Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease.
Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease.
复制标题
α-1抗胰蛋白酶缺乏症和慢性阻塞性肺疾病中肺气肿的独特和共享的全身生物标志物。
DOI：
10.1016/j.ebiom.2022.104262
复制
发表时间：
2022-10
期刊：
影响因子：
11.1
通讯作者：
Bowler, R. P.
中科院分区：
文献类型：
--
作者：
Serban, K. A.;Pratte, K. A.;Strange, C.;Sandhaus, R. A.;Turner, A. M.;Beiko, T.;Spittle, D. A.;Maier, L.;Hamzeh, N.;Silverman, E. K.;Hobbs, B. D.;Hersh, C. P.;DeMeo, D. L.;Cho, M. H.;Bowler, R. P.
α-1抗胰蛋白酶（AAT）缺乏症（AATD）是肺气肿最常见的遗传原因，在受影响的受试者中存在无法解释的表型异质性。我们的目的是确定独特的和共享的AATD血浆生物标志物与慢性阻塞性肺疾病（COPD）可能解释AATD表型异质性。在SomaScan V4.0平台上分析了来自4个AATD和COPD队列的5，924例受试者的血浆或血清。使用多变量线性回归、逆方差随机效应荟萃分析和最小绝对收缩和选择算子（LASSO）回归，我们检测了不同AATD基因型中4，720种单独蛋白质或蛋白质评分组合与肺气肿（通过第15百分位数肺密度（PD 15）或弥散量（DLCO）测量）之间的相关性（Pi*ZZ、Pi*SZ、Pi*MZ）和非AATD、PiMM COPD受试者。使用受试者工作特征曲线分析测试AAT SOMAmer鉴定AATD的准确性。在PiZZ AATD受试者中，2种独特蛋白质与PD 15相关，98种蛋白质与DLCO相关。其中，68例也与COPD中的DLCO相关，并富含三种细胞成分途径：胰岛素样生长因子、脂滴和肌球蛋白复合物。PiMZ AATD受试者与COPD受试者具有相似的DLCO相关蛋白。我们的肺气肿蛋白评分包括262例SOMAmer，并预测AATD和COPD受试者的肺气肿。SOMAmer AAT水平<7.99相对荧光单位（RFU）对鉴定Pi*ZZ的敏感性和特异性为100%，但对其他AATD基因型的敏感性和特异性较低。使用SomaScan，我们确定了AATD和COPD受试者之间独特和共享的血浆生物标志物，并生成了与COPD和AATD中的肺气肿密切相关的蛋白质评分。此外，我们在PiZZ AATD中发现了与DLCO和肺气肿相关的独特生物标志物。这项工作得到了Alpha-1基金会向RPB提供的赠款的支持。COPDGene获得了美国国家心脏、肺和血液研究所的U 01 HL 089897和U 01 HL 089856奖的支持。COPDGene的蛋白质组学得到NIH 1 R 01 HL 137995的支持。GRADS获得了美国国家心脏、肺和血液研究所颁发的U 01 HL 112707、U 01 HL 112695奖和CCTSI颁发的UL 1 TRR 002535奖的支持; QUANTUM-1由国家心肺和血液研究所，罕见疾病办公室通过罕见肺病临床研究网络提供支持（1U 54 RR 019498 -01，Trapnell PI）和Alpha-1基金会。COPD基因还得到了COPD基金会的支持，该基金会向包括阿斯利康、拜耳制药、勃林格殷格翰、基因泰克、葛兰素史克、诺华、辉瑞和Sunovion在内的行业咨询委员会捐款。
Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.
登录
查看更多内容
影响因子：
4.6
作者：
Candia J;Cheung F;Kotliarov Y;Fantoni G;Sellers B;Griesman T;Huang J;Stuccio S;Zingone A;Ryan BM;Tsang JS;Biancotto A
通讯作者：
Biancotto A
影响因子：
82.9
作者：
Niewczas, Monika A.;Pavkov, Meda E.;Krolewski, Andrzej S.
通讯作者：
Krolewski, Andrzej S.
影响因子：
3.4
作者：
Raffield, Laura M.;Dang, Hong;Bowler, Russell P.
通讯作者：
Bowler, Russell P.
DOI：
10.1164/rccm.202106-1404oc
发表时间：
2022-02-01
影响因子：
24.7
作者：
Ghosh, Auyon J.;Hobbs, Brian D.;Hersh, Craig P.
通讯作者：
Hersh, Craig P.
影响因子：
1.6
作者：
Choi, M. -G.;Sohn, T. S.;Kim, S.
通讯作者：
Kim, S.