生物与医学2021nutrition.bmj.com
维生素D与欧洲裔人群新冠严重程度无关
Vitamin D uncorrelated with Covid severity in those of European descent
入门 · 约 45 分钟读完前置知识：流行病学基础、孟德尔随机化概念、全基因组关联研究(GWAS)基础
导读
这篇论文用孟德尔随机化方法，通过遗传变异预测的维生素D水平，研究维生素D与新冠严重程度之间的因果关系，结论是在欧洲裔人群中两者无显著关联。作者指出这可部分替代随机对照试验，但仍需后续试验验证。
HN 关注点：疫情期间维生素D能否预防或减轻新冠是热门话题，此前多项观察性研究结论不一，这项研究用遗传学方法挑战了补充维生素D的说法，引发方法论讨论。
HN 评论精选
这几条评论里：质疑 2 补充 2
质疑提醒这是间接推断的回顾性研究，不能视为定论
注意这项研究既不是安慰剂对照试验，甚至也不是基于实际维生素D水平的数据，而是使用工具变量的回顾性分析。我不是说它的结论错了，只是在我看来它并非决定性的研究。
WoodenChair查看英文原文
Note that this study was not a placebo controlled trial, and it was not even based on data about actual vitamin D levels. Instead, it was retrospective analysis using instrumental variables. I'm not saying its conclusions are wrong, I'm just saying that IMHO it's not a definitive study. Quoting the study: "Although we will need well-powered and carefully executed randomised trials and a subsequent meta-analysis of the different studies to provide an accurate estimate of the effect of vitamin D on COVID-19 prevention and severity, we can anticipate the results of such studies by comparing individuals who are genetically predisposed to lower vitamin D levels with those who are not, based on the Mendelian randomisation (MR) paradigm. In a randomised controlled trial, we would minimise the effect of confounding factors by randomly assigning participants to a treatment group receiving vitamin D supplements or to a control group receiving a placebo and thus estimate the true effect of the intervention. In the natural experiment of MR, genetic variants predisposing the individual to higher levels of vitamin D are assigned randomly at conception, based on the genetic polymorphisms of their parents, in relation to other possible confounding traits. As genetic polymorphisms remain constant throughout life and the individual does not change their vitamin D intake according to their genotype, the use of this information can provide indirect evidence of causality.18 Here, using data from genome-wide association (GWA) studies for vitamin D levels, vitamin D deficiency and COVID-19 incidence and severity, we test whether genetically increased vitamin D levels are associated with SARS-CoV-2 infection risk and COVID-19 severity."
质疑详细解释孟德尔随机化方法及其多效性假设的隐患
两点想法：1) 维生素D水平与身体活动量强相关，单纯观察性研究可能存在严重混杂，这或许能解释为何本研究与以往相关性研究结论不一致。2) 这是孟德尔随机化研究：由于无法随机分配维生素D水平，就假设遗传是随机的，若相关基因变异与新冠结局相关，就归因于维生素D。问题在于必须假设这些基因只通过维生素D起作用——而这些变异是通过全基因组关联筛查找出来的，很可能同时影响其他因素（多效性），使因果推断变得困难。
tgb查看英文原文
Two thoughts: 1) Vitamin D levles is strongly correlated with physical activity levels, so a mere observational study can be strongly confounded - which may be part of why this study finds disagrees with some the merely correlational studies in the past. 2) This study is a Mendelian Randomization study, where since you haven't randomized individuals' Vitamin D levels, you instead assume that their genetics are random (you either get a variant from your parent or not, by chance) and that genetics may cause Vitamin D levels. So if those genetic variants are correlated with COVID outcomes, then we say it's because of Vitamin D. Notice the problem? You need to assume that the genetics do not affect anything else except via Vitamin D. Now I think that's where this is very tricky: they're identified variants that predispose someone to high/low Vitamin D via a genome-wide study, i.e. just check everything for correlation with Vitamin D. The obvious problem is that correlation isn't causation so some or most or all of those variants will influence other factors too, and it becomes harder to say that Vitamin D is the reason COVID was severe or not. Ideally you have instead hand-picked variants with obvious known mechanisms as to how they affect Vitamin D metabolism, say. In lieu of that, you have to do various tests that try to spot how problematic this problem is. (Look for "pleiotropy" in the paper. Back-causation is the other problem you need to consider generally, but it's not really a concern here.) Personally I don't trust those tests further than I can throw them as they make some questionable assumptions. The main method this paper uses is MR-Egger, which (IIRC) assumes that the non-Vitamin D ways the variants affect the outcome are inconsistent across different variants. Like, this variant might act on Vitamin D and immune system but this other one acts on Vitamin D and your cardiac system so we don't expect the non-Vitamin D portion to be consistent. That seems highly questionable, even I would expect the typical state to not be that, where variants that affect Vitamin D are likely in pathways that also affect specific, consistent other attributes. The authors are aware of these difficulties. I can't assess whether they've succeeded in addressing them or not, but I believe the problem is extremely difficult and they have an up-hill battle.
补充提供相关研究汇总资源
这个网站收录了几乎所有关于维生素D与新冠的研究，评论前建议至少读一下这些摘要。
nradov查看英文原文
This site has an index of most of the studies on Vitamin D and COVID-19. Before commenting here I recommend at least reading those abstracts. https://vitamin-d-covid.shotwell.ca/
补充从纬度和演化适应角度解释欧洲裔人群的特殊性
我的理解是：欧洲相比其他国家纬度很高，冬季日照极少，欧洲人在演化上已经适应了长期少晒太阳的生活，我们本来就 predisposed 长时间待在室内。
lmilcin查看英文原文
My understanding is this. Europe is very far north compared to other countries. Half of people in Canada leave as close or closer to equator than Croatia, which in Europe is thought as hot climate. But that doesn't change the fact that for most of the Europe there is very little sunlight during winter and that europeans had to adapt to it by being more resistant to low amounts of sunlinght. See, we are already predisposed to sitting at home for extended periods of time.
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