Population, Epidemiological, and Functional Genetics of Gastric Cancer Candidate Genes in Peruvians with Predominant Amerindian Ancestry
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Gastric adenocarcinoma is associated with chronic infection by Helicobacter pylori and with the host inflammatory response triggered by it, with substantial inter-person variation in the immune response profile due to host genetic factors.
To investigate the diversity of the proinflammatory genes IL8, its receptors and PTGS2 in Amerindians; to test whether candidate SNPs in these genes are associated with gastric cancer in an admixed population with high Amerindian ancestry from Lima, Peru; and to assess whether an IL8RB promoter-derived haplotype affects gene expression.
We performed a Sanger-resequencing population survey, a candidate-gene association study (220 cases, 288 controls) and meta-analyses. We also performed an in vitro validation by a reporter gene assay of IL8RB promoter.
The diversity of the promoter of studied genes in Native Americans is similar to Europeans. Although an association between candidate SNPs and gastric cancer was not found in Peruvians, trend in our data is consistent with meta-analyses results that suggest PTGS2-rs689466-A is associated with H. pylori-associated gastric cancer in East Asia. IL8RB promoter-derived haplotype (rs3890158-A/rs4674258-T), common in Peruvians, was up-regulated by TNF-α unlike the ancestral haplotype (rs3890158-G/rs4674258-C). Bioinformatics analysis suggests that this effect stemmed from creation of a binding site for the FOXO3 transcription factor by rs3890158G>A.
Our updated meta-analysis reinforces the role of PTGS2-rs689466-A in gastric cancer in Asians, although more studies that control for ancestry are necessary to clarify its role in Latin Americans. Finally, we suggest that IL8RB-rs3890158G>A is a cis-regulatory SNP.
KeywordsAmerindians Ancestry Association studies Gastric cancer Meta-analyses Proinflammatory genes
We thank Gifone Rocha, Denise Carmona, Carolina Gomes, Gilderlanio S Araujo, Giordano Soares Souza, Moara Machado, Mateus H Gouveia for discussions on different parts of the project and for technical help.
Fogarty International Center and National Cancer Institute (5R01TW007894) funded this study. The study and its participants also received funding and fellowships from the following Brazilian agencies: Brazilian National Research Council (CNPq), Ministry of Education (CAPES), Ministry of Health (PNPD-Saúde Program), and the Minas Gerais State Research Agency (FAPEMIG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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