Roxana Zamudio1,2, Latife Pereira1, Carolina D Rocha3, Douglas E Berg4, Thaís Muniz-Queiroz1, Hanaisa P Sant Anna1, Lilia Cabrera2,5, Juan M Combe6, Phabiola Herrera2,5, Martha H Jahuira2,5, Felipe B Leão3, Fernanda Lyon1, William A Prado7, Maíra R Rodrigues1, Fernanda Rodrigues-Soares1, Meddly L Santolalla1, Camila Zolini1, Aristóbolo M Silva3, Robert H Gilman2,5,8, Eduardo Tarazona-Santos1, Fernanda S G Kehdy9,10. 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. 2. Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru. 3. Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. 4. Department of Medicine, University California San Diego, La Jolla, CA, USA. 5. Asociación Benéfica PRISMA, Lima, Peru. 6. Departamento de Gastroenterologia, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru. 7. Servicio de Gastroenterologia, Hospital Dos de Mayo, Lima, Peru. 8. Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. 9. 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. fsgkehdy@gmail.com. 10. Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, FIOCRUZ-RJ, Rio de Janeiro, Brazil. fsgkehdy@gmail.com.
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.
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.
Entities:
Keywords:
Amerindians; Ancestry; Association studies; Gastric cancer; Meta-analyses; Proinflammatory genes
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