This study surveyed whether the bacterial factor dupA in H. pylori or single nucleotide polymorphisms of MMPs and TIMPs correlated with the susceptibility of gastroduodenal ulcers after H. pylori infection. It shows a rather low prevalence (23.8%) of dupA-positive H. pylori infection in Taiwan. Moreover, such a low prevalence limits its association to susceptibility to gastroduodenal ulcers after H. pylori infection.
The negative finding is consistent with several studies worldwide [8, 10, 11] but differs from Lu et al., who support the promoting role of H. pylori dupA . In their positive report , dupA-positive prevalence is nearly 50% and it can be attributed as the promoting role of ulceration. Their data suggest that there should be some other bacterial virulence factor of H. pylori as CagA, babA2, vacA, or host factors, which determine the susceptibility of ulceration. In Taiwan, there is nearly a 100% prevalence of CagA, babA2, vacA triple-positive infection [4, 15]. The current study area should be a good place to validate the host factor predisposing to ulcer risk.
In the in vitro promoter functional assay of fibroblasts and vascular smooth muscle cells, the MMP-3 -1612 as 5A allele has greater promoter activities than the 6A allele . This implies that patients carrying the lower promoter activity genotype 6A6A in the MMP-3 promoter are accompanied by lower MMP-3 expressions of the gastric mucosa. This study discloses the host genotype MMP-3 -1612 as 6A6A, which expresses lower MMP-3 carries a 2.4-fold risk of having duodenal ulcers among females after H. pylori infection (p < 0.05) (Table 3). Moreover, TIMP-1 372, as CC, contributes a higher risk of duodenal ulcers to MMP-3 -1612 6A6A (Table 4). This data suggests that patients with higher MMP-3 expression may have lower ulcer risk, but the reasons remain uncertain.
In general, MMP-3 can degrade a wide range of substrates, including fibronectin, type IV, V, IX, and X collagens, elastin, laminins, gelatin, and proteoglycan core proteins, and is thus helpful during wound healing of the skin [27–29]. Moreover, the gastric mucosa at the ulcer site also has significantly higher expression of MMP-3 than those in the antrum , which suggests MMP-3 is abundant in the ulcer part, and this may help the process of re-epithelialization and contribute to wound healing.
Hellmig et al. disclose the positive associations of MMP-7 promoter -181 and MMP-9 exon 6 SNPs to the presence of gastric ulcer among Germans . However, this may be due to distinct ethnic or racial variations and such positive linkage is not disclosed in the current study from Taiwan.
This is the first report to show that there is no direct association between the genotypes of TIMP-1 372 at exon 5 and TIMP-2 at promoter -418, and the presence of gastroduodenal ulcers (Table 3). However, because TIMP-1 genotypes may modulate MMP-3 activity, further testing if the MMP-3-1612 /TIMP-1372 Combined genotypes contribute to increased risk of duodenal ulcers shows that the combined MMP-3/TIMP-1 genotype as 6A6A/CC has a 3.6-fold increased risk of duodenal ulcer (p < 0.05) in H. pylori-infected females. This data suggests that TIMP-1 may also have a supportive role in interacting with MMP-3 during ulcerogenesis by H. pylori infection, especially in females.
However, the exact reason why such a combined MMP-3/TIMP-1 genotype as 6A6A/CC has just an increased risk of duodenal ulcer in H. pylori-infected females, but not in male, remains uncertain. If such a regulation between MMP-3 and TIMP-1 play a role in female's ulceration, our data at least imply some other host or environment factors in male should be more dominant than such combined genotype.
The study has a limitation of just providing 181 isolates for the analysis of the dupA status of H. pylori, which disclose a rather low 20% dupA-positive prevalence rate. Accordingly, the study became limited to only 103 patients to provide both analyses on the infected isolate's dupA status and the host's SNPs (Figure 2). It thus cannot provide an adequate statistical power to determine the exact impact of MMP-3 SNPs under dupA-negative specific conditions.