H. PYLORI INFECTION AND GI DISEASE IN ALASKA NATIVES

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DESCRIPTION (Adapted from the Applicant's Abstract): Helicobacter pylori (Hp), one of the most genetically diverse of bacterial species, chronically infects the gastric mucosa of more than half of all persons world wide. It is the major cause of severe gastritis and peptic ulcers, and a risk factor for gastric cancer, although most infections are asymptomatic. Infection is more common in Alaska Natives than in mainstream US populations, and the spectrum of associated diseases is distinct. Most striking is an Hp-associated hemorrhagic gastritis and iron deficiency anemia that is common only in Alaska Natives. Here the investigators propose to study the genetics of Hp from Alaska natives. First, they will seek to define the population genetic structure of Hp in Alaska Natives. In these experiments they will (a) test the view that the Alaska Native Hp gene pool is far less diverse than that in other human populations, (b) learn whether Hp from some regions or linguistic/ethnic groups of Alaska Natives differs significantly from that in others, and (c) test the idea that Hp lineages in this population are far more nearly clonal (less scrambled by recombination) than has been seen in other human populations. They propose that recombination is important, assuming that Hp colonization of individual hosts is often associated with considerable adaptation on the part of the bacterium to that given person, and that the formation of recombinants during even transiently mixed infection can markedly speed this process. These tests will entail arbitrarily primed PCR (RAPD) typing of several hundred Hp isolates from Alaska Natives, and then multilocus DNA sequence typing (MLST) of informative gene loci from many representative strains. The data will also help assess whether much or any significant portion of the Hp gene pool of Alaska Natives is of Asian origin, as defined by studies of Hp isolates from Eastern China and Japan, and as might be expected if the ancestors of current Alaska Natives carried Hp with them when they migrated from Asia many millennia ago. Second, they will search for previously unknown genes affecting Hp virulence, with special interest in genes affecting the risk of hemorrhagic gastritis or iron deficiency anemia. This will be based on new subtractive hybridization and DNA microarray-based comparative genomic methods. Third, they will search for genes or alleles of divergent gene families that may contribute to the growth of individual strains in particular human hosts. This will entail analyses of recombinant derivatives of individual strains that emerge in Alaska Native populations, often, they postulate, as the result of selection for a gene or allele that may have been transferred from an unrelated Hp strain.