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National Emphysema Treatment Trial state of the art: genetics of emphysema.

ABSTRACT: Although a hereditary contribution to emphysema has been long suspected, severe alpha1-antitrypsin deficiency remains the only conclusively proven genetic risk factor for chronic obstructive pulmonary disease (COPD). Recently, genome-wide linkage analysis has led to the identification of two promising candidate genes for COPD: TGFB1 and SERPINE2. Like multiple other COPD candidate gene associations, even these positionally identified genes have not been universally replicated across all studies. Differences in phenotype definition may contribute to nonreplication in genetic studies of heterogeneous disorders such as COPD. The use of precisely measured phenotypes, including emphysema quantification on high-resolution chest computed tomography scans, has aided in the discovery of additional genes for clinically relevant COPD-related traits. The use of computed tomography scans to assess emphysema and airway disease as well as newer genetic technologies, including gene expression microarrays and genome-wide association studies, has great potential to detect novel genes affecting COPD susceptibility, severity, and response to treatment.

SUBMITTER: Hersh CP

PROVIDER: S-EPMC2645324 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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National Emphysema Treatment Trial state of the art: genetics of emphysema.

Hersh Craig P CP DeMeo Dawn L DL Silverman Edwin K EK

Proceedings of the American Thoracic Society 20080501 4

Although a hereditary contribution to emphysema has been long suspected, severe alpha1-antitrypsin deficiency remains the only conclusively proven genetic risk factor for chronic obstructive pulmonary disease (COPD). Recently, genome-wide linkage analysis has led to the identification of two promising candidate genes for COPD: TGFB1 and SERPINE2. Like multiple other COPD candidate gene associations, even these positionally identified genes have not been universally replicated across all studies. ...[more]

PMID: 18453360

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Project description:RationaleHypercapnia develops in one third of patients with advanced chronic obstructive pulmonary disease (COPD) and is associated with increased morbidity and mortality. Multiple factors in COPD are thought to contribute to the development of hypercapnia including increased carbon dioxide (CO2) production, increased dead space ventilation, and the complex interactions of deranged respiratory system mechanics, inspiratory muscle overload and the ventilatory control center in the brainstem. However, these factors have not previously been systematically analyzed in a large, well-characterized population of severe COPD patients.MethodsThis is a secondary analysis of the clinical, physiologic and imaging data from the National Emphysema Treatment Trial (NETT). All patients with complete baseline data for the key predictor variables were included. An inclusive list of 32 potential predictor variables were selected a priori based on consensus of the investigators and literature review. Stepwise variable selection yielded 10 statistically significant associations in multivariate regression.ResultsA total of 1419 patients with severe COPD were included in the analysis; mean age 66.4 years (standard deviation 6.3), 38% females, and 422 (29.7%) had baseline hypercapnia. Key variables associated with hypercapnia were low resting partial pressure of oxygen in blood, low minute ventilation (Ve), high volume of exhaled carbon dioxide, low forced expiratory volume in 1 second, high residual volume, lower % emphysema on chest computed tomography, use of oxygen, low ventilatory reserve (high Ve/maximal voluntary ventilation), and not being at high altitude. Low diffusing capacity for carbon monoxide showed a positive association with hypercapnia in univariate analysis but a negative correlation in multivariate analysis. Measures of dyspnea and quality of life did not associate with degree of hypercapnia in multivariable analysis.ConclusionHypercapnia in a well-characterized cohort with severe COPD and emphysema is chiefly related to poor lung mechanics, high CO2 production, and a reduced ventilatory capability. Hypercapnia is less impacted by gas exchange abnormalities or the presence of emphysema.

Project description:Anti-neutrophil cytoplasm antibodies (ANCA) are associated with small vessel vasculitides (AASV) affecting the lungs and kidneys. Structured clinical assessment using the Birmingham Vasculitis Activity Score and Vasculitis Damage Index should form the basis of a treatment plan and be used to document progress, including relapse. Severe disease with organ or life threatening manifestations needs cyclophosphamide or rituximab, plus high dose glucocorticoids, followed by lower dose steroid plus azathioprine, or methotrexate. Additional plasmapheresis is effective for very severe disease, reducing dialysis dependence from 60 to 40% in the first year, but with no effect on mortality or long-term renal function, probably due to established renal damage. In milder forms of ANCA-associated vasculitis, methotrexate, leflunomide, or mycophenolate mofetil are effective. Mortality depends on initial severity: 25% in patients with renal failure or severe lung hemorrhage; 6% for generalized non-life threatening AASV but rising to 30-40% at 5?years. Mortality from GPA is four times higher than the background population. Early deaths are due to active vasculitis and infection. Subsequent deaths are more often due to cardiovascular events, infection, and cancer. We need to improve the long-term outcome, by controlling disease activity but also preventing damage and drug toxicity. By contrast, in large vessel vasculitis where mortality is much less but morbidity potentially greater, such as giant cell arteritis (GCA) and Takayasu arteritis, therapeutic options are limited. High dose glucocorticoid results in significant toxicity in over 80%. Advances in understanding the biology of the vasculitides are improving therapies. Novel, mechanism based therapies such as rituximab in AASV, mepolizumab in eosinophilic granulomatosis with polyangiitis, and tocilizumab in GCA, but the lack of reliable biomarkers remains a challenge to progress in these chronic relapsing diseases.

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National Emphysema Treatment Trial state of the art: genetics of emphysema.

Publications

National Emphysema Treatment Trial state of the art: genetics of emphysema.

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