22 Gut and Liver, Vol. 6, No. 1, January 2012 H. pylori infection is a necessary but not a sufficient factor in gastric carcinogenesis. The hypothetical causal link between H. pylori infection and gastric cancer was challenged by Hol- combe,16 making reference to several countries in Africa where the infection was practically universal but the gastric cancer rates were very low. He called this phenomenon the “African enigma.” Similar trends have been observed in other popula- tions around the world, and since gastric cancer is considered a multifactorial disease, factors such as diet and co-infections have been offered as potential explanations for the enigma.17-19 Independent from other factors that may modulate the risk of acquiring gastric cancer, the genotype of the infecting H. pylori strain is a determining factor. The carcinogenic effects of H. pylori infection have been linked to its virulence factors, mainly the cag pathogenicity island (cag PAI) and the vacuolating cy- totoxin gene A (vacA).2,20,21 The cag PAI is a ~40 kb locus that contains 27 to 31 genes, hypothesized to have been acquired horizontally and integrated into the glutamate racemase gene.22 Present day isolates of H. pylori may or may not contain the cag PAI. The cytotoxin-associated gene A (cagA)23 is the most investigated gene of the cag PAI and the main recognized viru- lence factor. It encodes CagA, an oncoprotein that is injected into mammalian cells, undergoes phosphorylation by host cell kinases, and affects cytoskeletal and tissue structure, as well as cell proliferation.24,25 Several of the genes in the cag PAI encode for a type IV secretion system26 used for the injection of CagA into host cells. Infection with cagA -positive H. pylori strains is associated with high risk of peptic ulcers and gastric carci- noma.20,21,25 In East Asian countries, virtually all of the H. pylori isolates are cagA -positive, whereas in Western countries ap- proximately 60% to 70% of isolates are cagA-positive.27 Mixed infections with cagA -positive and cagA -negative strains have been reported.28 CagA is known for the variability in its C-terminal region, which includes a Glu-Pro-Ile-Tyr-Ala (EPIYA) sequence that is present in variable numbers in CagA from different strains. On the basis of sequences flanking the EPIYA motifs, four dis- tinct segments have been described: EPIYA-A, -B, -C and -D. EPIYA-A and EPIYA-B are in almost all CagA isolates. EPIYA- C is characteristic of CagA from H. pylori from Europe, North America, and Australia (thus named “Western CagA”). EPIYA-D is specific to CagA produced by H. pylori circulating in East Asian countries (termed “East Asian CagA”). Most CagA isolates contain three EPIYA segments (ABC or ABD), but the number can vary from one to seven.27 Studies have shown greater phos- phorylation and oncogenic potential in East Asian CagA (due to the presence of the EPIYA-D segment) compared to Western CagA.29,30 Also, among Western CagA species, greater phos- phorylation and oncogenic potential has been observed in those with a greater number of EPIYA-C motifs.27,31,32 Therefore, dis- tinct CagA isoforms may contribute to the differences in gastric cancer rates between East Asian and Western countries. Unlike the cag PAI, the gene vacA is present in virtually all H. pylori strains examined.33,34 It encodes VacA, a protein that may damage epithelial cells by inducing the formation of vacuoles. Strains vary considerably in production of cytotoxin activity, primarily due to variations in vacA gene structure. The regions of greatest diversity are localized near the 5’ end of vacA (signal sequence, showing allele types s1a, s1b, s1c, or s2) and in the mid-region of vacA (alleles m1 or m2). H. pylori strains that possess vacA s1m1 genotypes are associated with increase in gastric epithelial cell injury and greater risk of peptic ulcer and gastric cancer compared with vacA s2m2 strains.35,36 vacA s1a predominates in Northern Europe; s1b in the Iberian peninsula and in Latin America; s1c is only found in South Eastern Asia.37 The relationship between vacA s1m1 alleles and gastric cancer is consistent with the distribution of vacA genotypes through- out the world. In regions where the prevalence rate gastric can- cer is high, such as Colombia and Japan, most H. pylori strains contain type s1m1 alleles. Strains with vacA s2 alleles are more Fig. 1. World map indicating hu- man migrations (arrows) and time range in years since the migrations happened. H. pylori accompanied man during the migrations and the four major H. pylori populations (as known in 1999: Europe, Northern Asia, Southern Asia, and New Zea- land) are represented by concentric circles of different colors. Light green areas indicate the locations where development of agriculture and animal breeding started, result- ing in expansion of human popula- tions (From Covacci A, et al. Science 1999;284:1328-1333, with permis- sion).26