Helicobacter pylori cagL amino acid polymorphisms and its association with gastroduodenal diseases

Gastric Cancer, Jul 2013

CagL is a pilus protein of Helicobacter pylori that interacts with host cellular α5β1 integrins through its arginine-glycine-aspartate (RGD) motif, guiding proper positioning of the T4SS and translocation of CagA. Deletion or sequence variations of cagL significantly diminished the ability of H. pylori to induce secretion of IL-8 by the host cell. Therefore, this study was undertaken to investigate the association of cagL and its amino acid sequence polymorphisms with gastric cancer (GC), peptic ulcer disease (PUD), and non-ulcer dyspepsia (NUD) as there are no such studies from India. In total, 200 adult patients (NUD 120, PUD 30, GC 50) who underwent an upper gastrointestinal endoscopy were enrolled. H. pylori infection was diagnosed by rapid urease test, culture, histopathology, and PCR. The collected isolates were screened for cagL genotype by PCR and assessed for amino acid sequence polymorphisms using sequence translation. The prevalence of H. pylori infection in study population was 52.5 %. Most of the isolates were cagL genopositive (86.6 %), and all had RGD motif in their amino acid sequences. D58 and K59 polymorphisms in cagL-genopositive strains were significantly higher in GC patients (P < 0.05). Combined D58K59 polymorphism was associated with higher risk of GC (3.8-fold) when compared to NUD. In conclusion, H. pylori cagL amino acid polymorphisms such as D58K59 are correlated with a higher risk of GC in the Indian population. Further studies are required to know the exact role of particular cagL amino acid polymorphisms in the pathogenicity of H. pylori infection.

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Helicobacter pylori cagL amino acid polymorphisms and its association with gastroduodenal diseases

Gastric Cancer Helicobacter pylori cagL amino acid polymorphisms and its association with gastroduodenal diseases Sanket Kumar Shukla 0 1 2 3 Kashi Nath Prasad 0 1 2 3 Aparna Tripathi 0 1 2 3 Virendra Jaiswal 0 1 2 3 Jahanarah Khatoon 0 1 2 3 Uday Chand Ghsohal 0 1 2 3 Narendra Krishnani 0 1 2 3 Nuzhat Husain 0 1 2 3 0 N. Krishnani Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences , Lucknow 226 014 , India 1 U. C. Ghsohal Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences , Lucknow 226 014 , India 2 S. K. Shukla K. N. Prasad (&) A. Tripathi V. Jaiswal J. Khatoon Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences , Lucknow 226 014 , India 3 N. Husain Department of Pathology, Ram Manohar Lohia Institute of Medial Sciences , Lucknow , India CagL is a pilus protein of Helicobacter pylori that interacts with host cellular a5b1 integrins through its arginine-glycine-aspartate (RGD) motif, guiding proper positioning of the T4SS and translocation of CagA. Deletion or sequence variations of cagL significantly diminished the ability of H. pylori to induce secretion of IL-8 by the host cell. Therefore, this study was undertaken to investigate the association of cagL and its amino acid sequence polymorphisms with gastric cancer (GC), peptic ulcer disease (PUD), and non-ulcer dyspepsia (NUD) as there are no such studies from India. In total, 200 adult patients (NUD 120, PUD 30, GC 50) who underwent an upper gastrointestinal endoscopy were enrolled. H. pylori infection was diagnosed by rapid urease test, culture, histopathology, and PCR. The collected isolates were screened for cagL genotype by PCR and assessed for amino acid sequence polymorphisms using sequence translation. The prevalence of H. pylori infection in study population was 52.5 %. Most of the isolates were cagL genopositive (86.6 %), and all had RGD motif in their amino acid sequences. D58 and K59 polymorphisms in cagLgenopositive strains were significantly higher in GC patients (P 0.05). Combined D58K59 polymorphism was associated with higher risk of GC (3.8-fold) when compared to NUD. In conclusion, H. pylori cagL amino acid polymorphisms such as D58K59 are correlated with a higher risk of GC in the Indian population. Further studies are required to know the exact role of particular cagL amino acid polymorphisms in the pathogenicity of H. pylori infection. Helicobacter pylori genotypes; Gastric cancer; CagL polymorphism - The incidence of Helicobacter pylori (H. pylori) infection continues to be higher in developing countries and is estimated at 310 % per year in contrast to approximately 1 % per year in developed countries [1]. Many virulence factors have been identified in H. pylori: urease, the blood group antigen-binding adhesin (babA), the cag pathogenicity island, the vacuolating cytotoxin (vacA), and H. pylori neutrophil-activating protein (HP-NAP) are the important ones [2]. A 40-kb cag pathogenicity island (cag PAI) encodes T4SS, which injects the CagA oncoprotein as well as peptidoglycan into host cells, resulting in induction of potent proinflammatory chemokines such as interleukin (IL)-8 [3]. Translocated CagA undergoes tyrosine phosphorylation by Src, leading to actin cytokine rearrangements, scattering, and elongation of infected host cells. Previously we reported a high prevalence of cagA in our study populations [80 % in gastric cancer (GC), 83.3 % in peptic ulcer disease (PUD), and 76.7 % in non-ulcer dyspepsia (NUD)] and also found no correlation of cagA with GC and PUD [4]. Therefore, it is likely that cagA cannot be considered as the sole virulence marker for the determination of disease outcome, at least in India. Hence, it is possible that some other genes of cagA-PAI are responsible for pathogenicity and disease outcome. Genotyping of cagL would be the better molecular tool to understand this problem. CagL is a pilus protein that interacts with host cellular a5b1 integrins through its arginine-glycine-aspartate (RGD) motif, guiding proper positioning of the T4SS and translocation of CagA [5]. Consequent activation of host signaling pathways stimulates the transcription factor NF-jB and upregulates inflammation-associated genes such as IL-8. Therefore, in the current study our aim was to determine the prevalence of cagL genopositivity and its amino acid polymorphisms in patients with GC, PUD, and NUD. Materials and methods Patient population We enrolled 200 adult patients (NUD 120, PUD 30, GC 50) undergoing upper gastrointestinal endoscopies at Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, between September 2007 and October 2010. The diagnosis of gastroduodenal diseases was based on clinical, endoscopic, and histopathological examination. Patients with NUD were considered as controls in our study. The ethics committee of the institute granted approval for the study, and all the patients gave (...truncated)


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Sanket Kumar Shukla, Kashi Nath Prasad, Aparna Tripathi, Virendra Jaiswal, Jahanarah Khatoon, Uday Chand Ghsohal, Narendra Krishnani, Nuzhat Husain. Helicobacter pylori cagL amino acid polymorphisms and its association with gastroduodenal diseases, Gastric Cancer, 2013, pp. 435-439, Volume 16, Issue 3, DOI: 10.1007/s10120-012-0189-7