Hansel N N, Gao L, Rafaels N M, Mathias R A, Neptune E R, Tankersley C, Grant A V, Connett J, Beaty T H, Wise R A, Barnes K C
Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Eur Respir J. 2009 Jul;34(1):103-10. doi: 10.1183/09031936.00120408. Epub 2009 Feb 5.
Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD), suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD. In total, 429 European Americans were randomly selected from the National Heart Lung and Blood Institute Lung Health Study. 36 single nucleotide polymorphisms (SNPs) in LEPR were genotyped using the Illumina GoldenGate platform (Broad Institute, Cambridge, MA, USA). Mean annual decline in forced expiratory volume in 1 s % predicted over the 5-yr period was calculated using linear regression. Linear regression models were also used to adjust for potential confounders. In addition, in vivo expression of the receptor gene was assessed with immunohistochemistry on lungs from smoke-exposed inbred mice. We identified significant associations (p<0.05) between lung function decline and 21 SNPs. Haplotype analyses confirmed several of these associations seen with individual markers. Immunohistochemistry results in inbred mice strains support a potential role of LEPR in COPD pathogenesis. We identified genetic variants in the LEPR gene significantly associated with lung function decline in a population of smokers with COPD. Our results support a role for LEPR as a novel candidate gene for COPD.
只有一小部分吸烟者会患慢性阻塞性肺疾病（COPD），这表明遗传易感性起了很大作用。瘦素受体（LEPR）存在于人体肺组织中，可能在COPD发病机制中发挥作用。本研究调查了LEPR基因的遗传变异与COPD患者肺功能下降之间的关联。总共从美国国立心肺血液研究所肺部健康研究中随机选取了429名欧裔美国人。使用Illumina GoldenGate平台（美国马萨诸塞州剑桥市布罗德研究所）对LEPR中的36个单核苷酸多态性（SNP）进行基因分型。使用线性回归计算5年期间预测的1秒用力呼气量百分比的年均下降率。线性回归模型也用于调整潜在的混杂因素。此外，通过对暴露于烟雾的近交系小鼠的肺组织进行免疫组织化学评估受体基因的体内表达。我们发现肺功能下降与21个SNP之间存在显著关联（p<0.05）。单倍型分析证实了其中一些与单个标记所见的关联。近交系小鼠品系的免疫组织化学结果支持LEPR在COPD发病机制中的潜在作用。我们在患有COPD的吸烟者群体中发现LEPR基因的遗传变异与肺功能下降显著相关。我们的结果支持LEPR作为COPD的一个新候选基因的作用。
