Medical Research Council Integrative Epidemiology Unit (MRC IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom.
Medical Research Council Integrative Epidemiology Unit (MRC IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom.
EBioMedicine. 2021 Feb;64:103228. doi: 10.1016/j.ebiom.2021.103228. Epub 2021 Feb 3.
Developing insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to overcome the global pandemic caused by coronavirus disease 2019 (covid-19). In this study, we have applied Mendelian randomization (MR) to systematically evaluate the effect of 10 cardiometabolic risk factors and genetic liability to lifetime smoking on 97 circulating host proteins postulated to either interact or contribute to the maladaptive host response of SARS-CoV-2.
We applied the inverse variance weighted (IVW) approach and several robust MR methods in a two-sample setting to systemically estimate the genetically predicted effect of each risk factor in turn on levels of each circulating protein. Multivariable MR was conducted to simultaneously evaluate the effects of multiple risk factors on the same protein. We also applied MR using cis-regulatory variants at the genomic location responsible for encoding these proteins to estimate whether their circulating levels may influence severe SARS-CoV-2.
In total, we identified evidence supporting 105 effects between risk factors and circulating proteins which were robust to multiple testing corrections and sensitivity analyzes. For example, body mass index provided evidence of an effect on 23 circulating proteins with a variety of functions, such as inflammatory markers c-reactive protein (IVW Beta=0.34 per standard deviation change, 95% CI=0.26 to 0.41, P = 2.19 × 10) and interleukin-1 receptor antagonist (IVW Beta=0.23, 95% CI=0.17 to 0.30, P = 9.04 × 10). Further analyzes using multivariable MR provided evidence that the effect of BMI on lowering immunoglobulin G, an antibody class involved in protection from infection, is substantially mediated by raised triglycerides levels (IVW Beta=-0.18, 95% CI=-0.25 to -0.12, P = 2.32 × 10, proportion mediated=44.1%). The strongest evidence that any of the circulating proteins highlighted by our initial analysis influence severe SARS-CoV-2 was identified for soluble glycoprotein 130 (odds ratio=1.81, 95% CI=1.25 to 2.62, P = 0.002), a signal transductor for interleukin-6 type cytokines which are involved in inflammatory response. However, based on current case samples for severe SARS-CoV-2 we were unable to replicate findings in independent samples.
Our findings highlight several key proteins which are influenced by established exposures for disease. Future research to determine whether these circulating proteins mediate environmental effects onto risk of SARS-CoV-2 infection or covid-19 progression are warranted to help elucidate therapeutic strategies for severe covid-19 disease.
The Medical Research Council, the Wellcome Trust, the British Heart Foundation and UK Research and Innovation.
深入了解严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的发病机制对于克服由 2019 年冠状病毒病（covid-19）引起的全球大流行至关重要。在这项研究中，我们应用孟德尔随机化（MR）系统地评估了 10 种心血管代谢风险因素和终生吸烟的遗传易感性对 97 种假定与 SARS-CoV-2 的适应性宿主反应相互作用或有助于该反应的循环宿主蛋白的影响。
我们在两样本设置中应用了逆方差加权（IVW）方法和几种稳健的 MR 方法，依次系统地估计每个风险因素在每个循环蛋白水平上的遗传预测效应。多变量 MR 用于同时评估多个风险因素对同一蛋白的影响。我们还应用了在负责编码这些蛋白的基因组位置的顺式调节变异来估计它们的循环水平是否可能影响严重的 SARS-CoV-2。
总共，我们确定了 105 种支持风险因素和循环蛋白之间的关联的证据，这些证据在经过多次测试校正和敏感性分析后仍然可靠。例如，体重指数（BMI）为 23 种具有多种功能的循环蛋白提供了证据，例如炎症标志物 C 反应蛋白（IVW Beta=0.34 标准差变化，95%CI=0.26 至 0.41，P=2.19×10）和白细胞介素-1 受体拮抗剂（IVW Beta=0.23，95%CI=0.17 至 0.30，P=9.04×10）。使用多变量 MR 进行的进一步分析提供了证据，表明 BMI 对降低免疫球蛋白 G（一种参与抗感染的抗体类别）的作用主要是通过升高的甘油三酯水平介导的（IVW Beta=-0.18，95%CI=-0.25 至-0.12，P=2.32×10，介导比例=44.1%）。我们最初分析中强调的任何循环蛋白影响严重 SARS-CoV-2 的最强证据是可溶性糖蛋白 130（比值比=1.81，95%CI=1.25 至 2.62，P=0.002），这是白细胞介素-6 型细胞因子的信号转导物，这些细胞因子参与炎症反应。然而，基于目前严重 SARS-CoV-2 的病例样本，我们无法在独立样本中复制发现。
我们的研究结果突出了几种受疾病既定暴露影响的关键蛋白。为了确定这些循环蛋白是否介导环境对 SARS-CoV-2 感染风险或 covid-19 进展的影响，有必要进行进一步的研究，以帮助阐明严重 covid-19 疾病的治疗策略。
英国医学研究理事会、惠康信托基金会、英国心脏基金会和英国研究与创新署。
