Results of studies regarding the relationship of H. pylori oipA gene with PUD and GC risks turn out to be controversial [9, 11, 12, 14, 16–18, 21]. To our knowledge, this is the first meta-analysis evaluating the association between oipA gene status and PUD and GC. By performing the current meta-analysis, we found that when oipA gene exists, the oipA “on” status was associated with increased risks of PUD and GC compared with gastritis and FD controls. Null association was found between the presence of oipA gene and PUD or GC risks.
For the pooled analysis of oipA gene on/off status, we found association of oipA gene “on” status with increased overall risk of PUD compared with gastritis and FD controls, and no significant heterogeneity among studies was observed. Consistently, increased risks for PUD were observed in subgroup analyses although associations in Asia and GU subgroups did not reach statistical significance, which possibly due to small sample size of the PUD cases in Asia and GU subgroups (28 and 33 cases respectively). The potential influence of geographical region, age and detection method on the association strengthen between oipA “on” status and PUD risk was further clarified by homogeneity test. Observations indicated that children infected by H. pylori with oipA “on” status have a higher PUD risk than adults. One of the possible reasons explaining this phenomenon is that the gastric microenvironment of children may be more suitable for H. pylori with oipA “on” status to induce PUD. Another possible reason is the relatively low defense ability of children against pathogenic factor. Nevertheless, this different effect of oipA “on” status between children and adults was obtained with small groups of strains, which therefore requires future validation.
The pooled estimate also demonstrated that the oipA “on” status was associated with an increased risk of GC compared with gastritis and FD controls, and no significant heterogeneity among studies was observed. Subgroup analyses indicated that oipA “on” status showed a consistent tendency toward increasing the risk of GC development although Europe, Asia, PCR-sequencing subgroups did not reach statistical significance. However, the test for homogeneities between subgroups indicated no significant difference for Europe/Asia/America subgroups. Statistical different effect was only indicated between PCR-sequencing and immunoblot subgroups. Although the PCR-based sequencing determines the functional status of oipA gene by detecting the number of CT repeats in its signal-peptide region, this method could not guarantee the expression of OipA protein. The high degree of genetic diversity of oipA gene may also complicate the interpretation of PCR based methods and may possibly result in an underestimation of the frequency of the functional status of the oipA gene.
Some mechanism studies may partially explain the association between oipA “on” status with PUD and GC. In 2000, by gene knockout models, Yamaoka et al. initially linked oipA gene “on” status with increased IL-8 production in gastric cancer cells . Similar effects were detected in Straubinger et al’s study using cat models . Subsequently, by challenging the volunteers with a cagA negative, oipA functional “on” strain of H. pylori, Graham et al. confirmed the role of oipA “on” status in inducing IL-8 levels in human. This author reported that the IL-8 levels in gastric mucosa increased even up to 20-fold by two weeks after inoculation . Yamaoka et al. further unraveled that OipA was necessary for full activation of the IL-8 promoter and acted via the STAT1-IRF1-ISRE pathway . Importantly, the IL-8 is one of the most essential proinflammatory factors, which acts as a potent chemoattractant and activator of neutrophils . It has been suggested that IL-8 is closely linked with the tumorigenesis, angiogenesis and intracellular adhesion of cancer . Therefore, it is tempting to speculate that the association of oipA “on” status with increased PUD and GC risks may be, at least in part, explained by a role in inducing IL-8 secretion.
It is worth noting that the detection of the presence/absence of oipA gene could not reflect the specific functional status of this gene, since the signal-peptide region of oipA gene varies significantly among H. pylori strains. Merely assessing the presence/absence of oipA gene would result in an underestimation of the influence of the functional status of oipA gene on PUD and GC development. Therefore, more caution should be taken when link the presence of oipA gene with phenotypic risk regardless of its functional status. The investigators that only examined the presence/absence of oipA gene may overlook the importance of the on/off status of oipA or could not perform the sequencing. The synthesis of the data in the present meta-analysis also suggested that only studying the “presence/absence” of oipA gene provided insufficient evidence to investigate the exact role of H. pylori oipA gene in gastrointestinal diseases. Normally, investigators should sequence oipA gene and take the functional on/off status of oipA into consideration.
The prevention and treatment for PUD and GC cause significant financial burdens around the world [36, 37]. Because H. pylori is one important cause for PUD and GC, the identification of specific type of H. pylori isolates associated with PUD and GC risks would significantly reduce the costs of the screening and prevention for PUD and GC. The OR for PUD was found to be higher than that of GC (3.97 vs. 2.43) in this meta-analysis. The predictive role of oipA functional status in risks of PUD and GC may differ because of their distinct pathogenic mechanisms. However, we could not definitely conclude that the oipA “on” status is more closely linked with PUD than GC by numerically judging the OR values based on the currently-limited study samples. It is anticipated that oipA “on” status would be a promising indicator for H. pylori infected patients with increased risk for PUD or GC in the future.
We are aware that this meta-analysis has its own limitations. First, only articles in English or Chinese were selected. And we searched four databases without referring to other databases like EMBASE, which may result in selection bias. Second, the quality assessment of NOS indicated that most studies were at an intermediate level of quality mainly due to not matching for age or gender. In addition, the control group mixed the gastritis and FD, and some studies did not clearly describe that the control group excluded other kinds of diseases, which may result in an underestimation of the effect of oipA gene. Third, the sample size is not sufficiently large which may partially due to the limitation of the present laboratory technique for the isolation and cultivation of H. pylori isolates. Besides, numbers of included studies were relatively small, so the power for publication bias test was relatively low. Fourth, most studies were from Asia, thus the generalizability of our conclusion was limited. Fifth, significant heterogeneities were indicated for some comparisons particularly in presence/absence analysis, which could not be explained by subgroup analyses or sensitivity analyses. Moreover, the limited number of included studies precluded us from performing meta-regression to further explore the source of heterogeneity. Sixth, other important data such as age, gender, family history, status of other virulence factors and environment factors were not available to investigate the interaction between oipA gene status and these factors. The combined effect of oipA and other virulent factors should also be studied in future study.