Dataset Information

Analysis of exonic elastin variants in severe, early-onset chronic obstructive pulmonary disease.

ABSTRACT: The destruction of elastic fibers has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Emphysema has been described in autosomal dominant cutis laxa, which can be caused by mutations in the elastin gene. Previously, a rare functional mutation in the terminal exon of elastin was found in a case of severe, early-onset COPD. To test the hypothesis that other similar elastin mutations may predispose to COPD, we screened 90 probands from the Boston Early-Onset COPD Study and 90 smoking control subjects from the Normative Aging Study for mutations in elastin exons using high-resolution DNA melt analysis followed by resequencing. Rare nonsynonymous single-nucleotide polymorphisms (SNPs) seen only in cases were examined for segregation with airflow obstruction within pedigrees. Common nonsynonymous SNPs were tested for association with COPD in a family-based analysis of 949 subjects from the Boston Early-Onset COPD Study, and in a case-control analysis in 389 COPD cases from the National Emphysema Treatment Trial and 472 control subjects from the Normative Aging Study. Of 28 elastin variants found, 3 were nonsynonymous SNPs found only in cases. The previously described Gly773Asp mutation was found in another proband. The other two SNPs did not clearly segregate with COPD within families. Two common nonsynonymous SNPs did not demonstrate significant associations in either a family-based or case-control analysis. Exonic SNPs in the elastin gene do not appear to be common risk factors for severe COPD.

SUBMITTER: Cho MH

PROVIDER: S-EPMC2689920 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Analysis of exonic elastin variants in severe, early-onset chronic obstructive pulmonary disease.

Cho Michael H MH Ciulla Dawn M DM Klanderman Barbara J BJ Hersh Craig P CP Litonjua Augusto A AA Sparrow David D Raby Benjamin A BA Silverman Edwin K EK

American journal of respiratory cell and molecular biology 20081121 6

The destruction of elastic fibers has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Emphysema has been described in autosomal dominant cutis laxa, which can be caused by mutations in the elastin gene. Previously, a rare functional mutation in the terminal exon of elastin was found in a case of severe, early-onset COPD. To test the hypothesis that other similar elastin mutations may predispose to COPD, we screened 90 probands from the Boston Early-Onset COPD ...[more]

PMID: 19029017

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Project description:Despite being a major cause of morbidity and mortality, chronic obstructive pulmonary disease (COPD) is frequently undiagnosed. Yet the burden of disease among the undiagnosed is significant, as these individuals experience symptoms, exacerbations, and excess mortality compared to those without COPD. The U.S. Preventive Services Task Force recommends against routine screening of asymptomatic individuals with spirometry. Hence, case-finding approaches are needed. A recently developed instrument, the five-item COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk questionnaire plus peak expiratory flow, demonstrates good sensitivity and specificity for distinguishing cases from control subjects and is being studied prospectively in primary care settings to determine its impact on patient outcomes. However, finding the undiagnosed is only half the battle. Mounting evidence suggests significant COPD-like respiratory burden among individuals without airflow obstruction. Many experience dyspnea, mucus production, and exacerbation events and have emphysema and airway abnormalities on computed tomographic (CT) imaging of the chest. However, it is still unclear how to best treat these individuals and which individuals go on to develop spirometric obstruction. These challenges underline the importance of defining what constitutes "early disease." A recently proposed definition characterizes early COPD as either: 1) airflow limitation, 2) compatible CT imaging abnormalities, or 3) accelerated forced expiratory volume in 1 second decline in persons younger than 50 years and with greater than a 10 pack-year smoking history. Although it is recognized that this definition does not encompass all individuals who will develop COPD, it is an attempt to identify a group of individuals with most rapid decline to better understand mechanisms of disease development and where disease-modifying interventions are most likely to be successful. Ultimately, leveraging tools such as chest CT imaging, the electronic medical record, and machine learning algorithms may aid in the identification of such individuals.

Dataset Information

Analysis of exonic elastin variants in severe, early-onset chronic obstructive pulmonary disease.

Publications

Analysis of exonic elastin variants in severe, early-onset chronic obstructive pulmonary disease.

Similar Datasets

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