Abstract：
Age-related chronic inflammatory lung diseases impose a threat on public health, including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, their etiology and potential targets have not been clarified. We performed genome-wide meta-analysis for IPF with the largest sample size (2883 cases and 741,929 controls) and leveraged the summary statistics of COPD (17,547 cases and 617,598 controls). Transcriptome-wide and proteome-wide Mendelian randomization (MR) designs, together with genetic colocalization, were implemented to find robust targets. The mediation effect was assessed using leukocyte telomere length (LTL). The single-cell transcriptome analysis was performed to link targets with cell types. Individual-level data from UK Biobank (UKB) were used to validate our findings. Sixteen genetically predicted plasma proteins were causally associated with the risk of IPF and 6 proteins were causally associated with COPD. Therein, genetically-elevated plasma level of SCARF2 protein should reduce the risk of both IPF (odds ratio, OR = 0.9974 [0.9970, 0.9978]) and COPD (OR = 0.7431 [0.6253, 0.8831]) and such effects were not mediated by LTL. Genetic colocalization further corroborated these MR results of SCARF2. The transcriptome-wide MR confirmed that higher expression level of SCARF2 was associated with a reduced risk of both. However, the single-cell RNA analysis indicated that SCARF2 expression level was only relatively lower in epithelial cells of COPD lung tissue compared to normal lung tissue. UKB data implicated an inverse association of serum SCARF2 protein with COPD (hazard ratio, HR = 1.215 [1.106, 1.335]). The SCARF2 gene should be a novel target for COP.
摘要：
与年龄相关的慢性炎症性肺病对公众健康构成威胁，包括特发性肺纤维化（IPF）和慢性阻塞性肺疾病（COPD）。然而,其病因和潜在靶点尚未明确.我们对样本量最大的IPF（2883例和741,929例对照）进行了全基因组荟萃分析，并利用了COPD的汇总统计数据（17,547例和617,598例对照）。全转录组和全蛋白质组孟德尔随机化（MR）设计，连同遗传共定位，是为了找到强大的目标而实施的。使用白细胞端粒长度（LTL）评估调解效果。进行单细胞转录组分析以将靶标与细胞类型联系起来。来自英国生物库（UKB）的个体水平数据用于验证我们的发现。16种基因预测的血浆蛋白与IPF的风险有因果关系，6种蛋白与COPD有因果关系。其中,基因升高的血浆SCARF2蛋白水平应降低两种IPF的风险(比值比，OR=0.9974[0.9970，0.9978]）和COPD（OR=0.7431[0.6253，0.8831]）等效应不是由LTL介导的。遗传共定位进一步证实了SCARF2的这些MR结果。全转录组MR证实，较高的SCARF2表达水平与两者的风险降低有关。然而,单细胞RNA分析表明,与正常肺组织相比,SCARF2在COPD肺组织上皮细胞中的表达水平仅相对较低.UKB数据暗示血清SCARF2蛋白与COPD呈负相关(风险比，HR=1.215[1.106,1.335])。SCARF2基因应该是COP的新靶标。
