title: Epigenetic and genetic variation in GATA5 is associated with gastric disease risk.
abstract: Gastric cancer incidence varies considerably among populations, even those with comparable rates of Helicobacter pylori infection. To test the hypothesis that genetic variation plays a role in gastric disease, we assessed the relationship between genotypes and gastric histopathology in a Colombian study population, using a genotyping array of immune-related single nucleotide polymorphisms (SNPs). Two synonymous SNPs (rs6061243 and rs6587239) were associated with progression of premalignant gastric lesions in a dominant-effects model after correction for multiple comparisons (p = 2.63E-07 and p = 7.97E-07, respectively); effect sizes were β = -0.863 and β = -0.815, respectively, where β is an estimate of effect on histopathology scores, which ranged from 1 (normal) to 5 (dysplasia). In our replication cohort, a second Colombian population, both SNPs were associated with histopathology when additively modeled (β = -0.256, 95 % CI = -0.47, -0.039; and β = -0.239, 95 % CI = -0.45, -0.024), and rs6587239 was significantly associated in a dominant-effects model (β = -0.330, 95 % CI = -0.66, 0.00). Because promoter methylation of GATA5 has previously been associated with gastric cancer, we also tested for the association of methylation status with more advanced histopathology scores in our samples and found a significant relationship (p = 0.001). A multivariate regression model revealed that the effects of both the promoter methylation and the exonic SNPs in GATA5 were independent. A SNP-by-methylation interaction term was also significant. This interaction between GATA5 variants and GATA5 promoter methylation indicates that the association of either factor with gastric disease progression is modified by the other.
authors.affiliation: Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Rafal S
authors.initials: RS
authors.lastname: Sobota
authors.affiliation: Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.|Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Nuri
authors.initials: N
authors.lastname: Kodaman
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA.
authors.forename: Robertino
authors.initials: R
authors.lastname: Mera
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA.
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Department of Pathology, School of Medicine, Universidad del Valle, Cali 760043, Colombia.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Bravo
authors.affiliation: Department of Biology, University of Nariño, Pasto 520002, Colombia.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pazos
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Jovanny
authors.initials: J
authors.lastname: Zabaleta
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA.
authors.forename: Alberto G
authors.initials: AG
authors.lastname: Delgado
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Veterans Affairs, Veterans Affairs Tennessee Valley Healthcare System and Office of Medical Research, Nashville, TN, USA.
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Morgan
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA.|Department of Veterans Affairs, Veterans Affairs Tennessee Valley Healthcare System and Office of Medical Research, Nashville, TN, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA.
authors.forename: Pelayo
authors.initials: P
authors.lastname: Correa
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.|Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232, USA.
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Schneider
mesh_terms: D000328:Adult; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D050992:GATA5 Transcription Factor / Q000235:genetics*; D056726:Genetic Association Studies; D005838:Genotype; D016481:Helicobacter Infections / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000472:pathogenicity; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology / Q000473:pathology
chemical_list: D050992:GATA5 Transcription Factor; C494755:GATA5 protein, human