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Gene-Gene Interaction Between CCR3 and Eotaxin Genes: The Relationship With Blood Eosinophilia in Asthma.

ABSTRACT: PURPOSE:Eosinophils function as an effector cell in the development of asthma and allergic disease. Eotaxins are cytokines that promote pulmonary eosinophilia via the receptor CCR3. Single-nucleotide polymorphisms (SNPs) in CCR3 and eotaxin genes are associated with asthma. In this study, genetic interactions among SNPs of several eotaxin genes and CCR3 were assessed and their relationship with blood eosinophilia in asthma was examined. METHODS:A total of 533 asthmatics were enrolled in this study. Asthmatics with eosinophilia (>0.5×10(9)/L) were compared with those without eosinophilia (?0.5×10(9)/L). Chi-square tests were used to compare SNP frequencies. Two different models were used to evaluate gene-gene interactions: logistic regression and generalized multifactor dimensionality reduction (GMDR). RESULTS:EOT2+304C>A (29L>I) was significantly associated with 3 of the 4 CCR3 SNPs among asthmatics with eosinophilia (P=0.037-0.009). EOT2+304C>A (29L>I) and the CCR3 SNPs were also significantly associated with blood eosinophilia in an interaction model constructed by logistic regression (P=0.0087). GMDR analysis showed that the combination of EOT2+304C>A (29L>I) and CCR3-174C>T was the best model (accuracy=0.536, P=0.005, CVC 9/10). CONCLUSIONS:The epistatic influence of CCR3 on eotaxin gene variants indicates that these variants may be candidate markers for eosinophilia in asthma.

SUBMITTER: Lee JH

PROVIDER: S-EPMC3881401 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Gene-Gene Interaction Between CCR3 and Eotaxin Genes: The Relationship With Blood Eosinophilia in Asthma.

Lee June-Hyuk JH Jang An-Soo AS Park Sung-Woo SW Kim Do-Jin DJ Park Choon-Sik CS

Allergy, asthma & immunology research 20131226 1

<h4>Purpose</h4>Eosinophils function as an effector cell in the development of asthma and allergic disease. Eotaxins are cytokines that promote pulmonary eosinophilia via the receptor CCR3. Single-nucleotide polymorphisms (SNPs) in CCR3 and eotaxin genes are associated with asthma. In this study, genetic interactions among SNPs of several eotaxin genes and CCR3 were assessed and their relationship with blood eosinophilia in asthma was examined.<h4>Methods</h4>A total of 533 asthmatics were enrol ...[more]

PMID: 24404394

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Project description:ObjectiveBesides reducing gastric acid secretion, proton pump inhibitors (PPIs) suppress Th2-cytokine-stimulated expression of an eosinophil chemoattractant (eotaxin-3) by esophageal epithelial cells through acid-independent, anti-inflammatory mechanisms. To explore acid-inhibitory and acid-independent, anti-inflammatory PPI effects in reducing esophageal eosinophilia, we studied eotaxin-3 expression by the proximal and distal esophagus of children with esophageal eosinophilia before and after PPI therapy. In vitro, we studied acid and bile salt effects on IL-13-stimulated eotaxin-3 expression by esophageal epithelial cells.DesignAmong 264 children with esophageal eosinophilia seen at a tertiary pediatric hospital from 2008 through 2012, we identified 10 with esophageal biopsies before and after PPI treatment alone. We correlated epithelial cell eotaxin-3 immunostaining with eosinophil numbers in those biopsies. In vitro, we measured eotaxin-3 protein secretion by esophageal squamous cells stimulated with IL-13 and exposed to acid and/or bile salt media, with or without omeprazole.ResultsThere was strong correlation between peak eosinophil numbers and peak eotaxin-3-positive epithelial cell numbers in esophageal biopsies. Eotaxin-3 expression decreased significantly with PPIs only in the proximal esophagus. In esophageal cells, exposure to acid-bile salt medium significantly suppressed IL-13-induced eotaxin-3 secretion; omeprazole added to the acid-bile salt medium further suppressed that eotaxin-3 secretion, but not as profoundly as at pH-neutral conditions.ConclusionIn children with esophageal eosinophilia, PPIs significantly decrease eotaxin-3 expression in the proximal but not the distal esophagus. In esophageal squamous cells, acid and bile salts decrease Th2 cytokine-stimulated eotaxin-3 secretion profoundly, possibly explaining the disparate PPI effects on the proximal and distal esophagus. In the distal esophagus, where acid reflux is greatest, a PPI-induced reduction in acid reflux (an effect that could increase eotaxin-3 secretion induced by Th2 cytokines) might mask the acid-independent, anti-inflammatory PPI effect of decreasing cytokine-stimulated eotaxin-3 secretion.

Dataset Information

Gene-Gene Interaction Between CCR3 and Eotaxin Genes: The Relationship With Blood Eosinophilia in Asthma.

Publications

Gene-Gene Interaction Between CCR3 and Eotaxin Genes: The Relationship With Blood Eosinophilia in Asthma.

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