Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity
Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity
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特发性肺纤维化与 COVID-19 严重程度之间存在共同的遗传病因
DOI：
10.1101/2020.12.15.20248279
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Fadista J
中科院分区：
文献类型：
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作者：
Fadista J
背景特发性肺纤维化（IPF）是一种复杂的肺部疾病，其特征是进行性肺部疤痕形成。重症 COVID-19 与严重肺炎相关，并且与 IPF 有许多共同的主要危险因素。本研究旨在确定 IPF 与重症 COVID-19 之间的遗传相关性，并评估遗传性增加的 IPF 风险对 COVID-19 严重程度的潜在因果作用。方法通过连锁不平衡 (LD) 评分回归估计 IPF 与 COVID-19 严重程度之间的遗传相关性。我们对 COVID-19 中的 IPF 因果关系进行了孟德尔随机化 (MR) 研究。之前的全基因组关联研究 (GWAS) 中与 IPF 易感性相关的遗传变异 (P<5 × 10−8) 被用作工具变量 (IV)。这些 IV 对 COVID-19 严重程度的影响估计是从 COVID-19 宿主遗传学倡议的 GWAS 荟萃分析中收集的（4,336 例病例和 623,902 名对照）。结果我们检测到 IPF 与 COVID-19 严重程度存在正向遗传相关性（rg=0·31 [95% CI 0·04–0·57]，P= 0·023）。重症 COVID-19 的 MR 估计并未揭示任何遗传关联（OR 1·05，[95% CI 0·92–1·20]，P= 0·43）。然而，离群值分析显示，MUC5B 处的 IPF 风险等位基因 rs35705950 与其他变体相比具有不同的影响。当排除 rs35705950 时，MR 结果提供了证据，表明 IPF 遗传风险增加对 COVID-19 严重程度具有因果影响（OR 1·21，[95% CI 1·06–1·38]，P= 4·24 × 10−3）。此外，MUC5B 处的 IPF 风险等位基因仅在老年人中表现出对 COVID-19 住院的明显保护作用（OR 0·86，[95% CI 0·73–1·00]，P= 2·99 × 10−2）。解释 IPF 最强的遗传决定因素，MUC5B 处的 rs35705950，似乎可以提供针对 COVID-19 的保护作用，而综合作用所有其他 IPF 风险位点似乎都会带来 COVID-19 严重程度的风险。观察到的 rs35705950 效应可能是由于粘蛋白过量产生对气道的保护作用，也可能是由于 (1) rs35705950 T 高度富集的患者群体采取严格的自我隔离和/或 (2) 由于 rs35705950 非 IPF 风险等位基因携带者的生存偏差造成的选择偏差的结果。由于 IPF 因果变异对 SARS-CoV-2 感染的影响多种多样，可能存在选择偏差作为解释，因此需要进一步研究来解决 MUC5B 变异与其他 IPF 遗传风险因素之间的这种明显悖论。资助诺和诺德基金会和 Oak 基金会。
BackgroundIdiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity.MethodsThe genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10−8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls).FindingsWe detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04–0·57],P= 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92–1·20],P= 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 atMUC5Bhad a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06–1·38],P= 4·24 × 10−3). Furthermore, the IPF risk-allele atMUC5Bshowed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73–1·00],P= 2·99 × 10−2) .InterpretationThe strongest genetic determinant of IPF, rs35705950 atMUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance atMUC5Band other IPF genetic risk factors.FundingNovo Nordisk Foundation and Oak Foundation.
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影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
鉴定与特发性肺纤维化相关的 SPDL1 中的新型错义变异
DOI：
--
发表时间：
2020
期刊：
bioRxiv
影响因子：
--
作者：
R. Dhindsa;J. Mattsson;A. Nag;Quanli Wang;L. Wain;R. Allen;E. Wigmore;K. Ibáñez;D. Vitsios;Sri V. V. Deevi;Sebastian Wasilewski;M. Karlsson;G. Lassi;H. Olsson;D. Muthas;A. Mackay;L. Murray;S. Young;C. Haefliger;T. Maher;M. Belvisi;G. Jenkins;P. Molyneaux;A. Platt;S. Petrovski
通讯作者：
S. Petrovski
影响因子：
30.8
作者：
Verbanck M;Chen CY;Neale B;Do R
通讯作者：
Do R
影响因子：
18.2
作者：
Cho SJ;Stout-Delgado HW
通讯作者：
Stout-Delgado HW
MUC5B 启动子多态性与严重的 COVID-19 相关
DOI：
10.1101/2020.05.12.20099333
发表时间：
2020
期刊：
medRxiv
影响因子：
--
作者：
C. V. van Moorsel;J. J. van der Vis;C. Benschop;H. Ruven;M. Quanjel;J. Grutters
通讯作者：
J. Grutters