Fusaro Maria, De Caterina Raffaele, Tripepi Giovanni
National Research Council (CNR), Institute of Clinical Physiology (IFC), Pisa, Italy.
Department of Medicine, University of Padua, Padua, Italy.
Curr Vasc Pharmacol. 2025;23(1):67-72. doi: 10.2174/0115701611331890241007112502.
Mendelian Randomization (MR) studies have emerged as a powerful tool for investigating causal relationships between modifiable risk factors and clinical outcomes, using genetic variants as instrumental variables. In the context of vitamin D research, MR is a promising approach to elucidate the effects of vitamin D on various health outcomes, including adverse cardiovascular events. However, the validity of MR analyses relies heavily on the strength of the genetic associations found. "Weak instrument bias", arising from instruments with low explanatory power for the exposure of interest, can lead to biased estimates and compromise causal inference. We have, herein, briefly reviewed the challenges posed by weak instrument bias in a large MR study on vitamin D [25(OH)D] and stroke, exploring implications for the study's validity and reliability of findings. We have then added an original meta-analysis stratified by 25(OH)D levels. By using aggregated data from a recent MR study, an original meta-analysis stratified by population mean levels of 25(OH)D has indicated that interventions based on vitamin D supplementations in population mean levels ranging from 50 to 70 nmol/L are likely to translate into a 13% reduction of stroke risk (pooled odds ratio=0.873, 95% CI: 0.764-0.997, p-value=0.04). MR studies are a valuable approach for discerning causal relationships between exposures, such as vitamin D, and health outcomes. However, the effectiveness of MR analyses depends on the robustness of the genetic instruments employed. By recognizing and addressing weak instrument bias in MR studies of vitamin D, researchers can enhance the credibility and utility of causal inference in understanding the health effects of this essential nutrient. A metaanalysis stratified by population mean levels of 25(OH)D has revealed the potential benefits of targeted interventions with vitamin D supplementations for stroke.
孟德尔随机化（MR）研究已成为一种强大的工具，用于利用基因变异作为工具变量来研究可改变的风险因素与临床结局之间的因果关系。在维生素D研究的背景下，MR是阐明维生素D对包括不良心血管事件在内的各种健康结局影响的一种有前景的方法。然而，MR分析的有效性在很大程度上依赖于所发现的基因关联的强度。由对感兴趣的暴露解释力低的工具变量引起的“弱工具变量偏差”，可能导致有偏差的估计并损害因果推断。在此，我们简要回顾了在一项关于维生素D[25（OH）D]与中风的大型MR研究中弱工具变量偏差所带来的挑战，探讨其对研究有效性和结果可靠性的影响。然后我们增加了一项按25（OH）D水平分层的原创荟萃分析。通过使用来自最近一项MR研究的汇总数据，一项按人群平均25（OH）D水平分层的原创荟萃分析表明，在人群平均水平为50至70 nmol/L的情况下基于维生素D补充的干预措施可能会使中风风险降低13%（合并比值比=0.873，95%置信区间：0.764-0.997，p值=0.04）。MR研究是识别诸如维生素D等暴露与健康结局之间因果关系的一种有价值的方法。然而，MR分析的有效性取决于所采用基因工具变量的稳健性。通过认识并解决维生素D的MR研究中的弱工具变量偏差，研究人员可以提高在理解这种必需营养素对健康影响方面因果推断的可信度和实用性。一项按人群平均25（OH）D水平分层的荟萃分析揭示了针对中风进行维生素D补充的靶向干预措施的潜在益处。
