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TNF polymorphisms modify endotoxin exposure-associated longitudinal lung function decline.

ABSTRACT: Endotoxin exposure induces airway inflammation, hyper-responsiveness and higher expression of tumour necrosis factor (TNF). This study was conducted to investigate whether TNF polymorphisms modify the effect of endotoxin exposure on chronic declines in lung function.Associations between TNF and LTA polymorphisms, endotoxin exposure and lung function were analysed in 263 cotton workers and 230 silk workers as a reference group, who were prospectively followed for 20 years. Multiple linear regression models were used to assess the association, with adjustment for smoking and other covariates.Endotoxin exposure was associated with faster lung function decline among genotypes associated with higher TNF expression levels, with estimates of annual FEV1 change in relation to endotoxin exposure of -2.9 ml and -6.8 ml in the G/G and G/A+AA genotypes, respectively, for the TNF polymorphism; and -2.0 ml, -4.0 ml and -3.6 ml in A/A, A/G and G/G genotypes, respectively, for the LTA polymorphism. When joint effects of endotoxin exposure and smoking were considered, the effect modification of TNF and LTA polymorphisms was prominent in never smokers.TNF and LTA polymorphisms may modify the association between occupational endotoxin exposure and longitudinal lung function decline, which was more clearly observed in never smokers.

SUBMITTER: Zhang H

PROVIDER: S-EPMC2078509 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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TNF polymorphisms modify endotoxin exposure-associated longitudinal lung function decline.

Zhang Hongxi H Hang Jingqing J Wang Xiaorong X Zhou Wei W Sun Bixiong B Dai Helian H Su Li L Christiani David C DC

Occupational and environmental medicine 20070301 6

<h4>Objectives</h4>Endotoxin exposure induces airway inflammation, hyper-responsiveness and higher expression of tumour necrosis factor (TNF). This study was conducted to investigate whether TNF polymorphisms modify the effect of endotoxin exposure on chronic declines in lung function.<h4>Methods</h4>Associations between TNF and LTA polymorphisms, endotoxin exposure and lung function were analysed in 263 cotton workers and 230 silk workers as a reference group, who were prospectively followed fo ...[more]

PMID: 17332138

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Project description:The Rationale: Molecular markers of disease activity that are predictive of forced vital capacity (FVC) progression in idiopathic pulmonary fibrosis are needed. Objectives: Develop a predictor using longitudinal within-patient gene expression differences (ΔGE) in peripheral blood mononuclear cells (PBMC) to predict of FVC progression. Methods: Patients in the training cohort (n=74) experiencing ≥10% relative reduction in FVC% of predicted over 12 months were categorized as progressors in contrast to the remaining stable patients. Baseline to 4-month within-patient ΔGE were correlated with FVC status. FVC-predictor genes were prioritized by two-group comparison with FDR<5%, logistic LASSO regression with p<0.05, and 10-Fold Cross-Validation with ≥50% support. Receiver operating characteristic with area under the curve (AUC) analyses were conducted in training subsets and independent validation cohorts from UChicago (n=27), UPMC (n=35), and Imperial (n=24) where different transcriptome assay platforms and varying transcriptome sampling times were used to derive ΔGE. Results: Intra-subject Compared to cross-sectional analysis of baseline GE, our longitudinal ΔGE variation approach demonstratedlargely reduced within-group sample variation and increased statistic power fin progressor and stable groups for prediction model development. A 25-gene FVC-predictor separated “progressors” from “stable” by Principal Component Analysis in the training and subsets of the training cohort. The resulting FVC-predictor consistently demonstrated high discriminatory performance independent of transcriptome assay platforms and varying sampling times in validation cohorts (AUC= 0.77-0.80). TGF beta was the highest-ranking canonical pathway by Gene Set Enrichment Analysis. Conclusions: Our novel short-term longitudinal within-patient ΔGE approach identified a FVC-predictor which may reflect disease activity and prove to be a reliable biomarker predictive of future FVC decline.

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TNF polymorphisms modify endotoxin exposure-associated longitudinal lung function decline.

Publications

TNF polymorphisms modify endotoxin exposure-associated longitudinal lung function decline.

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