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Extreme Trait Whole-Genome Sequencing Identifies PTPRO as a Novel Candidate Gene in Emphysema with Severe Airflow Obstruction.

ABSTRACT: RATIONALE:Genetic association studies in chronic obstructive pulmonary disease have primarily tested for association with common variants, the results of which explain only a portion of disease heritability. Because rare variation is also likely to contribute to susceptibility, we used whole-genome sequencing of subjects with clinically extreme phenotypes to identify genomic regions enriched for rare variation contributing to chronic obstructive pulmonary disease susceptibility. OBJECTIVES:To identify regions of rare genetic variation contributing to emphysema with severe airflow obstruction. METHODS:We identified heavy smokers that were resistant (n?=?65) or susceptible (n?=?64) to emphysema with severe airflow obstruction in the Pittsburgh Specialized Center of Clinically Oriented Research cohort. We filtered whole-genome sequencing results to include only rare variants and conducted single variant tests, region-based tests across the genome, gene-based tests, and exome-wide tests. MEASUREMENTS AND MAIN RESULTS:We identified several suggestive associations with emphysema with severe airflow obstruction, including a suggestive association of all rare variation in a region within the gene ZNF816 (19q13.41; P?=?4.5?×?10-6), and a suggestive association of nonsynonymous coding rare variation in the gene PTPRO (P?=?4.0?×?10-5). Association of rs61754411, a rare nonsynonymous variant in PTPRO, with emphysema and obstruction was demonstrated in all non-Hispanic white individuals in the Pittsburgh Specialized Center of Clinically Oriented Research cohort. We found that cells containing this variant have decreased signaling in cellular pathways necessary for survival and proliferation. CONCLUSIONS:PTPRO is a novel candidate gene in emphysema with severe airflow obstruction, and rs61754411 is a previously unreported rare variant contributing to emphysema susceptibility. Other suggestive candidate genes, such as ZNF816, are of interest for future studies.

SUBMITTER: Radder JE

PROVIDER: S-EPMC5519967 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Extreme Trait Whole-Genome Sequencing Identifies PTPRO as a Novel Candidate Gene in Emphysema with Severe Airflow Obstruction.

Radder Josiah E JE Zhang Yingze Y Gregory Alyssa D AD Yu Shibing S Kelly Neil J NJ Leader Joseph K JK Kaminski Naftali N Sciurba Frank C FC Shapiro Steven D SD

American journal of respiratory and critical care medicine 20170701 2

<h4>Rationale</h4>Genetic association studies in chronic obstructive pulmonary disease have primarily tested for association with common variants, the results of which explain only a portion of disease heritability. Because rare variation is also likely to contribute to susceptibility, we used whole-genome sequencing of subjects with clinically extreme phenotypes to identify genomic regions enriched for rare variation contributing to chronic obstructive pulmonary disease susceptibility.<h4>Objec ...[more]

PMID: 28199135

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Project description:BackgroundVery severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease.MethodsWe measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects.ResultsOf the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (-4.1 ml; 95% confidence interval [CI], -3.3 to -4.9; P<0.001), stroke volume (-2.7 ml; 95% CI, -2.2 to -3.3; P<0.001), and cardiac output (-0.19 liters per minute; 95% CI, -0.14 to -0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction.ConclusionsIn a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction.

Project description:UnlabelledLung CD4+ T cells accumulate as chronic obstructive pulmonary disease (COPD) progresses, but their role in pathogenesis remains controversial. To address this controversy, we studied lung tissue from 53 subjects undergoing clinically-indicated resections, lung volume reduction, or transplant. Viable single-cell suspensions were analyzed by flow cytometry or underwent CD4+ T cell isolation, followed either by stimulation with anti-CD3 and cytokine/chemokine measurement, or by real-time PCR analysis. In lung CD4+ T cells of most COPD subjects, relative to lung CD4+ T cells in smokers with normal spirometry: (a) stimulation induced minimal IFN-γ or other inflammatory mediators, but many subjects produced more CCL2; (b) the T effector memory subset was less uniformly predominant, without correlation with decreased IFN-γ production. Analysis of unstimulated lung CD4+ T cells of all subjects identified a molecular phenotype, mainly in COPD, characterized by markedly reduced mRNA transcripts for the transcription factors controlling TH1, TH2, TH17 and FOXP3+ T regulatory subsets and their signature cytokines. This mRNA-defined CD4+ T cell phenotype did not result from global inability to elaborate mRNA; increased transcripts for inhibitory CD28 family members or markers of anergy; or reduced telomerase length. As a group, these subjects had significantly worse spirometry, but not DLCO, relative to subjects whose lung CD4+ T cells expressed a variety of transcripts. Analysis of mRNA transcripts of unstimulated lung CD4+ T cell among all subjects identified two distinct molecular correlates of classical COPD clinical phenotypes: basal IL-10 transcripts correlated independently and inversely with emphysema extent (but not spirometry); by contrast, unstimulated IFN-γ transcripts correlated independently and inversely with reduced spirometry (but not reduced DLCO or emphysema extent). Aberrant lung CD4+ T cells polarization appears to be common in advanced COPD, but also exists in some smokers with normal spirometry, and may contribute to development and progression of specific COPD phenotypes.Trial registrationClinicalTrials.gov as NCT00281229.

Project description:BACKGROUND:Low lung function is known to predict mortality in the general population, but the prognostic significance of emphysema on computed tomography (CT) in persons without chronic obstructive pulmonary disease (COPD) is uncertain. OBJECTIVE:To determine whether greater emphysema-like lung on CT is associated with all-cause mortality among persons in the general population without airflow obstruction or COPD. DESIGN:Prospective cohort study. SETTING:Population-based, multiethnic sample from 6 U.S. communities. PARTICIPANTS:2965 participants aged 45 to 84 years without airflow obstruction on spirometry. MEASUREMENTS:Emphysema-like lung was defined as the number of lung voxels with attenuation less than -950 Hounsfield units on cardiac CT and was adjusted for the number of total imaged lung voxels. RESULTS:Among 2965 participants, 50.9% of whom had never smoked, there were 186 deaths over a median of 6.2 years. Greater emphysema-like lung was independently associated with increased mortality (adjusted hazard ratio per one-half interquartile range, 1.14 [95% CI, 1.04 to 1.24]; P=0.004) after adjustment for potential confounders, including cardiovascular risk factors and FEV1. Generalized additive models supported a linear association between emphysema-like lung and mortality without evidence for a threshold. The association was of greatest magnitude among smokers, although multiplicative interaction terms did not support effect modification by smoking status. LIMITATIONS:Cardiac CT scans did not include lung apices. The number of deaths was limited among subgroup analyses. CONCLUSION:Emphysema-like lung on CT was associated with all-cause mortality among persons without airflow obstruction or COPD in a general population sample, particularly among smokers. Recognition of the independent prognostic significance of emphysema on CT among patients without COPD on spirometry is warranted. PRIMARY FUNDING SOURCE:National Heart, Lung, and Blood Institute.

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Extreme Trait Whole-Genome Sequencing Identifies PTPRO as a Novel Candidate Gene in Emphysema with Severe Airflow Obstruction.

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Extreme Trait Whole-Genome Sequencing Identifies PTPRO as a Novel Candidate Gene in Emphysema with Severe Airflow Obstruction.

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