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Open AccessArticle

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

1
Department of Genetics, University of Georgia, Athens, GA 30602, USA
2
School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
3
College of Life Sciences, Wuhan University, Wuhan 430072, China
4
Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA
5
Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108, USA
6
Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA
*
Author to whom correspondence should be addressed.
Nutrients 2020, 12(10), 3174; https://doi.org/10.3390/nu12103174
Received: 14 September 2020 / Revised: 13 October 2020 / Accepted: 14 October 2020 / Published: 17 October 2020
(This article belongs to the Section Nutrigenetics and Nutrigenomics)
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. View Full-Text
Keywords: iron; copper; phenome-wide association study; Mendelian randomization; lipid metabolism disorder iron; copper; phenome-wide association study; Mendelian randomization; lipid metabolism disorder
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Zhou, J.; Liu, C.; Francis, M.; Sun, Y.; Ryu, M.-S.; Grider, A.; Ye, K. The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study. Nutrients 2020, 12, 3174.

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