Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19.
Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19.
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DOI：
10.1016/s2665-9913(20)30345-3
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发表时间：
2020-11
期刊：
影响因子：
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通讯作者：
Holmes MV
中科院分区：
文献类型：
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作者：
Bovijn J;Lindgren CM;Holmes MV
严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染的有效治疗选择很少。IL-6受体阻断剂已被提议作为一种潜在的治疗策略，目前正在进行40多项抗IL-6受体抗体（包括托珠单抗和sar）在SARS-CoV-2感染背景下的临床试验（附录p 2）。来自观察性研究和开放标签、非对照试验的早期证据表明，IL-6受体阻滞剂可能会带来益处，特别是在重度COVID-19患者中。1人类遗传学使药物再利用的潜在机会得以消除。我们利用大规模的人类遗传数据来研究IL-6受体阻断剂是否可以在COVID-19中提供治疗益处。最近发现，由IL-6 R中或接近IL-6 R的7种遗传变异组成的遗传工具（成对r²≤ 0· 1;附录第8-9页）与C反应蛋白、纤维蛋白原、循环IL-6和可溶性IL-6受体浓度的改变相关，与药理学IL-6受体阻断剂的已知作用一致（附录第4页）。2我们使用来自COVID-19宿主遗传学倡议的数据研究了这些IL 6 R变体对COVID-19住院风险和其他SARS-CoV-2相关结果的影响（附录pp 2-3，10）。3根据英国生物银行的数据，IL 6 R变体被证实与较低的血清C反应蛋白浓度相关（附录第5-6页）。规模估计的荟萃分析确定了类风湿关节炎的风险较低（比值比0.93/0.1 SD降低C反应蛋白; 95% CI 0.90 - 0.96，p<0.0001;附录pp 5-6），支持IL-6受体抑制剂的既定适应症（例如，托珠单抗和sar），以及冠心病的风险较低（0.96; 0.95 - 0.98，p<0.0001），这与IL 6 R的遗传变异有关。4 IL 6 R仪器也与COVID-19住院风险较低相关（0.88; 0.78 - 0.99，p= 0.03;附录第5-6页）。当使用基于人群的对照组时，我们发现了一致的相关性（即，所有非病例; 0· 91; 0· 87-0· 96，p= 0· 0005;附录pp 5-6）。在进一步评估SARS-CoV-2相关结果时，我们发现IL-6 R仪器与SARS-CoV-2感染风险相关（0.92; 0.89 - 0.95，p<0.0001，使用基于人群的对照组;附录第5-6页），但没有证据表明与死亡或呼吸支持需求相关。主要分析的结果对各种敏感性分析具有稳健性（附录第7页）。我们的研究结果表明，模拟IL-6受体治疗抑制的IL 6 R变体与COVID-19住院风险降低相关，COVID-19是一种与疾病严重程度相关的表型（例如，需要补充氧气是住院的典型原因）。这一结果表明，IL-6受体的药理学阻断可能会导致COVID-19严重程度降低。我们还发现了与SARS-CoV-2感染风险较低的相关性;尽管这一发现可能表明IL-6受体阻断剂降低了对SARS-CoV-2感染的易感性，但这些表型可能因症状严重程度而存在偏倚（即，症状更严重的个体可能更有可能接受检测、提供检测或检测呈阳性）。与需要呼吸支持或导致死亡的非常严重的COVID-19缺乏相关性可能与sar在需要机械通气的COVID-19患者中进行的III期随机对照试验中宣布失败有关。第五，基因分析…
Few effective therapeutic options are available for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. IL-6 receptor blockade has been proposed as one potential therapeutic strategy, and more than 40 clinical trials of anti-IL-6 receptor antibodies (including tocilizumab and sarilumab) in the setting of SARS-CoV-2 infection are underway (appendix p 2). Early evidence from observational studies and open-label, uncontrolled trials has suggested that IL-6 receptor blockers might confer benefit, particularly in patients with severe COVID-19. 1 Human genetics enables the investiga tion of potential opportunities for drug repurposing. We leveraged largescale human genetic data to investigate whether IL-6 receptor blockade might confer therapeutic benefit in COVID-19. A genetic instrument consisting of seven genetic variants in or close to IL6R (pairwise r²≤ 0· 1; appendix pp 8–9) was recently shown to be associated with altered concentrations of C-reactive protein, fibrinogen, circulating IL-6, and soluble IL-6 receptor, concordant with known effects of pharmacological IL-6 receptor blockade (appendix p 4). 2 We investigated the effect of these IL6R variants on risk of hospitalisation for COVID-19 and other SARS-CoV-2-related outcomes using data from the COVID-19 Host Genetics Initiative (appendix pp 2–3, 10). 3 Based on data from UK Biobank, the IL6R variants were confirmed to be associated with lower serum C-reactive protein concentrations (appendix pp 5–6). Meta-analysis of scaled estimates identified a lower risk of rheumatoid arthritis (odds ratio 0· 93 per 0· 1 SD lower C-reactive protein; 95% CI 0· 90–0· 96, p< 0· 0001; appendix pp 5–6), supporting this established indica tion for IL-6 receptor inhibitors (eg, tocilizumab and sarilumab), as well as a lower risk of coronary heart disease (0· 96; 0· 95–0· 98, p< 0· 0001), which has previously been linked to genetic variation in IL6R. 4 The IL6R instrument was also associated with a lower risk of hospitalisation for COVID-19 (0· 88; 0· 78–0· 99, p= 0· 03; appendix pp 5–6). We found a consistent association when using a population-based control group (ie, all non-cases; 0· 91; 0· 87–0· 96, p= 0· 0005; appendix pp 5–6). On evaluation of further SARS-CoV-2-related outcomes, we detected an association of the IL6R instrument with risk of SARS-CoV-2 infection (0· 92; 0· 89–0· 95, p< 0· 0001 using a population-based con trol group; appendix pp 5–6), but no evi dence of association with death or need for res piratory support. The results of the main analysis were robust to various sensitivity analyses (appendix p 7). Our findings show that IL6R variants mimicking therapeutic inhibition of IL-6 receptor are associated with a lower risk of hospitalisation for COVID-19, a phenotype that is associated with disease severity (eg, requiring supplemental oxygen is a typical reason for hospitalisation). This result suggests that pharmacological blockade of IL-6 receptor might be expected to lead to reduced COVID-19 severity. We also found an association with lower risk of SARS-CoV-2 infection; although this finding might suggest that IL-6 receptor blockade lowers susceptibility to SARS-CoV-2 infection, these phenotypes could be biased by symptom severity (ie, individuals with more severe symptoms might be more likely to present for testing, to be offered testing, or to have a positive test). The lack of association with very severe COVID-19 requiring respiratory support or leading to death might be relevant in the context of the announced failure of sarilumab in a phase 3 randomised controlled trial in patients with COVID-19 requiring mechanical ventilation. 5 However, the genetic analysis …