Population Health Research Institute, Hamilton, Ontario, Canada.
Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
JAMA Netw Open. 2023 Jul 3;6(7):e2325914. doi: 10.1001/jamanetworkopen.2023.25914.
Cardiometabolic parameters are established risk factors for COVID-19 severity. The identification of causal or protective biomarkers for COVID-19 severity may facilitate the development of novel therapies.
To identify protein biomarkers that promote or reduce COVID-19 severity and that mediate the association of cardiometabolic risk factors with COVID-19 severity.
DESIGN, SETTING, AND PARTICIPANTS: This genetic association study using 2-sample mendelian randomization (MR) was conducted in 2022 to investigate associations among cardiometabolic risk factors, circulating biomarkers, and COVID-19 hospitalization. Inputs for MR included genetic and proteomic data from 4147 participants with dysglycemia and cardiovascular risk factors collected through the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial. Genome-wide association study summary statistics were obtained from (1) 3 additional independent plasma proteome studies, (2) genetic consortia for selected cardiometabolic risk factors (including body mass index [BMI], type 2 diabetes, type 1 diabetes, and systolic blood pressure; all n >10 000), and (3) the COVID-19 Host Genetics Initiative (n = 5773 hospitalized and 15 497 nonhospitalized case participants with COVID-19). Data analysis was performed in July 2022.
Genetically determined concentrations of 235 circulating proteins assayed with a multiplex biomarker panel from the ORIGIN trial for the initial analysis.
Hospitalization status of individuals from the COVID-19 Host Genetics Initiative with a positive COVID-19 test result.
Among 235 biomarkers tested in samples totaling 22 101 individuals, MR analysis showed that higher kidney injury molecule-1 (KIM-1) levels reduced the likelihood of COVID-19 hospitalization (odds ratio [OR] per SD increase in KIM-1 levels, 0.86 [95% CI, 0.79-0.93]). A meta-analysis validated the protective association with no observed directional pleiotropy (OR per SD increase in KIM-1 levels, 0.91 [95% CI, 0.88-0.95]). Of the cardiometabolic risk factors studied, only BMI was associated with KIM-1 levels (0.17 SD increase in biomarker level per 1 kg/m2 [95% CI, 0.08-0.26]) and COVID-19 hospitalization (OR per 1-SD biomarker level, 1.33 [95% CI, 1.18-1.50]). Multivariable MR analysis also revealed that KIM-1 partially mitigated the association of BMI with COVID-19 hospitalization, reducing it by 10 percentage points (OR adjusted for KIM-1 level per 1 kg/m2, 1.23 [95% CI, 1.06-1.43]).
In this genetic association study, KIM-1 was identified as a potential mitigator of COVID-19 severity, possibly attenuating the increased risk of COVID-19 hospitalization among individuals with high BMI. Further studies are required to better understand the underlying biological mechanisms.
心脏代谢参数是 COVID-19 严重程度的既定危险因素。确定 COVID-19 严重程度的因果或保护生物标志物，可能有助于开发新的治疗方法。
确定促进或降低 COVID-19 严重程度的蛋白质生物标志物，以及介导心脏代谢危险因素与 COVID-19 严重程度之间关联的生物标志物。
设计、地点和参与者：这是一项使用两样本孟德尔随机化（MR）的遗传关联研究，于 2022 年进行，旨在调查心脏代谢危险因素、循环生物标志物与 COVID-19 住院之间的关联。MR 的输入包括来自 4147 名患有糖代谢紊乱和心血管危险因素的参与者的遗传和蛋白质组数据，这些数据是通过 Outcome Reduction With Initial Glargine Intervention (ORIGIN) 试验收集的。全基因组关联研究汇总统计数据来自（1）另外 3 项独立的血浆蛋白质组研究，（2）包括体重指数（BMI）、2 型糖尿病、1 型糖尿病和收缩压在内的特定心脏代谢危险因素的遗传联盟（所有 n>10000），以及（3）COVID-19 宿主遗传学倡议（n=5773 名 COVID-19 住院和 15497 名非住院病例参与者）。数据分析于 2022 年 7 月进行。
使用来自 ORIGIN 试验的多重生物标志物分析面板，对 235 种循环蛋白的遗传决定浓度进行初始分析。
COVID-19 宿主遗传学倡议中 COVID-19 检测呈阳性的个体的住院状况。
在总共 22101 名个体的样本中，对 235 种生物标志物进行了测试，MR 分析表明，较高的肾损伤分子-1（KIM-1）水平降低了 COVID-19 住院的可能性（KIM-1 水平每增加 1 个标准差的比值比[OR]，0.86[95%CI，0.79-0.93]）。Meta 分析验证了这种保护关联，未观察到方向上的偏倚（KIM-1 水平每增加 1 个标准差的 OR，0.91[95%CI，0.88-0.95]）。在所研究的心脏代谢危险因素中，只有 BMI 与 KIM-1 水平相关（生物标志物水平每增加 1kg/m2，增加 0.17 个标准差[95%CI，0.08-0.26]）和 COVID-19 住院（每增加 1 个 SD 生物标志物水平的 OR，1.33[95%CI，1.18-1.50]）。多变量 MR 分析还表明，KIM-1 部分减轻了 BMI 与 COVID-19 住院之间的关联，使关联降低了 10 个百分点（调整 KIM-1 水平后，每增加 1kg/m2的 BMI，OR 为 1.23[95%CI，1.06-1.43]）。
在这项遗传关联研究中，KIM-1 被确定为 COVID-19 严重程度的潜在缓解因素，可能减轻 BMI 较高的个体 COVID-19 住院的风险增加。需要进一步的研究来更好地了解潜在的生物学机制。
