Associations between genetically predicted iron status and cardiovascular disease risk: A Mendelian randomization study.
Associations between genetically predicted iron status and cardiovascular disease risk: A Mendelian randomization study.
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基因预测铁状态与心血管疾病风险之间的关联：孟德尔随机研究。
DOI：
10.1101/2024.02.05.24302373
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Pressman,EvaK
中科院分区：
文献类型：
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作者：
Barad,Alexa;Clark,AndrewG;O'Brien,KimberlyO;Pressman,EvaK
背景孟德尔随机化（MR）研究提示铁营养状况对心血管疾病（CVD）风险具有因果效应，但尚不清楚这些关联是否被工具变量对CVD风险因素的多效性效应所混淆。方法和结果铁生物标志物工具变量（总铁结合力[n=208 422]、转铁蛋白饱和度[n=198 516]、血清铁[n=236 612]、铁蛋白[n=257 953]）选自欧洲全基因组关联研究Meta分析。我们对MEGASTROKE（n=440 328）和CARDIOGRAMplusC 4 D（冠状动脉疾病全基因组复制和Meta‐分析加上冠状动脉疾病遗传学）（n=183 305）的CVD结局（全因缺血性卒中、心源性缺血性卒中、大动脉缺血性卒中、小血管缺血性卒中和冠心病）进行了每种铁特征的双样本单变量MR。然后，我们对来自独立欧洲样本的7个CVD危险因素进行了多变量MR调节，以评估其对所观察到的铁-CVD相关性的潜在混杂或介导作用。通过单变量MR分析，我们发现较高的遗传预测铁状态与心源性栓塞性缺血性卒中的较高风险相关（转铁蛋白饱和度：比值比，1.17 [95% CI，1.03-1.33];血清铁：比值比，1.21 [95% CI，1.02-1.44];总铁结合能力：比值比，0.81 [95%CI，0.69-0.94]）。校正CVD危险因素后，铁营养状况对心源性缺血性卒中危险的不利影响未受影响（均P <0.05）。此外，我们发现舒张压介导了铁状态对心源性栓塞性缺血性卒中发病率总影响的7.1%至8.8%。单变量MR最初提示铁状态对大动脉卒中和冠心病具有保护作用，但使用多变量MR控制CVD因素显著降低了这些相关性（均P>0.05）.结论较高的铁状态与心源性栓塞性缺血性卒中的风险增加相关，与CVD风险因素无关，这种作用部分由舒张压介导。这些发现支持铁状态作为心源性栓塞性缺血性卒中的一个可改变的危险因素的作用。
BackgroundMendelian randomization (MR) studies suggest a causal effect of iron status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables on CVD risk factors. We aimed to investigate the effect of iron status on CVD risk controlling for CVD risk factors.Methods and ResultsIron biomarker instrumental variables (total iron‐binding capacity [n=208 422], transferrin saturation [n=198 516], serum iron [n=236 612], ferritin [n=257 953]) were selected from a European genome‐wide association study meta‐analysis. We performed 2‐sample univariate MR of each iron trait on CVD outcomes (all‐cause ischemic stroke, cardioembolic ischemic stroke, large‐artery ischemic stroke, small‐vessel ischemic stroke, and coronary heart disease) from MEGASTROKE (n=440 328) and CARDIoGRAMplusC4D (Coronary Artery Disease Genome Wide Replication and Meta‐Analysis Plus the Coronary Artery Disease Genetics) (n=183 305). We then implemented multivariate MR conditioning on 7 CVD risk factors from independent European samples to evaluate their potential confounding or mediating effects on the observed iron–CVD associations. With univariate MR analyses, we found higher genetically predicted iron status to be associated with a greater risk of cardioembolic ischemic stroke (transferrin saturation: odds ratio, 1.17 [95% CI, 1.03–1.33]; serum iron: odds ratio, 1.21 [95% CI, 1.02–1.44]; total iron‐binding capacity: odds ratio, 0.81 [95% CI, 0.69–0.94]). The detrimental effects of iron status on cardioembolic ischemic stroke risk remained unaffected when adjusting for CVD risk factors (allP<0.05). Additionally, we found diastolic blood pressure to mediate between 7.1 and 8.8% of the total effect of iron status on cardioembolic ischemic stroke incidence. Univariate MR initially suggested a protective effect of iron status on large‐artery stroke and coronary heart disease, but controlling for CVD factors using multivariate MR substantially diminished these associations (allP>0.05).ConclusionsHigher iron status was associated with a greater risk of cardioembolic ischemic stroke independent of CVD risk factors, and this effect was partly mediated by diastolic blood pressure. These findings support a role of iron status as a modifiable risk factor for cardioembolic ischemic stroke.