Distinct variants of Helicobacter pylori cagA are associated with vacA subtypes

The diversity of the cytotoxin-associated gene (cagA) of Helicobacter pylor i was analyzed in 45 isolates obtained from nine countries. We examined var iation in the 5' end of the cagA open reading frame as determined by PCR an d sequencing. Phylogenetic analysis revealed the existence of at least two distinct types of cagA. One variant (cagA1) was found exclusively in strain s from Europe, the United States, and Australia, whereas a novel variant (c agA2) was found in strains from East Asia. The greatest diversity between c agA1 and cagA2 was found in the first 20 amino acids of the cagA open readi ng frame, where several consistent insertions or deletions were observed, A dditional cagA sequence variants that could be classified as separate subty pes were found in two of three Peruvian and in five of seven U.S. strains t ested. The calculated isoelectric point of the first 154 amino acids of the cagA1 variants (7.52 +/- 1.54) was significantly higher than that of the f irst 154 amino acids of the cagA2 variants (5.61 +/- 0.93; P < 0.001), Most cagA2 strains contained vacA subtype s1c (P < 0.001), and in vac4 m1 strai ns cagA1 was more frequently observed than cagA2. These results shots the e pidemiological relationship between cagA and vacA at the subtype level and indicate the existence of distinct H. pylori lineages that are not uniforml y distributed over the globe.