Background: Blood levels of iron and copper, even within their normal ranges, have been associated with a wide range of clinical outcomes. Available epidemiological evidence on blood iron and copper association with potential clinical effects, such as lipid metabolism disorder, is inconsistent and scarce. This study aims to examine and disentangle the causal clinical effects of iron and copper. Methods: Genetic instruments for the blood level of iron and copper were curated from existing genome-wide association studies. Candidate clinical outcomes were identified based on a phenome-wide association study (PheWAS) between these genetic instruments and multiple phenotypes in 310,999 unrelated individuals of European ancestry from the UK Biobank. All signals passing stringent correction for multiple testing were followed by Mendelian randomization (MR) analyses, with replication in independent data sources where possible. Results: Genetically predicted higher blood levels of iron and copper are both associated with lower risks of iron deficiency anemia (OR = 0.75, 95% CI:0.67-0.85, p =1.90e-06 for iron; OR = 0.88, 95% CI: 0.78-0.98, p =0.03 for cooper), lipid metabolism disorders and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI:0.85-0.96, p =6.44e-04 for iron; OR = 0.92, 95% CI:0.87-0.98, p = 5.51e-03 for cooper) and hypercholesterolemia (OR = 0.90, 95% CI:0.84-0.95, p = 5.34e-04 for iron; OR = 0.93, 95% CI:0.89-0.99, p =0.02 for cooper). Consistently, they are also associated with lower blood levels of total cholesterol and low-density lipoprotein cholesterol. Multiple sensitivity tests were applied to assess the pleiotropy and stability of the estimation, and consistent evidence across different approaches was obtained. Additionally, the unique clinical effects of each blood mineral were also pinpointed, and sex-stratified MR analysis further revealed the clinical implication of iron and copper exhibits some degree of sex differences. Conclusions: Our comparative PheWAS-MR study of iron and copper comprehensively characterized their shared and unique clinical effects, highlighting their novel causal roles in hyperlipidemia and hypercholesterolemia. Given the modifiable and variable nature of blood mineral status, these findings warrant further investigation.

中文翻译：

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血铁和铜对脂质代谢疾病的因果关系：基于全现象的孟德尔随机研究的证据

背景：铁和铜的血液水平，即使在其正常范围内，也与广泛的临床结果有关。关于铁和铜与血脂代谢异常等潜在临床效应的相关流行病学证据并不一致且稀缺。这项研究旨在检查和弄清铁和铜的因果关系。方法：从现有的全基因组关联研究中选择了铁和铜的血液水平遗传仪器。根据英国生物库中310,999名欧洲血统的不相关个体的这些遗传工具与多种表型之间的全表型关联研究（PheWAS），确定了候选临床结果。对所有通过严格校正的信号进行多次测试，然后进行孟德尔随机（MR）分析，并在可能的情况下在独立的数据源中进行复制。结果：从基因上预测铁和铜的血药水平较高与铁缺乏性贫血的风险较低相关（OR = 0.75，95％CI：0.67-0.85，p = 1.90e-06； OR = 0.88，95％CI ：0.78-0.98，库珀p = 0.03），脂质代谢紊乱及其两个子类别，高脂血症（铁= OR = 0.90，95％CI：0.85-0.96，p = 6.44e-04; OR = 0.92，95％CI ：0.87-0.98，铜= p = 5.51e-03）和高胆固醇血症（铁= OR = 0.90，95％CI：0.84-0.95，p = 5.34e-04； OR = 0.93，95％CI：0.89-0.99，对于库珀，p ＝ 0.02。一致地，它们还与总胆固醇和低密度脂蛋白胆固醇的较低血液水平有关。应用多重敏感性测试评估估计的多效性和稳定性，并获得了不同方法的一致证据。此外，还明确了每种血液矿物质的独特临床作用，并且按性别分层的MR分析进一步揭示了铁和铜的临床意义表现出一定程度的性别差异。结论：我们对铁和铜的比较性PheWAS-MR研究全面表征了它们共同和独特的临床作用，突显了它们在高脂血症和高胆固醇血症中的新型因果作用。考虑到血液矿物质状态的可变性和可变性，这些发现值得进一步研究。此外，还明确了每种血液矿物质的独特临床作用，并且按性别分层的MR分析进一步揭示了铁和铜的临床意义表现出一定程度的性别差异。结论：我们对铁和铜的比较性PheWAS-MR研究全面表征了它们共同和独特的临床作用，突显了它们在高脂血症和高胆固醇血症中的新型因果作用。考虑到血液矿物质状态的可变性和可变性，这些发现值得进一步研究。此外，还明确了每种血液矿物质的独特临床作用，并且按性别分层的MR分析进一步揭示了铁和铜的临床意义表现出一定程度的性别差异。结论：我们对铁和铜的比较性PheWAS-MR研究全面表征了它们共同和独特的临床作用，突显了它们在高脂血症和高胆固醇血症中的新型因果作用。考虑到血液矿物质状态的可变性和可变性，这些发现值得进一步研究。我们对铁和铜进行的PheWAS-MR比较研究全面表征了它们共享和独特的临床效果，突出了它们在高脂血症和高胆固醇血症中的新型因果作用。考虑到血液矿物质状态的可变性和可变性，这些发现值得进一步研究。我们对铁和铜进行的PheWAS-MR比较研究全面表征了它们共享和独特的临床效果，突出了它们在高脂血症和高胆固醇血症中的新型因果作用。考虑到血液矿物质状态的可变性和可变性，这些发现值得进一步研究。