Our present meta-analysis shows that the presence of the
dupA gene was significantly associated with DU. Although several studies failed to show the positive association between the
dupA status and clinical outcomes, the meta-analysis confirmed the original report in 2005 [
7]. Especially, the presence of the
dupA gene was associated with DU in Asian countries; however it was not in Western countries. This difference may be due to the different prevalence of the
dupA gene between Asian and Western countries. Furthermore, the study by Gomes
et al. was the resource of heterogeneity due to larger difference compared with other studies. This mean the simple combined calculation such as the report by Hussein [
13] is not strictly accurate to concluded although the trend was not changed. In addition, we found that the several miscount exist in the report by Hussein (e.g., he counted the mean age but not the number of subjects from the study Zhang
et al. [
24] and mistook the calculation from the study by Pacheco
et al. [
23]).
When Argent
et al. combined Belgian and South African populations, the presence of the
dupA gene was significantly associated with the presence of GC. There was also a non-significant trend towards an association between the
dupA gene and DU in the combined Belgian and South African population. However, we did not include the South Africa in Western countries. It is not relevant to combine random populations since it is unclear whether the South African strains were taken from patients of European descent and recent studies confirmed that the genomic structures of some South African strains (i.e., HpAfrica2 type) were relatively different from those from the European population (i.e., HpEurope type) [
25,
26].
In a study examining strains from Brazilian children and adults, the prevalence of the
dupA gene was extremely high (92%; 445/482) irrespective of clinical outcomes [
10]. Interestingly, the frequency of the
dupA gene was significantly higher in strains from children than in those from adults.
H. pylori infection is typically acquired in childhood and persists throughout life unless treated with a combination of anti-acid and antimicrobial therapy, so it is speculated that the
dupA gene might be lost during long-term infections in which the gastric mucosa gradually develop chronic atrophic gastritis and GC. Therefore, their results might partially support the original hypothesis that the
dupA gene is a marker associated with gastric damage that leads to the development of gastric cancer. Therefore, we need to pay attention to the age of each disease in case-control study. For example, mean age of DU was younger than that of gastritis in the study by Zhang
et al. (41 years old in DU vs 59 years old in gastritis) [
24]. Case-control study matched age- and sex- should be performed in the future.
Overall, there are distinct geographical variations in the prevalence of the
dupA gene, and there appears to be an association between
dupA and DU in some populations but not in others. As Argent
et al. [
8] reported, the association of
dupA with DU in only some populations could reflect differences in the definition or diagnosis of ulcers or in the use of drugs that either cause or heal ulcers in these populations. In addition, the discrepancy could be related to the limitation of PCR techniques for detecting the intact
dupA gene. In some studies, only one set of primer pairs for
jhp0917 and
jhp0918 was used [
7,
9,
23,
24]: use of multiple primer pairs is recommended for detection of the
dupA gene in future studies. None of the previous reports considered the frameshift mutation after position 1385 as a criterion for the presence of the
dupA gene [
7,
10]. More importantly, Gomes
et al. reported frameshift mutations in 14/86 (16%)
dupA-positive sequenced samples [
10]; a single adenine insertion after position 1426 of
dupA or at position 2998 of the
jhp0917-
jhp0918 gene of the J99 strain that created a premature stop codon and may have considerable effects on protein expression or function. In their study, they counted the truncated samples as
dupA-positive; however, it is clear that these mutated sequences would not produce intact DupA protein. For example, the expression of the blood group antigen binding adhesin (BabA) protein does not always correlated with the
babA gene expression [
27]. It will be better to detect intact
dupA by measuring intact DupA protein using immunoblotting techniques, which has not been reported previously. In addition, the
vir genes exist before and after the region of the
dupA locus [
16]. In the strain Shi470, for example,
virB2, virB3, virB4 (dupA), virB8, virB9, virB10, virB11, virD4, and
virD2 were detected. These are structurally similar to the type IV secretion system (T4SS) called
cag PAI and ComB and thought to be the third T4SS. Recently, T4SS containing
dupA was named as
tfs3a, and T4SS having
virB4 sequence, but not
dupA was named as
tfs3b[
28]. These observations suggest that only strains that are intact
dupA-positive and form a novel type IV secretion system might be involved in gastroduodenal diseases. If this is true, examining the presence of DupA/
dupA alone might not be sufficient. Study on DupA is still in their early stages, and great progress is expected in the near future.