title: Population, Epidemiological, and Functional Genetics of Gastric Cancer Candidate Genes in Peruvians with Predominant Amerindian Ancestry.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: 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.|Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru.
authors.forename: Roxana
authors.initials: R
authors.lastname: Zamudio
authors.affiliation: 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.
authors.forename: Latife
authors.initials: L
authors.lastname: Pereira
authors.affiliation: Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Carolina D
authors.initials: CD
authors.lastname: Rocha
authors.affiliation: Department of Medicine, University California San Diego, La Jolla, CA, USA.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Berg
authors.affiliation: 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.
authors.forename: Thaís
authors.initials: T
authors.lastname: Muniz-Queiroz
authors.affiliation: 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.
authors.forename: Hanaisa P
authors.initials: HP
authors.lastname: Sant Anna
authors.affiliation: Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru.|Asociación Benéfica PRISMA, Lima, Peru.
authors.forename: Lilia
authors.initials: L
authors.lastname: Cabrera
authors.affiliation: Departamento de Gastroenterologia, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Combe
authors.affiliation: Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru.|Asociación Benéfica PRISMA, Lima, Peru.
authors.forename: Phabiola
authors.initials: P
authors.lastname: Herrera
authors.affiliation: Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru.|Asociación Benéfica PRISMA, Lima, Peru.
authors.forename: Martha H
authors.initials: MH
authors.lastname: Jahuira
authors.affiliation: Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Felipe B
authors.initials: FB
authors.lastname: Leão
authors.affiliation: 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.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Lyon
authors.affiliation: Servicio de Gastroenterologia, Hospital Dos de Mayo, Lima, Peru.
authors.forename: William A
authors.initials: WA
authors.lastname: Prado
authors.affiliation: 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.
authors.forename: Maíra R
authors.initials: MR
authors.lastname: Rodrigues
authors.affiliation: 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.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Rodrigues-Soares
authors.affiliation: 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.
authors.forename: Meddly L
authors.initials: ML
authors.lastname: Santolalla
authors.affiliation: 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.
authors.forename: Camila
authors.initials: C
authors.lastname: Zolini
authors.affiliation: Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Aristóbolo M
authors.initials: AM
authors.lastname: Silva
authors.affiliation: Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru.|Asociación Benéfica PRISMA, Lima, Peru.|Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gilman
authors.affiliation: 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.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tarazona-Santos
authors.affiliation: 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.|Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, FIOCRUZ-RJ, Rio de Janeiro, Brazil. fsgkehdy@gmail.com.
authors.forename: Fernanda S G
authors.identifier: http://orcid.org/0000-0001-8964-9049
authors.initials: FS
authors.lastname: Kehdy
mesh_terms: D000230:Adenocarcinoma / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics*; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D019295:Computational Biology; D051546:Cyclooxygenase 2 / Q000235:genetics*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D007199:Indians, South American / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics*; D010568:Peru / Q000453:epidemiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D044465:White People / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C508606:CXCL8 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016209:Interleukin-8; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: Amerindians; Ancestry; Association studies; Gastric cancer; Meta-analyses; Proinflammatory genes