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Gene Expression in Respiratory Disease

By Shweta Trivedi
September 2008

Following the lecture, Crystal, right, spoke with NIEHS Acting Director Sam Wilson about ways his research approach can also offer insight into other environmental exposures’ effects on respiratory diseases. (Photo courtesy of John Maruca)

Noted research pulmonologist Ron Crystal, M.D., presented a lecture to NIEHS scientists on August 5 in Rodbell Auditorium titled “Why Are Some Individuals More Sensitive to the Environment than Others? Genetic Variation and Modulation of Gene Expression in the Human Airway Epithelium.” NIEHS Division of Extramural Research and Training Acting Deputy Director Pat Mastin, Ph.D., hosted the talk and encouraged the audience to consider future collaborations in translational research on the environmental dimensions of respiratory diseases.

Crystal is currently professor of Medicine and chair of the Department of Genetic Medicine at Weill Cornell Medical College and chief of the Division of Pulmonary and Critical Care Medicine at The New York Presbyterian Hospital. He served as the chief of the Pulmonary Branch, National Heart, Lung and Blood Institute from 1975 to 1993.

According to Crystal, his group utilizes microarray technologies for genome-wide characterization of gene expression, single nucleotide polymorphism and copy number variation profiles on clinical samples to identify candidate genes associated with complex diseases such as chronic obstructive pulmonary disease (COPD). “The first [hypothesis driving our research] is that transcriptional analysis of the small airway epithelium will lead to identification of the genes relevant to the risk from the environment,” he told the audience, “and the second is that variations in the response of the small airway transcriptome in response to the environment reflect genetic differences.”

Crystal compared his use of the Small Airway Epithelium (SAE), which he called “the canary of the lung,” for assessing the lung disease phenotype at biologic levels to the use of songbirds to warn miners of dangerous gases. Crystal uses fiberoptic bronchoscopy to brush airway epithelium to produce robust samples for RNA extractions.

The study populations include smokers who are “healthy” in terms of their lung functioning and imaging, healthy non-smokers, LENS (lung emphysema with normal spirometry) smokers and COPD smokers. One of Crystal’s significant findings was that, despite variability among individuals, more genes were found to be up- or down-regulated in SAE of healthy smokers, well before any functional changes were manifest, than in healthy non-smokers — with some genes differing as much as 60-fold.

Xenobiotic- and oxidant-related genes such as nrf2 and glutathione pathway genes were expressed differentially in SAE of healthy smokers compared to healthy non-smokers. Surprisingly, immune response genes were found to be mostly down-regulated. Composite indices of gene expression in SAE were utilized to assess variability, including nrf2 index, inflammation index, proliferation-related genes index and overall index of gene expression. Healthy non-smokers had the least variable gene expression. Healthy smokers were divided into low and high responders, and COPD smokers, the gold standard of disease phenotype, were high responders.

SNP analyses on five candidate genes — CHUR1, SNHG5, GPR135, CHP2 and ADRBK2 —revealed that there was a pairing control in SNP that could be correlated to gene expression in SAE. Copy number variations, where segments in the genome are missing or duplicated, also influenced the level of gene expression. The example Crystal highlighted from SAE was that of Glutathione-S-Transferases (GSTs). He suggested that it would be interesting to study the biologic influence of GST gene deletion in SAE of healthy smokers versus healthy non-smokers.

When Crystal compared DNA from SAE of healthy smokers to the DNA of their autologous blood, he observed that the genomes of SAE in healthy smokers had more cancer-related copy number variations — multiple deletions and amplifications — than the genomes of healthy non-smokers, indicating that there are acquired as well as SNP variations involved.

Turning to the future directions of his research, Crystal pointed to further exploration of signaling pathways from SAE and, for larger studies, trachea epithelium transcriptome to refine understanding of susceptibility. He also hopes to assess the effectiveness of interventions by characterizing their influence on gene expression.

(Shweta Trivedi, D.V.M., Ph.D., is a postdoctoral fellow in the Laboratory of Respiratory Biology Environmental Genetics Group)

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