TY - JOUR
T1 - Population, Epidemiological, and Functional Genetics of Gastric Cancer Candidate Genes in Peruvians with Predominant Amerindian Ancestry
AU - Zamudio, Roxana
AU - Pereira, Latife
AU - Rocha, Carolina D.
AU - Berg, Douglas E.
AU - Muniz-Queiroz, Thaís
AU - Sant Anna, Hanaisa P.
AU - Cabrera, Lilia
AU - Combe, Juan M.
AU - Herrera, Phabiola
AU - Jahuira, Martha H.
AU - Leão, Felipe B.
AU - Lyon, Fernanda
AU - Prado, William A.
AU - Rodrigues, Maíra R.
AU - Rodrigues-Soares, Fernanda
AU - Santolalla, Meddly L.
AU - Zolini, Camila
AU - Silva, Aristóbolo M.
AU - Gilman, Robert H.
AU - Tarazona-Santos, Eduardo
AU - Kehdy, Fernanda S.G.
N1 - Publisher Copyright:
© 2015, Springer Science+Business Media New York.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
KW - Amerindians
KW - Ancestry
KW - Association studies
KW - Gastric cancer
KW - Meta-analyses
KW - Proinflammatory genes
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U2 - 10.1007/s10620-015-3859-6
DO - 10.1007/s10620-015-3859-6
M3 - Article
C2 - 26391267
AN - SCOPUS:84952988220
SN - 0163-2116
VL - 61
SP - 107
EP - 116
JO - Digestive diseases and sciences
JF - Digestive diseases and sciences
IS - 1
ER -