Epigenetic and genetic variation in GATA5 is associated with gastric disease risk

• Published in: Human genetics 2016-08, Vol.135 (8), p.895-906
• Main Authors: Sobota, Rafal S., Kodaman, Nuri, Mera, Robertino, Piazuelo, M. Blanca, Bravo, Luis E., Pazos, Alvaro, Zabaleta, Jovanny, Delgado, Alberto G., El-Rifai, Wael, Morgan, Douglas R., Wilson, Keith T., Correa, Pelayo, Williams, Scott M., Schneider, Barbara G.
• Format: Article
• Language: English
• Subjects: Adult; Biomedical and Life Sciences; Biomedicine; Chromosomes; Development and progression; DNA methylation; DNA Methylation - genetics; Epigenetic inheritance; Epigenetics; Epigenomics; Female; Gastric cancer; GATA5 Transcription Factor - genetics; Gene Function; Genetic aspects; Genetic Association Studies; Genetic research; Genomes; Genotype; Health aspects; Helicobacter infections; Helicobacter Infections - genetics; Helicobacter Infections - microbiology; Helicobacter Infections - pathology; Helicobacter pylori; Helicobacter pylori - pathogenicity; Histochemistry; Histopathology; Human Genetics; Humans; Male; Medical research; Medicine; Metabolic Diseases; Methylation; Middle Aged; Molecular Medicine; Original Investigation; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk Factors; Single nucleotide polymorphisms; Stomach cancer; Stomach Neoplasms - genetics; Stomach Neoplasms - microbiology; Stomach Neoplasms - pathology
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-016-1687-1

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.