Analysis of Exonic Elastin Variants in Severe, Early-Onset Chronic Obstructive Pulmonary Disease
Analysis of Exonic Elastin Variants in Severe, Early-Onset Chronic Obstructive Pulmonary Disease
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DOI：
10.1165/rcmb.2008-0340oc
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发表时间：
2009-06-01
影响因子：
6.4
通讯作者：
Silverman, Edwin K.
中科院分区：
文献类型：
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作者：
Cho, Michael H.;Ciulla, Dawn M.;Silverman, Edwin K.
弹性纤维的破坏与慢性阻塞性肺疾病（COPD）的发病机制有关。肺气肿已被描述为常染色体显性皮肤拉克萨，这可能是由弹性蛋白基因突变引起的。以前，在一个严重的早发性COPD病例中发现了弹性蛋白末端外显子的罕见功能突变。为了验证其他类似的弹性蛋白突变可能易患COPD的假设，我们使用高分辨率DNA熔解分析和重新测序筛选了来自波士顿早发性COPD研究的90名先证者和来自规范性衰老研究的90名吸烟对照受试者的弹性蛋白外显子突变。罕见的非同义单核苷酸多态性（SNPs）的情况下，只看到分离气流阻塞的家系内进行了检查。在波士顿早发性COPD研究的949名受试者的基于家庭的分析中，以及在国家肺气肿治疗试验的389名COPD病例和标准老化研究的472名对照受试者的病例对照分析中，对常见的非同义SNP与COPD的相关性进行了测试。在发现的28种弹性蛋白变体中，3种是仅在病例中发现的非同义SNP。在另一个先证者中发现了先前描述的Gly773Asp突变。其他两个SNP在家族内与COPD没有明显的分离。两种常见的非同义SNPs在基于家族或病例对照的分析中均未显示出显著相关性。弹性蛋白基因的外显子SNPs似乎不是严重COPD的常见危险因素。
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.