Dataset Information

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control.

ABSTRACT:

Rationale

Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches.

Objectives

To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control.

Methods

We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each with gene expression data derived from either whole blood (WB) or unstimulated CD4⁺ T lymphocytes (CD4), and a self-reported asthma control score representing either the preceding 6 months (chronic) or 7 days (acute). Our study comprised a discovery WB cohort (n = 245, chronic) and three independent, nonoverlapping replication cohorts: a second WB set (n = 448, acute) and two CD4 sets (n = 300, chronic; n = 77, acute).

Measurements and main results

In the WB discovery cohort, we found significant overrepresentation of genes associated with asthma control in 1,106 gene sets from the Molecular Signatures Database (false discovery rate, <5%). Of these, 583 (53%) replicated in at least one replication cohort (false discovery rate, <25%). Suboptimal control was associated with signatures of eosinophilic and granulocytic inflammatory signals, whereas optimal control signatures were enriched for immature lymphocytic patterns. These signatures included two related biologic processes related to activation by TREM-1 (triggering receptor expressed on myeloid cells 1) and lipopolysaccharide.

Conclusions

Together, these results demonstrate the existence of specific, reproducible transcriptomic components in blood that vary with degree of asthma control and implicate a novel biologic target (TREM-1).

SUBMITTER: Croteau-Chonka DC

PROVIDER: S-EPMC5394783 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control.

Croteau-Chonka Damien C DC Qiu Weiliang W Martinez Fernando D FD Strunk Robert C RC Lemanske Robert F RF Liu Andrew H AH Gilliland Frank D FD Millstein Joshua J Gauderman W James WJ Ober Carole C Krishnan Jerry A JA White Steven R SR Naureckas Edward T ET Nicolae Dan L DL Barnes Kathleen C KC London Stephanie J SJ Barraza-Villarreal Albino A Carey Vincent J VJ Weiss Scott T ST Raby Benjamin A BA

American journal of respiratory and critical care medicine 20170101 2

<h4>Rationale</h4>Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches.<h4>Objectives</h4>To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control.<h4>Methods</h4>We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each ...[more]

PMID: 27494826

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Project description:Peripheral blood is an accessible and informative source of transcriptomal information for many human disease and pharmacogenomic studies. While there can be significant advantages to analyzing RNA isolated from whole blood, particularly in clinical studies, the preparation of samples for microarray analysis is complicated by the need to minimize artifacts associated with highly abundant globin RNA transcripts. The impact of globin RNA transcripts on expression profiling data can potentially be reduced by using RNA preparation and labeling methods that remove or block globin RNA during the microarray assay. We compared four different methods for preparing microarray hybridization targets from human whole blood collected in PAXGene tubes. Three of the methods utilized the Affymetrix one-cycle cDNA synthesis/in vitro transcription protocol but varied treatment of input RNA as follows: i. no treatment; ii. treatment with GLOBINclear; or iii. treatment with globin PNA oligos. In the fourth method cDNA targets were prepared with the Ovation amplification and labeling system.We find that microarray targets generated with labeling methods that reduce globin mRNA levels or minimize the impact of globin transcripts during hybridization detect more transcripts in the microarray assay compared with the standard Affymetrix method. Comparison of microarray results with quantitative PCR analysis of a panel of genes from the NF-kappa B pathway shows good correlation of transcript measurements produced with all four target preparation methods, although method-specific differences in overall correlation were observed. The impact of freezing blood collected in PAXGene tubes on data reproducibility was also examined. Expression profiles show little or no difference when RNA is extracted from either fresh or frozen blood samples.RNA preparation and labeling methods designed to reduce the impact of globin mRNA transcripts can significantly improve the sensitivity of the DNA microarray expression profiling assay for whole blood samples. While blockage of globin transcripts during first strand cDNA synthesis with globin PNAs resulted in the best overall performance in this study, we conclude that selection of a protocol for expression profiling studies in blood should depend on several factors, including implementation requirements of the method and study design. RNA isolated from either freshly collected or frozen blood samples stored in PAXGene tubes can be used without altering gene expression profiles.

Dataset Information

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control.

Similar Datasets

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