{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:59:24Z","timestamp":1787029164388,"version":"build-2736575974"},"reference-count":63,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T00:00:00Z","timestamp":1602892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000199","name":"United States Department of Agriculture","doi-asserted-by":"publisher","award":["MIN-18-118"],"award-info":[{"award-number":["MIN-18-118"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008796","name":"Allen Foundation","doi-asserted-by":"publisher","award":["xxx"],"award-info":[{"award-number":["xxx"]}],"id":[{"id":"10.13039\/100008796","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>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\u20130.85, p = 1.90 \u00d7 10\u22126 for iron; OR = 0.88, 95% CI: 0.78\u20130.98, p = 0.032 for copper), lipid metabolism disorders, and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI: 0.85\u20130.96, p = 6.44 \u00d7 10\u22124; OR = 0.92, 95% CI: 0.87\u20130.98, p = 5.51 \u00d7 10\u22123) and hypercholesterolemia (OR = 0.90, 95% CI: 0.84\u20130.95, p = 5.34 \u00d7 10\u22124; OR = 0.93, 95% CI: 0.89\u20130.99, 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\u20131.42, p = 4.34 \u00d7 10\u22126), while blood copper is positively associated with the risk of osteoarthrosis (OR = 1.07, 95% CI: 1.02\u20131.13, 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.<\/jats:p>","DOI":"10.3390\/nu12103174","type":"journal-article","created":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T05:45:51Z","timestamp":1602913551000},"page":"3174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9961-199X","authenticated-orcid":false,"given":"Jingqi","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Genetics, University of Georgia, Athens, GA 30602, USA"},{"name":"School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Georgia, Athens, GA 30602, USA"},{"name":"College of Life Sciences, Wuhan University, Wuhan 430072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1320-7161","authenticated-orcid":false,"given":"Michael","family":"Francis","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6564-8815","authenticated-orcid":false,"given":"Yitang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9533-9263","authenticated-orcid":false,"given":"Moon-Suhn","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Grider","sequence":"additional","affiliation":[{"name":"Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4658-7292","authenticated-orcid":false,"given":"Kaixiong","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Georgia, Athens, GA 30602, USA"},{"name":"Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13528","DOI":"10.1021\/acs.inorgchem.9b01029","article-title":"Emerging Opportunities To Manipulate Metal Trafficking for Therapeutic Benefit","volume":"58","author":"Hunsaker","year":"2019","journal-title":"Inorg. 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