In the present study, we estimated the frequency of peptic ulcer about 33% in Iranian patients infected with H. pylori, which despite of higher prevalence than global average, but confirms previous studies from Iran. Perhaps this phenomenon is to be due to some factors such as genetic properties of Iranian population, life style, and characteristics of circulating strains in Iran (6–7). Among the patient possessed peptic ulcer, frequency of duodenal ulcer was more than gastric ulcer, and also, the majority of patients were male. Further, like previous studies, age average of studied cases was measured about 41 years old (12, 52). Regarding the present results, vacA genotypes m1, s1, and s1m2 were the three most prevalent isolated genotypes from Iranian patients involved with peptic ulcer. As well as, we demonstrated that there is a significant relationship between infection by strains containing m1, s1m1, and s2m1 genotypes and progression to peptic ulcer. Besides, in this meta-analysis, frequency of strains containing coexistence of vacA and cagA genes in peptic ulcer patients was assessed about 33.35%. We showed that there is a meaningful relationship between infections by cagA/vacA positive strains and development to peptic ulcer. H. pylori possesses some unique characteristics which cause to persist of bacterial infection in acidic condition of stomach and also evading from immune system (53). The colonization by this bacterium is different in various regions worldwide; for example in Iran, 90% of population are infected with H. pylori (54). Nevertheless, most of infected people remain as an asymptomatic carriers throughout the life of themselves; peptic ulcer and gastric cancer happen in 10–15% and 2% of infected cases, respectively (54–55). Therefore, it seems that host genetic properties and pathogenicity power of H. pylori strains are as two determining factors in the onset of disease and final outcomes (55–56). According to review of the literature, global prevalence of peptic ulcer has been estimated about 10%, and this bacterium isolated from 90–100% and 60–90% cases of duodenal ulcer and gastric ulcer, respectively (55). Nonetheless, frequency of peptic ulcer in Iran is much more than world average, which is related to host genetic characteristics and virulence factors of bacterium (6, 55). Both surface antigens and cytotoxic enzymes such as VacA and CagA are accounted as the two main virulence factors of H. pylori (14, 57). Based on previous meta-analysis, some virulence factors of bacterium e.g. OipA, BabA, DupA, IceA, CagA, and VacA are related to progress to peptic ulcer disease (53, 57–64). Also, it seems that type of colonization can be effective in formation of peptic ulcer; in general, duodenal ulcer is create following antral colonization, but gastric ulcer is the result of corporal and pan-gastritis (55, 56). Although vacA gene is present in all H. pylori strains, but its functional protein, VacA toxin, expressed in only 50% of those. The VacA protein forms a channel in membrane of bacterium, which be able to uptake of different ions and metabolites to the inside the cytoplasm, and causes to survival of bacterium in stomach mucosal layer. Endocytosis of VacA into the host cell leads to some events such as vacuoles formation, releasing cytochrome c from mitochondria, and apoptosis. In addition, VacA toxin by impressing on different receptors leads to alteration in signaling pathways of MAPK/p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) (18, 66–68). Functional weight of VacA toxin is about 88 kDa, and forms two subunits p33 and p55. The p33 domain which contains residues 1–33 in N-terminal region (as signal sequence) of VacA toxin, and creates vacuole in host cell (66, 69). On the other, p55 domain acts as binding domain of toxin to the cell surface (66). The length of vacA gene is 3860–3940 bp, and contains both conserved and variable regions. Nowadays, it has been cleared that the variable regions can be effective in variations of vacA gene expression, and directly are related to clinical outcomes of infection by h. pylori (66, 69). For example, McClain et al. in 2001 showed that the hydrophobic amino acids near the cleavage site of s2, could integrated the VacA toxin with host cell membrane (70). According to literature, vacA gene possesses variable sequences in s (s1 and s2) and m (m1 and m2) regions. It is notable that vacA s1m1 has the most expression rate, and therefore high vacuolating, but vacA s1m2 is a moderate vacuolating genotype, as well as vacA s2m2 is not toxic, and finally, vacA s2m1 genotype is rare and non-toxic (71–74). Recently, two additional variable regions, i1/i2 and d1/d2, have recognized in m region, and also, each of s1 and m1 regions subdivided to different types such s1a, s1b, s1c, m1a, m1b and m1c (75–76). In the recent present, we showed that there is a significant relationship between infection by cagA positive H. pylori strains and peptic ulcer disease. Given that studies in this field, expression of cagA gene leads to increase of pathogenicity, and directly related to severity of diseases of bacterium (55). Our study confirmed previous studies (77–78). Moreover, we demonstrated that m1, s1m1, and s2m1 genotypes have direct correlation with peptic ulcer in Iranian population. But, due to limit information about the both d and i genotypes, we could not assessed the effect of these genotypes on development of infection to peptic ulcer. In 2014, Basiri et al. showed that the infection by d1 genotype of vacA gene raises the risk of primary infection towards gastric adenocarcinoma and peptic ulcer in Northwestern of Iran (79). In another study in 2014, Mottaghi et al studied on correlation between infection by i1 allele and development of infection into the gastric cancer and peptic ulcer in Azerbaijan, Iran; they found that vacA i1 genotype is significantly related to gastric cancer, however in their study, they did not find a meaningful relationship between infection by vacA i1/2 alleles and peptic ulcer gastric cancer diseases (80). According to various European studies, it has been demonstrated that there is a significant correlation between vacA genotypes of s1 and m1 with H. pylori-related gastrointestinal diseases (71, 76, 81–84). It is notable that due to decrease or absence of vacuolating activity, s2 and m2 genotypes rarely are related to peptic ulcer (76). In our analysis, we observed a similar correlation about frequency of s1 and m1 alleles in patients involved by peptic ulcer with other studies, which is due to some properties of these bacterial strains such as increased binding capacity, vacuolating activity, and alternation in normal signaling pathway (71). In addition, it is known that the origin of Iranian circulating strains is like to Western countries, in that, in 2010 Latifi-Navid et al. proved that the origin of Iranian strains is belonging to European H. pylori (hpEurope) strains. It seems that following migration of European to Iran, the hpEurope strains have been transferred to Iran, and this phenomenon can be effective in similarity of results of both our studies and Western countries (85). Overall, most recent studies have confirmed an intimate relationship between infection by s1m1 strains and progression to gastrointestinal diseases (76, 86–88). In 2005, Martins et al. represented that a significant relevance between colonization by vacA genotype s1m1 and peptic ulcer in Brazilian population (89). Likewise, several separate studies have confirmed relationship between H. pylori vacA s1m1 infection and peptic ulcer (87–90). Based on our results, s1, m1, and s1m2 were proposed as the most prevalent genotypes in peptic ulcer disease. In a study that was done by Sugimoto et al., in 2009, they demonstrated that the frequency of s1 and m1 genotypes in Middle East patients is more than 50%; they found that s1m1 and s2m1 were the most and lowest common genotypes in Middle East regions, respectively, which in turn their results were according to our results (91). While, based on Sugimoto et al. study, s1, m1, and s1m1 genotypes were related to peptic ulcer, but in our findings, m1, s1m1, and s2m1 were accounted as risk factor for peptic ulcer. It may be due to difference in distribution of patients; we only studies on Iranian patients’ samples (91). We declared that there is a direct association between vacA s2m1 with peptic ulcer in Iranian patients; this is while, it seems that the strains which harboring s2m1 are non-toxic, or low capacity of vacuolation, and this finding was challenging (92). Although due to limit information, we could not evaluate the presence of other virulence factors in s2m1 strains, it seems that these strains possess cagA gene or other required virulence factors for development to peptic ulcer. However, isolated strains from patients involved to peptic ulcer and gastric cancer in some regions such as Mexico, Latin America, Africa, and Western countries were contain vacA s2m1 genotype (83–84, 93). In the same year, Sugimoto et al. demonstrated that abundance of vacA s2m1 in Mexican population is about 12.2% (94). Furthermore, Zhang et al. displayed that infection by vacA s2m1 genotype and duodenal ulcer are significantly related with each other (OR: 2.30; 95% CIs: 1.17–4.50) (87). Yet, it needed to more study about the effect of vacA s2m1 strains on creation of peptic ulcer. The limitations of our study were including: 1) limited information of patients; 2) spatial constraints, so that most of the studies were conducted in Tehran; 3) limited information of vacA d and i alleles; 4) limited information of cagA and other bacterial virulence factors; 5) publication bias in some studies. Anyway, we showed that there is a significant relationship between vacA genotypes m1, s1m1, and s2m1, and development of infection to peptic ulcer disease in Iranian population.