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American journal of respiratory and critical care medicine 罕见SERPINA1 变异对螺病患者肺功能和肺气肿的影响。

影响因子：30.528 DOI：10.1164/rccm.201904-0769OC

作者： Ortega VE,Li X,O'Neal WK,Lackey L,Ampleford E,Hawkins GA,Grayeski PJ,Laederach A,Barjaktarevic I,Barr RG,Cooper C,Couper D,Han MK,Kanner RE,Kleerup EC,Martinez FJ,Paine R 3rd,Peters SP,Pirozzi C,Rennard SI,Woodruff PG,Hoffman EA,Meyers DA,Bleecker ER,NHLBI Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS). 发表时间：2020-07-10 20:00:40

from：《AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE》

keywords： Ortega VELi XO'Neal WKLackey LAmpleford EHawkins GAGrayeski PJLaederach ABarjaktarevic IBarr RGCooper CCouper DHan MKKanner REKleerup ECMartinez FJPaine R 3rdPeters SPPirozzi CRennard SIWoodruff PGHoffman EAMeyers DABleecker ERNHLBI Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS).

关键词： SERPINA1 Α-1 抗胰蛋白酶慢性阻塞性肺病肺气肿罕见变异

Abstract

:Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial.Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations.Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency < 0.05) in 16.9 kB of SERPINA1.Measurements and Main Results: White PI Z heterozygotes confirmed by sequencing (MZ; n = 74) had lower post-bronchodilator FEV1 (P = 0.007), FEV1/FVC (P = 0.003), and greater computed tomography-based emphysema (P = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as VR. PI Z-containing compound heterozygotes (ZS/ZVR; n = 7) had lower FEV1/FVC (P = 0.02) and forced expiratory flow, midexpiratory phase (P = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease (P = 0.007).Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.

摘要

: 原理: PI (蛋白酶抑制剂) Z型杂合子和其他罕见变异基因型在编码 α-1 抗胰蛋白酶的基因中的作用，SERPINA1 (serpin肽酶抑制剂，分支A，成员 1)，在确定慢性阻塞性肺疾病风险和严重程度方面存在争议。目标:使用深度基因重测序和 α-1 抗胰蛋白酶浓度综合评价罕见SERPINA1 变异对显著烟草烟雾暴露受试者肺功能和肺气肿表型的影响。方法: 对来自 1,693 名非西班牙裔白人、 385 名非裔美国人和 90 名吸烟 ≥ 20 包年的西班牙裔人的DNA样本进行重新测序，以鉴定罕见变异(等位基因频率 <0.05) 在 16.9 kB的serpina1 中。测量和主要结果: 经测序证实的白PI Z杂合子 (MZ; N = 74) 支气管扩张剂后FEV1 (p = 0.007) 、FEV1/FVC (p = 0.003) 较低，基于计算机断层扫描的肺气肿较大 (p = 0.02) 与 1,411 个没有PI Z，S的白人个体相比，或额外的罕见变体表示为VR。含PI Z的复合杂合子 (ZS/ZVR; N = 7) FEV1/FVC (p = 0.02) 和用力呼气流量较低，midexpiratory阶段 (p = 0.009)。与较低 α-1 抗胰蛋白酶相关的 5 种非S/Z编码变异的 19 例白色杂合子与无罕见变异的患者相比，基于计算机断层扫描的肺气肿更大。在非裔美国人中，5 '非翻译区插入 (rs568223361) 与较低的 α-1 抗胰蛋白酶和功能性小气道疾病相关 (p = 0.007)。结论: 在一项重度吸烟者和慢性阻塞性肺疾病队列中，SERPINA1 与 α-1 抗胰蛋白酶浓度的整合深度测序研究中，我们证实了PI Z杂合子和复合杂合子基因型的影响。我们证明了多种SERPINA1 变异对 α-1 抗胰蛋白酶缺乏、肺功能和肺气肿的累积作用，从而显著增加了高危吸烟者与呼吸系统疾病相关的SERPINA1 变异频率。

期刊介绍

《AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE》 (点击进入期刊详情)

英文简介 : The AJRCCM focuses on human biology and disease, as well as animal and in vitro studies that contribute to the understanding of pathophysiology and treatment of diseases that affect the respiratory system and critically ill patients.

中文简介 : （来自Google、百度翻译） AJRCCM侧重于人体生物学和疾病，以及有助于理解病理生理学和治疗影响呼吸系统和危重患者疾病的动物和体外研究。

CIRCULATION RESEARCH 期刊中科院评价数据

新中科院分区

大类(学科)	小类(学科)	学科排名
医学	CRITICAL CARE MEDICINE(危重症监护医学) RESPIRATORY SYSTEM(呼吸系统)	2/33 2/60

大类(学科)

小类(学科)

学科排名

医学

CRITICAL CARE MEDICINE(危重症监护医学)

RESPIRATORY SYSTEM(呼吸系统)

2/33
2/60

新发布的期刊年发文量

年度总发文量	年度论文发表量	年度综述发表量
252	239	13

总被引频次 :63074

特征因子 : 0.091170

影响因子趋势图

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