**5. The PZ-associated genes** *jhp0945***,** *jhp0947* **and** *jhp0949* **and their relationship with gastroduodenal disease**

Studies on the prevalence of *jhp0945*, *jhp0947* and *jhp0949* among *H. pylori* isolates of different geographical origins have proposed that these genes are disease markers, suggesting that they could play a role in the pathogenesis of *H. pylori* [12]. This relationship was discovered in Costa Rica, where the prevalence of 21 ORFs present in the PZ of the J99 strain (*jhp0914-jhp0961*) was assessed in 17 strains from patients with gastric cancer and 26 strains from patients with gastritis. The results showed a high prevalence of *jhp0940* and *jhp0947* in patients with gastric cancer [30]. Later, in a study conducted in Brazil that included 200 *H. pylori* isolates from patients with duodenal ulcers, gastric cancer or gastritis, only *jhp0947* continued to show an association with gastric cancer and duodenal ulcers [23]. However, in another study of strains from Brazil, an association between *jhp0947* and peptic ulcers was not observed [31]. A different study assessed the prevalence of the *jhp0945-jhp947-jhp0949* locus in a Dutch population with gastritis and duodenal ulcers. In addition to *jhp0947*, the presence of *jhp0949* was associated with duodenal ulcers, whereas *jhp0945* was not associated with this disease [32]. Another cluster of genes for which the prevalence was examined consisted of *jhp0926*, *jhp0931*, *jhp0933*, *jhp0944* and *jhp0945* in isolates from Turkish patients with gastritis and peptic ulcers. Among these genes, *jhp0931* was the most prevalent in patients with peptic ulcers [33].

exist regarding this gene and its role in *H. pylori* strains. To date*, jhp0947* is considered the best disease marker of the locus *jhp0945-jhp0947-jhp0949* because it seems to meet two of the conditions that Yamaoka et al. [12] suggest for an *H. pylori* virulence factor: (1) it has a disease or other *in vivo* correlation and (2) it is epidemiologically consistent across populations and regions.

*Helicobacter pylori* Genes *jhp0940*, *jhp0945*, *jhp0947* and *jhp0949* are Associated with Gastroduodenal Disease

http://dx.doi.org/10.5772/intechopen.81290

Among the *jhp0940*, *jhp0945*, *jhp0947* and jhp0949 genes, *jhp0940* is the best characterised. Rizwan et al. [25] purified recombinant JHP0940 protein, which, when incubated with macrophage cells (TPH-1), was able to induce the synthesis of TNF-α, IL-6 and IL-8 via translocation of NF-κB. This gene is currently known as *ctkA* (cell translocation kinase A), and the encoded protein has autophosphorylation activity [43]. In addition to being a serine/threonine kinase, CtkA can increase the phosphorylation of NF-κB by inducing TNF-α in a dose-dependent manner in HeLa cells [40]. However, Tenguria et al. [44] observed that *H. pylori* can secrete the CtkA and induce the expression of caspase-1 in macrophages (RAW264.7), generating an increase in the transcription of IL-1β and promoting the recruitment of infiltrated immune cells in the gastric mucosa. In addition, CtkA may be able to decrease cell viability through the Fas receptor. Recently, a study showed that CtkA is expressed from its native host and can induce stimulation of a pro-inflammatory response from gastric epithelial cells. This interaction is dependent upon a complement of the tfs3 T4SS genes but independent of the T4SS

The function of the genes *jhp0945*-*jhp0947-jhp0949* is not yet well understood. However, it has been proposed that since they are consecutive genes and are oriented in the same direction, it is possible that they are expressed as an operon [30]. A study of the Dutch population revealed that the presence of these three genes in *H. pylori* strains induced higher amounts of IL-12 than in strain 26695, which does not possess these genes. However, the disruption of this locus reduces the production of IL-12 in THP-1 monocytic cells [32]. The presence of these three genes in strains from India induces a greater amount of IL-8 and induction of cell death by apoptosis (caspase-3 activity) in AGS cells than in strains that lack these genes [22]. *jhp0947* shows homology with *jhp0938* (*hp0990*) and *jhp0253* (*hp1333*), but their functions are still unknown. This gene also shows homology in the 5′ region with *jhp0477* (*hp0528*), which encodes a *virB9* homologue, an important component of the T4SS encoded by the *cag* PAI [46].

The PZ of the *H. pylori* genome contains several genes that have not been fully explored but could be important for understanding the pathogenesis of *H. pylori* due to their location in an area of the genome associated with genetic exchange. Among the most studied genes are *jhp0945*, *jhp0947* and *jhp0949*, which have been found to be associated with gastroduodenal disease, although their mechanism is still not clearly defined. However, the prevalence and association of *jhp0940* with ulcer or gastric cancer is still not entirely clear, although progress has been made in the

**6. Functional characteristics of the** *jhp0940***,** *jhp094***5,** *jhp0947* **and** 

proteins encoded by either tfs4 or the *cag* PAI [45].

*jhp0949* **genes**

**7. Conclusion**

Yakoob et al. [27] observed that the *jhp0947* gene is more frequently present than *jhp0940* in strains associated with duodenal ulcers and gastric cancer. This association was determined to be independent of the presence of the virulence factor *cagA* in *H. pylori* strains. A study that included 296 Western isolates (from the United States and Colombia) and 217 East Asian isolates (from Korea and Japan) reported that the prevalence of *jhp0945*, *jhp0947* and *jhp0949* differs significantly between the two geographical regions. In the Western isolates, the presence of *jhp0945* was higher in isolates obtained from individuals with gastric ulcers, duodenal ulcers or gastric cancer than in those obtained from individuals with gastritis [21].

In *H. pylori* isolates of Chinese origin, the prevalence of *jhp0945*, *jhp0947* and *jhp0949* was significantly higher in individuals with duodenal ulcers and gastric cancer than in individuals with chronic gastritis [24]. Similarly, in isolates from India, the presence of *jhp0945*, *jhp0947* and *jhp0949* in *H. pylori* isolates was associated with disease [22]. The prevalence of *jhp0945*, *jhp0947* and *jhp0949* is associated with a greater risk of serious diseases in India [28]. PZ-associated genes (outside of locus *jhp0945*-*jhp0947*-*jhp0949*) that also have exhibited an association with disease include *jhp0950* and *jhp0917*-*jhp0918*. The *jhp0950* gene was associated with marginal zone B cell lymphomas (MZBL) and mucosa-associated lymphoid tissue (MALT) when its prevalence was examined in patients with gastritis, duodenal ulcers and gastric cancer [34]. Another gene considered a risk factor for the development of duodenal ulcers is the *dupA* gene (duodenal ulcer-promoting gene, *jhp0917*-*jhp0918*); its presence in strains from patients with this gastroduodenal pathology resulted in its association with this condition.

Predominant inflammation in the antrum region of the stomach as well as the infiltration of polymorphonuclear leukocytes can lead to the appearance of a duodenal ulcer [35]. The prevalence of the *dupA* gene among *H. pylori* strains varies according to the geographic region and duodenal pathology. The *dupA* gene is present in approximately 31% of strains in Asian countries and 64% of strains in Western countries [36–40].

However, two genotypes were observed for this gene, including strains with and without an extra 600 bp in the gene sequence [41]; another important characteristic is that it has high homology with VirB4, a component of the type IV secretion system (T4SS) of *H. pylori*, and recent studies suggest that *dupA* and the six homologues of adjacent vir genes (virB8-virB11, virD4 and virD2) in the PZ could form the third T4SS [42]. Many unanswered questions still exist regarding this gene and its role in *H. pylori* strains. To date*, jhp0947* is considered the best disease marker of the locus *jhp0945-jhp0947-jhp0949* because it seems to meet two of the conditions that Yamaoka et al. [12] suggest for an *H. pylori* virulence factor: (1) it has a disease or other *in vivo* correlation and (2) it is epidemiologically consistent across populations and regions.
