Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada.
PLoS Med. 2021 Jun 1;18(6):e1003605. doi: 10.1371/journal.pmed.1003605. eCollection 2021 Jun.
Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity.
Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency.
In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.
基于体外、观察性和生态学研究，维生素 D 水平（反映为 25-羟维生素 D（25OHD）测量值）升高被提出可预防 COVID-19。然而，维生素 D 水平与许多混杂变量相关，因此迄今为止描述的关联可能不是因果关系。维生素 D 孟德尔随机化（MR）研究提供的结果与大型维生素 D 随机试验一致。在这里，我们使用两样本 MR 来评估支持循环 25OHD 水平对 COVID-19 易感性和严重程度的因果效应的证据。
在一项包含 443734 名欧洲血统参与者（包括英国生物库中的 401460 名参与者）的全基因组关联研究（GWAS）中，与 25OHD 水平强烈相关的遗传变异被用作工具变量。COVID-19 宿主遗传学倡议的 COVID-19 易感性、住院和严重疾病的 GWAS 被用作结局 GWAS。这些 GWAS 包括来自 11 个国家的多达 14134 名 COVID-19 患者和多达 1284876 名无 COVID-19 的患者。SARS-CoV-2 阳性通过实验室检测或病历审查确定。没有 COVID-19 的人群对照也被纳入所有结局（包括住院和严重疾病）的对照组。在可能的情况下，分析仅限于欧洲血统的个体。使用逆加权 MR，25OHD 水平每增加一个标准差（对数标度）与 COVID-19 易感性没有显著关联（比值比 [OR] = 0.95；95%CI 0.84,1.08;p = 0.44），与住院（OR = 1.09；95%CI：0.89,1.33;p = 0.41）和严重疾病（OR = 0.97；95%CI：0.77,1.22;p = 0.77）也没有关联。我们使用了另外 6 种荟萃分析方法，并在去除水平性 pleiotropy 风险的变异后进行了敏感性分析，得到了类似的结果。这些结果可能受到某些分析中弱工具偏倚的限制。此外，我们的结果不适用于维生素 D 缺乏症患者。
在这项两样本 MR 研究中，我们没有观察到 25OHD 水平与 COVID-19 易感性、严重程度或住院之间存在关联的证据。因此，维生素 D 补充作为预防 COVID-19 结局恶化的一种手段，没有遗传证据支持。对于 COVID-19 随机对照试验，应给予其他治疗或预防方法更高的优先级。
