The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes.
The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes.
复制标题
DOI：
10.1183/13993003.01441-2020
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Richards JB
中科院分区：
文献类型：
--
作者：
Nakanishi T;Forgetta V;Handa T;Hirai T;Mooser V;Lathrop GM;Cookson WOCM;Richards JB
α-1抗胰蛋白酶缺乏症（AATD）是最常见的遗传性疾病之一，主要由SERPINA 1中的PI*ZZ基因型引起。由于它与高疾病负担相关，并且部分通过戒烟来预防，因此通过基因分型识别PI*ZZ个体可以改善健康结果。我们检测了来自英国生物样本库（UK Biobank）的患有和未患有AATD的个体中PI*ZZ基因型的频率，并评估了基因型与临床结局和死亡率的相关性。进行全表型关联研究（PheWAS）以揭示疾病与基因型的关联。采用多基因危险度评分（PRS）法测定第一秒用力呼气量（FEV 1）/用力肺活量（FVC）比值，评价PI*ZZ的变异率。在英国生物库的458164名欧洲血统参与者中，140人具有PI*ZZ基因型，其中只有9人（6.4%，95%CI 3.4-11.7%）被诊断为AATD。 PI*ZZ患者的COPD发生率显著较高（OR 8.8，95% CI 5.8-13.3），哮喘（OR 2.0，95% CI 1.4-3.0），支气管扩张（OR 7.3，95%CI 3.2-16.8），肺炎（OR 2.7，95% CI 1.5-4.9）和肝硬化（OR 7.8，95% CI 2.5-24.6）诊断和更高的死亡风险（2.4，95% CI 1.2-4.6）相比，PI*MM（野生型）（n=398 424）。这些关联在吸烟者中更强。PheWAS与脓胸、气胸、恶病质、红细胞增多症、动脉瘤和胰腺炎的发生率增加相关。多基因风险评分和PI*ZZ与FEV 1/FVC <0.7独立相关（OR 1.4/1-sd变化，95%CI 1.4-1.5和OR 4.5，95%CI 3.0-6.9）。AATD的重要诊断不足，其结果可以通过戒烟部分预防，可以通过基因型指导的诊断得到改善。在英国生物库中，只有6.4%的基因型定义的α-1抗胰蛋白酶缺乏症患者被诊断患有这种严重的疾病。基因型指导诊断可以帮助确定英国成千上万的人患有这种部分可预防的疾病。https://bit.ly/3dMu5Ng
Alpha-1 antitrypsin deficiency (AATD), mainly due to the PI*ZZ genotype in SERPINA1, is one of the most common inherited diseases. Since it is associated with a high disease burden and partially prevented by smoking cessation, identification of PI*ZZ individuals through genotyping could improve health outcomes. We examined the frequency of the PI*ZZ genotype in individuals with and without diagnosed AATD from UK Biobank, and assessed the associations of the genotypes with clinical outcomes and mortality. A phenome-wide association study (PheWAS) was conducted to reveal disease associations with genotypes. A polygenic risk score (PRS) for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio was used to evaluate variable penetrance of PI*ZZ. Among 458 164 European-ancestry participants in UK Biobank, 140 had the PI*ZZ genotype and only nine (6.4%, 95% CI 3.4–11.7%) of them were diagnosed with AATD. Those with PI*ZZ had a substantially higher odds of COPD (OR 8.8, 95% CI 5.8–13.3), asthma (OR 2.0, 95% CI 1.4–3.0), bronchiectasis (OR 7.3, 95%CI 3.2–16.8), pneumonia (OR 2.7, 95% CI 1.5–4.9) and cirrhosis (OR 7.8, 95% CI 2.5–24.6) diagnoses and a higher hazard of mortality (2.4, 95% CI 1.2–4.6), compared to PI*MM (wildtype) (n=398 424). These associations were stronger among smokers. PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythaemia, aneurysm and pancreatitis. Polygenic risk score and PI*ZZ were independently associated with FEV1/FVC <0.7 (OR 1.4 per 1-sd change, 95% CI 1.4–1.5 and OR 4.5, 95% CI 3.0–6.9, respectively). The important underdiagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis. Only 6.4% of those with genotype-defined alpha-1 antitrypsin deficiency had been diagnosed with this serious disease in UK Biobank. Genotype-guided diagnosis could help to identify the thousands of people in the UK with this partially preventable disease. https://bit.ly/3dMu5Ng
登录
查看更多内容
影响因子：
5
作者：
Fry A;Littlejohns TJ;Sudlow C;Doherty N;Adamska L;Sprosen T;Collins R;Allen NE
通讯作者：
Allen NE
全基因组关联荟萃分析产生了20个与胆结石疾病相关的基因座。
影响因子：
16.6
作者：
Ferkingstad E;Oddsson A;Gretarsdottir S;Benonisdottir S;Thorleifsson G;Deaton AM;Jonsson S;Stefansson OA;Norddahl GL;Zink F;Arnadottir GA;Gunnarsson B;Halldorsson GH;Helgadottir A;Jensson BO;Kristjansson RP;Sveinbjornsson G;Sverrisson DA;Masson G;Olafsson I;Eyjolfsson GI;Sigurdardottir O;Holm H;Jonsdottir I;Olafsson S;Steingrimsdottir T;Rafnar T;Bjornsson ES;Thorsteinsdottir U;Gudbjartsson DF;Sulem P;Stefansson K
通讯作者：
Stefansson K
影响因子：
--
作者：
Mahr, Alfred D.;Edberg, Jeffrey C.;Merkel, Peter A.
通讯作者：
Merkel, Peter A.
影响因子：
24.3
作者：
Miravitlles, Marc;Dirksen, Asger;Stockley, Robert A.
通讯作者：
Stockley, Robert A.
影响因子：
158.5
作者：
ERIKSSON, S;CARLSON, J;VELEZ, R
通讯作者：
VELEZ, R