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

Dig Dis Sci. 2016 Jan;61(1):107-16. doi: 10.1007/s10620-015-3859-6. Epub 2015 Sep 21.

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.

Keywords: Amerindians; Ancestry; Association studies; Gastric cancer; Meta-analyses; Proinflammatory genes.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenocarcinoma / ethnology*
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • African Continental Ancestry Group / genetics
  • Asian Continental Ancestry Group / genetics
  • Binding Sites
  • Biomarkers, Tumor / genetics*
  • Case-Control Studies
  • Computational Biology
  • Cyclooxygenase 2 / genetics*
  • European Continental Ancestry Group / genetics
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • Haplotypes
  • Humans
  • Indians, South American / genetics*
  • Interleukin-8 / genetics*
  • Peru / epidemiology
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • Risk Factors
  • Stomach Neoplasms / ethnology*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Transfection

Substances

  • Biomarkers, Tumor
  • CXCL8 protein, human
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Interleukin-8
  • Cyclooxygenase 2
  • PTGS2 protein, human