系统性晚期糖基化终产物受体是肺气肿的生物标志物，与慢性阻塞性肺疾病患者的AGER 基因变异有关。
Systemic soluble receptor for advanced glycation endproducts is a biomarker of emphysema and associated with AGER genetic variants in patients with chronic obstructive pulmonary disease.
机构信息
1 Hoffmann-La Roche Inc., Nutley, New Jersey.
出版信息
Am J Respir Crit Care Med. 2013 Oct 15;188(8):948-57. doi: 10.1164/rccm.201302-0247OC.
RATIONALE
Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost.
OBJECTIVES
To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemic biomarker identified in this study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics.
METHODS
Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1,847 patients with COPD, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated.
MEASUREMENTS AND MAIN RESULTS
sRAGE was identified as a biomarker of diffusing capacity of carbon monoxide and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased Global Initiative for Chronic Obstructive Lung Disease stage, and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (P < 0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (P = 0.0014) and ECLIPSE (7.07 × 10(-16)), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (P = 0.01) and diffusing capacity of carbon monoxide (P = 0.01) in the TESRA study.
CONCLUSIONS
Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels. Clinical trial registered with www.clinicaltrials.gov (NCT 00413205 and NCT 00292552).
背景
慢性阻塞性肺疾病（COPD）的肺气肿可以通过高分辨率胸部 CT（HRCT）进行特征描述；然而，由于担心辐射暴露和成本，HRCT 的重复使用受到限制。
目的
评估与肺气肿和 COPD 相关临床特征相关的生物标志物，并评估候选系统生物标志物可溶性晚期糖基化终产物受体（sRAGE）与基因编码 RAGE（AGER 基因座）的单核苷酸多态性（SNP）之间的关系以及与临床特征的关系。
方法
在 TESRA 研究中，对 410 名 COPD 患者的 111 种生物标志物进行了循环水平分析，以评估其与临床特征的关系。在 COPD 患者的 ECLIPSE 队列中，也测量了 1847 名 COPD 患者、298 名吸烟者和 204 名不吸烟者的 sRAGE。还研究了 AGER 基因座中的 21 个 SNP 与 sRAGE 水平和临床特征之间的关系。
测量和主要结果
sRAGE 被确定为 TESRA 队列中一氧化碳弥散量和肺密度的生物标志物。在 ECLIPSE 队列中，较低的 sRAGE 水平与肺气肿增加、全球倡议慢性阻塞性肺疾病（COPD）分期增加和 COPD 疾病状态有关。在两个队列中，与肺气肿的关联在调整协变量后仍然显著（P < 0.0001）。AGER 基因座中的一个 SNP，rs2070600，在 TESRA 中与循环 sRAGE 水平相关（P = 0.0014），在 ECLIPSE 中与循环 sRAGE 水平相关（7.07×10(-16)），超过了全基因组显著性阈值。另一个 SNP（rs2071288）也与 TESRA 研究中的 sRAGE 水平（P = 0.01）和一氧化碳弥散量（P = 0.01）相关。
结论
较低的循环 sRAGE 水平与肺气肿严重程度相关，AGER 基因座中的遗传多态性与全身 sRAGE 水平相关。临床试验在 www.clinicaltrials.gov 注册（NCT 00413205 和 NCT 00292552）。
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