone RK (2008) Prevalence of Helicobacter pylori vacA, cagA, cagE, iceA and babA2 genotypes in Thai dyspeptic patients. Int J Infect Dis 12(1):30–36. https://doi.org/10.1016/j.ijid.2007.03.012

    CAS  Article  Google Scholar 

  16. Maeda S, Yoshida H, Ikenoue T, Ogura K, Kanai F, Kato N, Shiratori Y, Omata M (1999) Structure of cag pathogenicity island in Japanese Helicobacter pylori isolates. Gut 44(3):336–341. https://doi.org/10.1136/gut.44.3.336

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Jenks PJ, Megraud F, Labigne A (1998) Clinical outcome after infection with Helicobacter pylori does not appear to be reliably predicted by the presence of any of the genes of the cag pathogenicity island. Gut 43(6):752–758. https://doi.org/10.1136/gut.43.6.752

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Deguchi R, Igarashi M, Watanabe K, Takagi A (2004) Analysis of the cag pathogenicity island and IS605 of Helicobacter pylori strains isolated from patients with gastric cancer in Japan. Aliment Pharmacol Ther 20(Suppl 1):13–16. https://doi.org/10.1111/j.1365-2036.2004.01982.x

    CAS  Article  Google Scholar 

  19. Yamaoka Y, Kodama T, Kashima K, Graham DY, Sepulveda AR (1998) Variants of the 3′ region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases. J Clin Microbiol 36(8):2258–2263

    CAS  Article  Google Scholar 

  20. Tomasini ML, Zanussi S, Sozzi M, Tedeschi R, Basaglia G, De Paoli P (2003) Heterogeneity of cag genotypes in Helicobacter pylori isolates from human biopsy specimens. J Clin Microbiol 41(3):976–980. https://doi.org/10.1128/jcm.41.3.976-980.2003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Ikenoue T, Maeda S, Ogura K, Akanuma M, Mitsuno Y, Imai Y, Yoshida H, Shiratori Y, Omata M (2001) Determination of Helicobacter pylori virulence by simple gene analysis of the cag pathogenicity island. Clin Diagn Lab Immunol 8(1):181–186. https://doi.org/10.1128/CDLI.8.1.181-186.2001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Lai CH, Perng CL, Lan KH, Lin HJ (2013) Association of IS605 and cag-PAI of Helicobacter pylori isolated from patients with gastrointestinal diseases in Taiwan. Gastroenterol Res Pract 2013:356217–356215. https://doi.org/10.1155/2013/356217

    Article  PubMed  PubMed Central  Google Scholar 

  23. Raei N, Latifi-Navid S, Zahri S (2015) Helicobacter pylori cag pathogenicity island cagL and orf17 genotypes predict risk of peptic ulcerations but not gastric cancer in Iran. Asian Pac J Cancer Prev 16(15):6645–6650. https://doi.org/10.7314/apjcp.2015.16.15.6645

    Article  Google Scholar 

  24. Lima VP, Silva-Fernandes IJ, Alves MK, Rabenhorst SH (2011) Prevalence of Helicobacter pylori genotypes (vacA, cagA, cagE and virB11) in gastric cancer in Brazilian’s patients: an association with histopathological parameters. Cancer Epidemiol 35(5):e32–e37. https://doi.org/10.1016/j.canep.2011.02.017

    CAS  Article  Google Scholar 

  25. Mukhopadhyay AK, Kersulyte D, Jeong JY, Datta S, Ito Y, Chowdhury A, Chowdhury S, Santra A, Bhattacharya SK, Azuma T, Nair GB, Berg DE (2000) Distinctiveness of genotypes of Helicobacter pylori in Calcutta, India. J Bacteriol 182(11):3219–3227. https://doi.org/10.1128/jb.182.11.3219-3227.2000

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Yadegar A, Mohabati Mobarez A, Zali MR (2019) Genetic diversity and amino acid sequence polymorphism in Helicobacter pylori CagL hypervariable motif and its association with virulence markers and gastroduodenal diseases. Cancer Med 8(4):1619–1632. https://doi.org/10.1002/cam4.1941

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Zhang C, Xu S, Xu D (2012) Risk assessment of gastric cancer caused by Helicobacter pylori using CagA sequence markers. PLoS One 7(5):e36844. https://doi.org/10.1371/journal.pone.0036844

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Merino E, Flores-Encarnacion M, Aguilar-Gutierrez GR (2017) Functional interaction and structural characteristics of unique components of Helicobacter pylori T4SS. FEBS J 284(21):3540–3549. https://doi.org/10.1111/febs.14092

    CAS  Article  Google Scholar 

  29. Tegtmeyer N, Wessler S, Backert S (2011) Role of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. FEBS J 278(8):1190–1202. https://doi.org/10.1111/j.1742-4658.2011.08035.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Podzorski RP, Podzorski DS, Wuerth A, Tolia V (2003) Analysis of the vacA, cagA, cagE, iceA, and babA2 genes in Helicobacter pylori from sixty-one pediatric patients from the Midwestern United States. Diagn Microbiol Infect Dis 46(2):83–88. https://doi.org/10.1016/s0732-8893(03)00034-8

    CAS  Article  Google Scholar 

  31. Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ (1991) Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med 325(16):1132–1136. https://doi.org/10.1056/NEJM199110173251604

    CAS  Article  Google Scholar 

  32. Day AS, Jones NL, Lynett JT, Jennings HA, Fallone CA, Beech R, Sherman PM (2000) cagE is a virulence factor associated with Helicobacter pylori-induced duodenal ulceration in children. J Infect Dis 181(4):1370–1375. https://doi.org/10.1086/315394

    CAS  Article  Google Scholar 

  33. Tafreshi M, Guan J, Gorrell RJ, Chew N, Xin Y, Deswaerte V, Rohde M, Daly RJ, Peek RM Jr, Jenkins BJ, Davies EM, Kwok T (2018) Helicobacter pylori type IV secretion system and its adhesin subunit, CagL, mediate potent inflammatory responses in primary human endothelial cells. Front Cell Infect Microbiol 8:22. https://doi.org/10.3389/fcimb.2018.00022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Bauer B, Moese S, Bartfeld S, Meyer TF, Selbach M (2005) Analysis of cell type-specific responses mediated by the type IV secretion system of Helicobacter pylori. Infect Immun 73(8):4643–4652. https://doi.org/10.1128/IAI.73.8.4643-4652.2005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Ahmadzadeh A, Ghalehnoei H, Farzi N, Yadegar A, Alebouyeh M, Aghdaei HA, Molaei M, Zali MR, Pour Hossein Gholi MA (2015) Association of CagPAI integrity with severeness of Helicobacter pylori infection in patients with gastritis. Pathol Biol (Paris) 63(6):252–257. https://doi.org/10.1016/j.patbio.2015.09.004

    CAS  Article  Google Scholar 

  36. Nguyen LT, Uchida T, Tsukamoto Y, Trinh TD, Ta L, Mai HB, Le HS, Ho DQ, Hoang HH, Matsuhisa T, Okimoto T, Kodama M, Murakami K, Fujioka T, Yamaoka Y, Moriyama M (2010) Clinical relevance of cagPAI intactness in Helicobacter pylori isolates from Vietnam. Eur J Clin Microbiol Infect Dis 29(6):651–660. https://doi.org/10.1007/s10096-010-0909-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Akopyants NS, Clifton SW, Kersulyte D, Crabtree JE, Youree BE, Reece CA, Bukanov NO, Drazek ES, Roe BA, Berg DE (1998) Analyses of the cag pathogenicity island of Helicobacter pylori. Mol Microbiol 28(1):37–53. https://doi.org/10.1046/j.1365-2958.1998.00770.x

    CAS  Article  Google Scholar 

  38. Kersulyte D, Akopyants NS, Clifton SW, Roe BA, Berg DE (1998) Novel sequence organization and insertion specificity of IS605 and IS606: chimaeric transposable elements of Helicobacter pylori. Gene 223(1–2):175–186. https://doi.org/10.1016/s0378-1119(98)00164-4

    CAS  Article  Google Scholar 

  39. Mattar R, Marques SB, Monteiro Mdo S, Dos Santos AF, Iriya K, Carrilho FJ (2007) Helicobacter pylori cag pathogenicity island genes: clinical relevance for peptic ulcer disease development in Brazil. J Med Microbiol 56(Pt 1):9–14. https://doi.org/10.1099/jmm.0.46824-0

    CAS  Article  Google Scholar 

  40. Hatakeyama M (2006) Helicobacter pylori CagA—a bacterial intruder conspiring gastric carcinogenesis. Int J Cancer 119(6):1217–1223. https://doi.org/10.1002/ijc.21831

    CAS  Article  Google Scholar 

  41. Higashi H, Tsutsumi R, Fujita A, Yamazaki S, Asaka M, Azuma T, Hatakeyama M (2002) Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci U S A 99(22):14428–14433. https://doi.org/10.1073/pnas.222375399

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Seo JW, Park JY, Shin TS, Kim JG (2019) The analysis of virulence factors and antibiotic resistance between Helicobacter pylori strains isolated from gastric antrum and body. BMC Gastroenterol 19(1):140. https://doi.org/10.1186/s12876-019-1062-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Mohamed R, Hanafiah A, Rose IM, Manaf MR, Abdullah SA, Sagap I, van Belkum A, Yaacob JA (2009) Helicobacter pylori cagA gene variants in Malaysians of different ethnicity. Eur J Clin Microbiol Infect Dis 28(7):865–869. https://doi.org/10.1007/s10096-009-0712-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Chomvarin C, Phusri K, Sawadpanich K, Mairiang P, Namwat W, Wongkham C, Hahnvajanawong C (2012) Prevalence of cagA EPIYA motifs in Helicobacter pylori among dyspeptic patients in Northeast Thailand. Southeast Asian J Trop Med Public Health 43(1):105–115

    CAS  Google Scholar 

  45. Vilaichone RK, Mahachai V, Tumwasorn S, Wu JY, Graham DY, Yamaoka Y (2004) Molecular epidemiology and outcome of Helicobacter pylori infection in Thailand: a cultural cross roads. Helicobacter 9(5):453–459. https://doi.org/10.1111/j.1083-4389.2004.00260.x

    Article  Google Scholar 

  46. Talarico S, Gold BD, Fero J, Thompson DT, Guarner J, Czinn S, Salama NR (2009) Pediatric Helicobacter pylori isolates display distinct gene coding capacities and virulence gene marker profiles. J Clin Microbiol 47(6):1680–1688. https://doi.org/10.1128/JCM.00273-09

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Zhang XS, Tegtmeyer N, Traube L, Jindal S, Perez-Perez G, Sticht H, Backert S, Blaser MJ (2015) A specific A/T polymorphism in Western tyrosine phosphorylation B-motifs regulates Helicobacter pylori CagA epithelial cell interactions. PLoS Pathog 11(2):e1004621. https://doi.org/10.1371/journal.ppat.1004621

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank the Unit of Endoscopy Medicine, Sunpasitthiprasong Hospital, for specimen collection. We also thank the Central Laboratory of Amnatcharoen Campus, Mahidol University, for supporting scientific facilities throughout this study.

Funding

This research was supported by Thailand Research Fund (MRG5980069) and Mahidol University (Talent Management).

Author information

Affiliations

  1. Department of Sciences and Liberal Arts, Mahidol University, Amnatcharoen Campus, Amnatcharoen, 37000, Thailand

    Wongwarut Boonyanugomol

  2. Unit of Endoscopy Medicine, Sunpasitthiprasong Hospital, Ubon Ratchathani, 34000, Thailand

    Worrarat Kongkasame

  3. Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand

    Prasit Palittapongarnpim

  4. Department of Microbiology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju, 52727, Republic of Korea

    Seung-Chul Baik, Myung-hwan Jung, Min-Kyoung Shin, Hyung-Lyun Kang & Woo-Kon Lee

Authors
  1. Wongwarut Boonyanugomol
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Worrarat Kongkasame
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Prasit Palittapongarnpim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seung-Chul Baik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Myung-hwan Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min-Kyoung Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hyung-Lyun Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Woo-Kon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The manuscript has been seen and approved by all the authors.

Corresponding author

Correspondence to Wongwarut Boonyanugomol.

Ethics declarations

This research was approved by the Institutional Human Ethics Committee (MU-CIRB 2019/004.1501) of Mahidol University.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Responsible Editor: Elizabeth Andrade Marques.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Boonyanugomol, W., Kongkasame, W., Palittapongarnpim, P. et al. Genetic variation in the cag pathogenicity island of Helicobacter pylori strains detected from gastroduodenal patients in Thailand. Braz J Microbiol 51, 1093–1101 (2020). https://doi.org/10.1007/s42770-020-00292-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42770-020-00292-3

Keywords

  • Helicobacter pylori
  • cag pathogenicity island
  • IS605
  • EPIYA motifs
  • Thailand