Human and Helicobacter pylori coevolution shapes the risk of gastric disease

Nuri Kodaman; Alvaro Pazos; Barbara G. Schneider; M. Blanca Piazuelo; Robertino Mera; Rafal S. Sobota; Liviu A. Sicinschi; Carrie L. Shaffer; Judith Romero-Gallo; Thibaut de Sablet; Reed H. Harder; Luis E. Bravo; Richard M. Peek; Keith T. Wilson; Timothy L. Cover; Scott M. Williams; Pelayo Correa

doi:10.1073/pnas.1318093111

Edited* by Stanley Falkow, Stanford University, Stanford, CA, and approved December 5, 2013 (received for review September 24, 2013)

Significance

Theory predicts that chronic pathogens with vertical or familial transmission should become less virulent over time because of coevolution. Although transmitted in this way, Helicobacter pylori is the major causative agent of gastric cancer. In two distinct Colombian populations with similar levels of H. pylori infection but different incidences of gastric cancer, we examined human and pathogen ancestry in matched samples to assess whether their genomic variation affects the severity of premalignant lesions. Interaction between human Amerindian ancestry and H. pylori African ancestry accounted for the geographic disparity in clinical presentation. We conclude that coevolutionary relationships are important determinants of gastric disease risk and that the historical colonization of the Americas continues to influence health in modern American populations.

Abstract

Helicobacter pylori is the principal cause of gastric cancer, the second leading cause of cancer mortality worldwide. However, H. pylori prevalence generally does not predict cancer incidence. To determine whether coevolution between host and pathogen influences disease risk, we examined the association between the severity of gastric lesions and patterns of genomic variation in matched human and H. pylori samples. Patients were recruited from two geographically distinct Colombian populations with significantly different incidences of gastric cancer, but virtually identical prevalence of H. pylori infection. All H. pylori isolates contained the genetic signatures of multiple ancestries, with an ancestral African cluster predominating in a low-risk, coastal population and a European cluster in a high-risk, mountain population. The human ancestry of the biopsied individuals also varied with geography, with mostly African ancestry in the coastal region (58%), and mostly Amerindian ancestry in the mountain region (67%). The interaction between the host and pathogen ancestries completely accounted for the difference in the severity of gastric lesions in the two regions of Colombia. In particular, African H. pylori ancestry was relatively benign in humans of African ancestry but was deleterious in individuals with substantial Amerindian ancestry. Thus, coevolution likely modulated disease risk, and the disruption of coevolved human and H. pylori genomes can explain the high incidence of gastric disease in the mountain population.

Footnotes

↵¹N.K. and A.P. contributed equally to this work.
↵²To whom correspondence should be addressed. E-mail: barbara.schneider{at}vanderbilt.edu.
↵³S.M.W. and P.C. contributed equally to this work.

Author contributions: N.K., A.P., B.G.S., R.M., L.E.B., R.M.P., K.T.W., T.L.C., S.M.W., and P.C. designed research; N.K., A.P., B.G.S., M.B.P., L.A.S., J.R.-G., T.d.S., and R.H.H. performed research; N.K., A.P., T.d.S., L.E.B., R.M.P., K.T.W., S.M.W., and P.C. contributed new reagents/analytic tools; N.K., M.B.P., R.M., R.S.S., C.L.S., and S.M.W. analyzed data; N.K., B.G.S., M.B.P., R.M., R.S.S., L.A.S., C.L.S., T.d.S., R.M.P., T.L.C., S.M.W., and P.C. wrote the paper; and M.B.P. and P.C. provided histopathological diagnoses.
The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.
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