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首页> 美国卫生研究院文献>Nutrients >The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study
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The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

机译：血氧铜和铜对脂质代谢疾病的因果影响：来自菲尼斯 - 广泛的孟德尔随机化研究的证据

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Blood levels of iron and copper, even within their normal ranges, have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. This study aims to examine the causal clinical effects of blood iron and copper with Mendelian randomization (MR) analyses. Genetic instruments for the blood levels 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 a wide range of phenotypes in 310,999 unrelated individuals of European ancestry from the UK Biobank. All signals passing stringent correction for multiple testing were followed by MR analyses, with replication in independent data sources where possible. We found that genetically predicted higher blood levels of iron and copper are both associated with lower risks of iron deficiency anemia (odds ratio (OR) = 0.75, 95% confidence interval (CI): 0.67–0.85, p = 1.90 × 10−6 for iron; OR = 0.88, 95% CI: 0.78–0.98, p = 0.032 for copper), lipid metabolism disorders, and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI: 0.85–0.96, p = 6.44 × 10−4; OR = 0.92, 95% CI: 0.87–0.98, p = 5.51 × 10−3) and hypercholesterolemia (OR = 0.90, 95% CI: 0.84–0.95, p = 5.34 × 10−4; OR = 0.93, 95% CI: 0.89–0.99, p = 0.022). 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 presence of pleiotropy and the robustness of causal estimates. Regardless of the approaches, consistent evidence was obtained. Moreover, the unique clinical effects of each blood mineral were identified. Notably, genetically predicated higher blood iron is associated with an enhanced risk of varicose veins (OR = 1.28, 95% CI: 1.15–1.42, p = 4.34 × 10−6), while blood copper is positively associated with the risk of osteoarthrosis (OR = 1.07, 95% CI: 1.02–1.13, p = 0.010). Sex-stratified MR analysis further revealed some degree of sex differences in their clinical effects. Our comparative PheWAS-MR study of iron and copper comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in hyperlipidemia and hypercholesterolemia. Given the modifiable nature of blood mineral status and the potential for clinical intervention, these findings warrant further investigation.
机译：血液水平的铁和铜，甚至在正常范围内，也与各种临床结果有关。这些协会的可用流行病学证据往往不一致，遭受混淆和逆转的因果关系。本研究旨在探讨血铁和铜与孟德利安随机化（MR）分析的因果临床疗效。用于血液水平的遗传仪器从现有的基因组 - 宽协会研究中愈合。基于这些遗传仪器之间的苯胺 - 范围的协会研究（PHEPAS）和来自英国Biobank的310,999个无关的个人的广泛表型，鉴定了候选临床结果。所有信号传递严格校正对于多个测试，然后是MR分析，在可能的情况下，在独立数据源中复制。我们发现遗传预测的较高血液水平的铁和铜均与缺铁性贫血的较低风险相关（差距比（或）= 0.75，95％置信区间（CI）：0.67-0.85，P = 1.90×10-6对于铁;或= 0.88,95％CI：0.78-0.98，P = 0.032，铜），脂质代谢紊乱及其两个子类别，高脂血症（或= 0.90,95％CI：0.85-0.96，P = 6.44×10 -4;或= 0.92,95％CI：0.87-0.98，P = 5.51×10-3）和高胆固醇血症（或= 0.90,95％CI：0.84-0.95，P = 5.34×10-4;或= 0.93， 95％CI：0.89-0.99，P = 0.022）。始终如一地，它们也与总胆固醇和低密度脂蛋白胆固醇的较低血液水平相关。应用多种敏感性试验以评估肺炎的存在和因果估计的鲁棒性。无论方法如何，都获得了一致的证据。此外，确定了每种血液矿物的独特临床疗效。值得注意的是，遗传越主的较高血氧含有增强的静脉静脉的风险（或= 1.28,95％CI：1.15-1.42，P = 4.34×10-6），而血铜与骨关节症的风险呈正相关（或= 1.07,95％CI：1.02-1.13，P = 0.010）。性分析的MR分析进一步揭示了他们的临床影响程度的性别差异。我们的比较PPEMAS-MR研究钢铁和铜全面地表征了它们的共同和独特的临床疗效，突出了其在高脂血症和高胆固醇血症中的潜在因果作用。鉴于血液矿产地位的可修改性质和临床干预潜力，这些调查结果需要进一步调查。

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