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

• Published in: Digestive diseases and sciences Vol. 61; no. 1; pp. 107 - 116
• Main Authors: Zamudio, Roxana, Pereira, Latife, Rocha, Carolina D., Berg, Douglas E., Muniz-Queiroz, Thaís, Sant Anna, Hanaisa P., Cabrera, Lilia, Combe, Juan M., Herrera, Phabiola, Jahuira, Martha H., Leão, Felipe B., Lyon, Fernanda, Prado, William A., Rodrigues, Maíra R., Rodrigues-Soares, Fernanda, Santolalla, Meddly L., Zolini, Camila, Silva, Aristóbolo M., Gilman, Robert H., Tarazona-Santos, Eduardo, Kehdy, Fernanda S. G.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-01-2016; Springer; Springer Nature B.V
• Subjects: Adenocarcinoma - ethnology; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Analysis; Asians - genetics; Binding Sites; Biochemistry; Biomarkers, Tumor - genetics; Blacks - genetics; Cancer; Case-Control Studies; Computational Biology; Cyclooxygenase 2 - genetics; Epidemiology; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gastroenterology; Gene expression; Gene Expression Regulation, Neoplastic; Gene Frequency; Genes; Genetic aspects; Genetic Association Studies; Genetic Predisposition to Disease; Genetic research; Haplotypes; Health aspects; HEK293 Cells; Hepatology; Humans; Immune response; Indians, South American - genetics; Infection; Interleukin-8 - genetics; Medicine; Medicine & Public Health; Native Americans; Oncology; Oncology, Experimental; Original Article; Peru - epidemiology; Phenotype; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk Factors; Single nucleotide polymorphisms; Stomach cancer; Stomach Neoplasms - ethnology; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Surveys; Transfection; Transplant Surgery; Whites - genetics; Peru; Association studies; Proinflammatory genes; Amerindians; Ancestry; Meta-analyses; Gastric cancer
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-015-3859-6

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.