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Population, Epidemiological, and Functional Genetics of Gastric Cancer Candidate Genes in Peruvians with Predominant Amerindian Ancestry

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Abstract

Background

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.

Aim

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgments

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.

Funding

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.

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Author notes

  1. Fernanda S. G. Kehdy

    Present address: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, FIOCRUZ-RJ, Rio de Janeiro, Brazil

Authors and Affiliations

  1. Department of General Biology, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antonio Carlos 6627, Pampulha, Belo Horizonte, Minas Gerais, CEP 31270-910, Brazil

    Roxana Zamudio, Latife Pereira, Thaís Muniz-Queiroz, Hanaisa P. Sant Anna, Fernanda Lyon, Maíra R. Rodrigues, Fernanda Rodrigues-Soares, Meddly L. Santolalla, Camila Zolini, Eduardo Tarazona-Santos & Fernanda S. G. Kehdy

  2. Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru

    Roxana Zamudio, Lilia Cabrera, Phabiola Herrera, Martha H. Jahuira & Robert H. Gilman

  3. Asociación Benéfica PRISMA, Lima, Peru

    Lilia Cabrera, Phabiola Herrera, Martha H. Jahuira & Robert H. Gilman

  4. Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Carolina D. Rocha, Felipe B. Leão & Aristóbolo M. Silva

  5. Department of Medicine, University California San Diego, La Jolla, CA, USA

    Douglas E. Berg

  6. Departamento de Gastroenterologia, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru

    Juan M. Combe

  7. Servicio de Gastroenterologia, Hospital Dos de Mayo, Lima, Peru

    William A. Prado

  8. Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Robert H. Gilman

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  1. Roxana Zamudio
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  2. Latife Pereira
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Correspondence to Fernanda S. G. Kehdy.

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Roxana Zamudio and Latife Pereira have equally contributed to this paper.

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Zamudio, R., Pereira, L., Rocha, C.D. et al. Population, Epidemiological, and Functional Genetics of Gastric Cancer Candidate Genes in Peruvians with Predominant Amerindian Ancestry. Dig Dis Sci 61, 107–116 (2016). https://doi.org/10.1007/s10620-015-3859-6

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  • DOI: https://doi.org/10.1007/s10620-015-3859-6

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