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Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias.

Steele MP, Luna LG, Coldren CD, Murphy E, Hennessy CE, Heinz D, Evans CM, Groshong S, Cool C, Cosgrove GP, Brown KK, Fingerlin TE, Schwarz MI, Schwartz DA, Yang IV - BMC Genomics (2015)

Bottom Line: This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, HIF-1α, SERPINA3, SERPINE2, and SELE) as well as novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15).Disease progression, as characterized by lower measures of FVC and DLCO, results in marked changes in expression of novel and established genes and pathways involved in IIPs.These genes and pathways represent strong candidates for biomarker studies and potential therapeutic targets for IIP severity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.

ABSTRACT

Background: Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable diseases characterized by progressive scarring of the interstitium. Since lung function is a key determinant of survival, we reasoned that the transcriptional profile in IIP lung tissue would be associated with measures of lung function, and could enhance prognostic approaches to IIPs.

Results: Using gene expression profiling of 167 lung tissue specimens with IIP diagnosis and 50 control lungs, we identified genes whose expression is associated with changes in lung function (% predicted FVC and % predicted DLCO) modeled as categorical (severe vs mild disease) or continuous variables while adjusting for smoking status and IIP subtype; false discovery rate (FDR) approach was used to correct for multiple comparisons. This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, HIF-1α, SERPINA3, SERPINE2, and SELE) as well as novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15). Protein-protein interactome analysis of 553 genes whose expression is significantly associated with lung function when modeled as continuous variables demonstrates that more severe presentation of IIPs is characterized by an increase in cell cycle progression and apoptosis, increased hypoxia, and dampened innate immune response. Our findings were validated in an independent cohort of 131 IIPs and 40 controls at the mRNA level and for one gene (RTKN2) at the protein level by immunohistochemistry in a subset of samples.

Conclusions: We identified commonalities and differences in gene expression among different subtypes of IIPs. Disease progression, as characterized by lower measures of FVC and DLCO, results in marked changes in expression of novel and established genes and pathways involved in IIPs. These genes and pathways represent strong candidates for biomarker studies and potential therapeutic targets for IIP severity.

No MeSH data available.


Related in: MedlinePlus

Categorical analysis of changes in gene expression based on lung disease severity categorized by % predicted DLCO (top) or % predicted FVC (bottom) for novel IIP candidate genes rhotekin 2 (RTKN2 - left), selectin E (SELE - middle), and peptidase inhibitor 15 (PI15 – right). Mild, moderate, and severe are defined as percent predicted DLCO (mild ≥65 %, moderate <65 % and >35 %, and severe ≤35 %), or FVC (mild ≥75 %, moderate <75 % and >40 %, and severe ≤40 %). p values for severe vs mild groups are shown in Table 2
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Fig1: Categorical analysis of changes in gene expression based on lung disease severity categorized by % predicted DLCO (top) or % predicted FVC (bottom) for novel IIP candidate genes rhotekin 2 (RTKN2 - left), selectin E (SELE - middle), and peptidase inhibitor 15 (PI15 – right). Mild, moderate, and severe are defined as percent predicted DLCO (mild ≥65 %, moderate <65 % and >35 %, and severe ≤35 %), or FVC (mild ≥75 %, moderate <75 % and >40 %, and severe ≤40 %). p values for severe vs mild groups are shown in Table 2

Mentions: To focus on genes that are the most likely to be involved in the pathogenesis of IIP, we identified differentially expressed transcripts in common to lower measures of DLCO and FVC. We first intersected 91 transcripts identified as significant in the categorical analysis of disease severity based on DLCO and 681 from the analogous analysis of FVC. Fifty eight transcripts that are in common to the two analyses are listed in Table 2. While a number of these transcripts, including ADAMTS family members (ADAMTS4, ADAMTS9) [10], AGER [11], HIF-1α [12, 13], serpin family members (SERPINA3, SERPINE2) [14], and selectin E (SELE) [15] have an established role in lung fibrosis, expression of novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15) is also significantly altered in severe compared to mild disease. Dot plots shown in Fig. 1 demonstrate decrease in RTKN2 but an increase in SELE and PI15 with a decrease in lung function. We confirmed expression levels of these three genes in the same set of LTRC samples by qRT-PCR (Fig. 2).Table 2


Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias.

Steele MP, Luna LG, Coldren CD, Murphy E, Hennessy CE, Heinz D, Evans CM, Groshong S, Cool C, Cosgrove GP, Brown KK, Fingerlin TE, Schwarz MI, Schwartz DA, Yang IV - BMC Genomics (2015)

Categorical analysis of changes in gene expression based on lung disease severity categorized by % predicted DLCO (top) or % predicted FVC (bottom) for novel IIP candidate genes rhotekin 2 (RTKN2 - left), selectin E (SELE - middle), and peptidase inhibitor 15 (PI15 – right). Mild, moderate, and severe are defined as percent predicted DLCO (mild ≥65 %, moderate <65 % and >35 %, and severe ≤35 %), or FVC (mild ≥75 %, moderate <75 % and >40 %, and severe ≤40 %). p values for severe vs mild groups are shown in Table 2
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4621862&req=5

Fig1: Categorical analysis of changes in gene expression based on lung disease severity categorized by % predicted DLCO (top) or % predicted FVC (bottom) for novel IIP candidate genes rhotekin 2 (RTKN2 - left), selectin E (SELE - middle), and peptidase inhibitor 15 (PI15 – right). Mild, moderate, and severe are defined as percent predicted DLCO (mild ≥65 %, moderate <65 % and >35 %, and severe ≤35 %), or FVC (mild ≥75 %, moderate <75 % and >40 %, and severe ≤40 %). p values for severe vs mild groups are shown in Table 2
Mentions: To focus on genes that are the most likely to be involved in the pathogenesis of IIP, we identified differentially expressed transcripts in common to lower measures of DLCO and FVC. We first intersected 91 transcripts identified as significant in the categorical analysis of disease severity based on DLCO and 681 from the analogous analysis of FVC. Fifty eight transcripts that are in common to the two analyses are listed in Table 2. While a number of these transcripts, including ADAMTS family members (ADAMTS4, ADAMTS9) [10], AGER [11], HIF-1α [12, 13], serpin family members (SERPINA3, SERPINE2) [14], and selectin E (SELE) [15] have an established role in lung fibrosis, expression of novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15) is also significantly altered in severe compared to mild disease. Dot plots shown in Fig. 1 demonstrate decrease in RTKN2 but an increase in SELE and PI15 with a decrease in lung function. We confirmed expression levels of these three genes in the same set of LTRC samples by qRT-PCR (Fig. 2).Table 2

Bottom Line: This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, HIF-1α, SERPINA3, SERPINE2, and SELE) as well as novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15).Disease progression, as characterized by lower measures of FVC and DLCO, results in marked changes in expression of novel and established genes and pathways involved in IIPs.These genes and pathways represent strong candidates for biomarker studies and potential therapeutic targets for IIP severity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.

ABSTRACT

Background: Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable diseases characterized by progressive scarring of the interstitium. Since lung function is a key determinant of survival, we reasoned that the transcriptional profile in IIP lung tissue would be associated with measures of lung function, and could enhance prognostic approaches to IIPs.

Results: Using gene expression profiling of 167 lung tissue specimens with IIP diagnosis and 50 control lungs, we identified genes whose expression is associated with changes in lung function (% predicted FVC and % predicted DLCO) modeled as categorical (severe vs mild disease) or continuous variables while adjusting for smoking status and IIP subtype; false discovery rate (FDR) approach was used to correct for multiple comparisons. This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, HIF-1α, SERPINA3, SERPINE2, and SELE) as well as novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15). Protein-protein interactome analysis of 553 genes whose expression is significantly associated with lung function when modeled as continuous variables demonstrates that more severe presentation of IIPs is characterized by an increase in cell cycle progression and apoptosis, increased hypoxia, and dampened innate immune response. Our findings were validated in an independent cohort of 131 IIPs and 40 controls at the mRNA level and for one gene (RTKN2) at the protein level by immunohistochemistry in a subset of samples.

Conclusions: We identified commonalities and differences in gene expression among different subtypes of IIPs. Disease progression, as characterized by lower measures of FVC and DLCO, results in marked changes in expression of novel and established genes and pathways involved in IIPs. These genes and pathways represent strong candidates for biomarker studies and potential therapeutic targets for IIP severity.

No MeSH data available.


Related in: MedlinePlus