Framingham Heart Study, Framingham, MA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Department of Biostatistics, Boston University School of Public Health, Boston, MA.
Chest. 2022 Jan;161(1):76-84. doi: 10.1016/j.chest.2021.06.053. Epub 2021 Jul 6.
There are few clinically useful circulating biomarkers of lung function and lung disease. We hypothesized that genome-wide association studies (GWAS) of circulating proteins in conjunction with GWAS of pulmonary traits represents a clinically relevant approach to identifying causal proteins and therapeutically useful insights into mechanisms related to lung function and disease.
Can an integrative genomic strategy using GWAS of plasma soluble receptor for advanced glycation end-products (sRAGE) levels in conjunction with GWAS of lung function traits identify putatively causal relations of sRAGE to lung function?
Plasma sRAGE levels were measured in 6,861 Framingham Heart Study participants and GWAS of sRAGE was conducted to identify protein quantitative trait loci (pQTL), including cis-pQTL variants at the sRAGE protein-coding gene locus (AGER). We integrated sRAGE pQTL variants with variants from GWAS of lung traits. Colocalization of sRAGE pQTL variants with lung trait GWAS variants was conducted, and Mendelian randomization was performed using sRAGE cis-pQTL variants to infer causality of sRAGE for pulmonary traits. Cross-sectional and longitudinal protein-trait association analyses were conducted for sRAGE in relation to lung traits.
Colocalization identified shared genetic signals for sRAGE with lung traits. Mendelian randomization analyses suggested protective causal relations of sRAGE to several pulmonary traits. Protein-trait association analyses demonstrated higher sRAGE levels to be cross-sectionally and longitudinally associated with preserved lung function.
sRAGE is produced by type I alveolar cells, and it acts as a decoy receptor to block the inflammatory cascade. Our integrative genomics approach provides evidence for sRAGE as a causal and protective biomarker of lung function, and the pattern of associations is suggestive of a protective role of sRAGE against restrictive lung physiology. We speculate that targeting the AGER/sRAGE axis may be therapeutically beneficial for the treatment and prevention of inflammation-related lung disease.
目前用于评估肺功能和肺部疾病的循环生物标志物非常有限。我们假设，通过对循环蛋白进行全基因组关联研究（GWAS）并结合肺功能相关性状的 GWAS，可能有助于鉴定与肺功能和疾病相关的因果蛋白，并为相关机制的治疗提供有价值的见解。
能否通过对血浆可溶性晚期糖基化终产物受体（sRAGE）水平进行 GWAS 并结合肺功能性状的 GWAS，利用综合基因组策略来确定 sRAGE 与肺功能之间的因果关系？
在 6861 名弗雷明汉心脏研究参与者中测量了血浆 sRAGE 水平，并对 sRAGE 进行了 GWAS 以鉴定蛋白质数量性状基因座（pQTL），包括位于 sRAGE 蛋白编码基因座（AGER）的 cis-pQTL 变体。我们将 sRAGE pQTL 变体与肺性状 GWAS 变体进行整合。对 sRAGE pQTL 变体与肺性状 GWAS 变体进行共定位，并使用 sRAGE cis-pQTL 变体进行孟德尔随机化以推断 sRAGE 对肺性状的因果关系。对 sRAGE 与肺性状的关系进行了横断面和纵向的蛋白质-性状关联分析。
共定位鉴定出 sRAGE 与肺性状存在共享的遗传信号。孟德尔随机化分析表明，sRAGE 对多种肺性状具有保护作用的因果关系。蛋白质-性状关联分析表明，较高的 sRAGE 水平与肺功能的保留在横断面和纵向均有关联。
sRAGE 由 I 型肺泡细胞产生，作为一种诱饵受体，阻断炎症级联反应。我们的综合基因组学方法为 sRAGE 作为肺功能的因果和保护生物标志物提供了证据，关联模式提示 sRAGE 对限制肺生理功能具有保护作用。我们推测，靶向 AGER/sRAGE 轴可能对炎症相关肺部疾病的治疗和预防具有治疗意义。
