The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study
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...
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MDPI AG
2020-10-01
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| Series: | Nutrients |
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| Online Access: | https://www.mdpi.com/2072-6643/12/10/3174 |
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| author | Jingqi Zhou Chang Liu Michael Francis Yitang Sun Moon-Suhn Ryu Arthur Grider Kaixiong Ye |
| author_facet | Jingqi Zhou Chang Liu Michael Francis Yitang Sun Moon-Suhn Ryu Arthur Grider Kaixiong Ye |
| author_sort | Jingqi Zhou |
| collection | DOAJ |
| description | 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, <i>p</i> = 1.90 × 10<sup>−6</sup> for iron; OR = 0.88, 95% CI: 0.78–0.98, <i>p</i> = 0.032 for copper), lipid metabolism disorders, and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI: 0.85–0.96, <i>p</i> = 6.44 × 10<sup>−4</sup>; OR = 0.92, 95% CI: 0.87–0.98, <i>p</i> = 5.51 × 10<sup>−3</sup>) and hypercholesterolemia (OR = 0.90, 95% CI: 0.84–0.95, <i>p</i> = 5.34 × 10<sup>−4</sup>; OR = 0.93, 95% CI: 0.89–0.99, <i>p</i> = 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, <i>p</i> = 4.34 × 10<sup>−6</sup>), while blood copper is positively associated with the risk of osteoarthrosis (OR = 1.07, 95% CI: 1.02–1.13, <i>p</i> = 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. |
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| spelling | doaj.art-b54feda470c94294bcbc9d8c618950462023-11-20T17:28:20ZengMDPI AGNutrients2072-66432020-10-011210317410.3390/nu12103174The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization StudyJingqi Zhou0Chang Liu1Michael Francis2Yitang Sun3Moon-Suhn Ryu4Arthur Grider5Kaixiong Ye6Department of Genetics, University of Georgia, Athens, GA 30602, USADepartment of Genetics, University of Georgia, Athens, GA 30602, USAInstitute of Bioinformatics, University of Georgia, Athens, GA 30602, USADepartment of Genetics, University of Georgia, Athens, GA 30602, USADepartment of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108, USADepartment of Foods and Nutrition, University of Georgia, Athens, GA 30602, USADepartment of Genetics, University of Georgia, Athens, GA 30602, USABlood 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, <i>p</i> = 1.90 × 10<sup>−6</sup> for iron; OR = 0.88, 95% CI: 0.78–0.98, <i>p</i> = 0.032 for copper), lipid metabolism disorders, and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI: 0.85–0.96, <i>p</i> = 6.44 × 10<sup>−4</sup>; OR = 0.92, 95% CI: 0.87–0.98, <i>p</i> = 5.51 × 10<sup>−3</sup>) and hypercholesterolemia (OR = 0.90, 95% CI: 0.84–0.95, <i>p</i> = 5.34 × 10<sup>−4</sup>; OR = 0.93, 95% CI: 0.89–0.99, <i>p</i> = 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, <i>p</i> = 4.34 × 10<sup>−6</sup>), while blood copper is positively associated with the risk of osteoarthrosis (OR = 1.07, 95% CI: 1.02–1.13, <i>p</i> = 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.https://www.mdpi.com/2072-6643/12/10/3174ironcopperphenome-wide association studyMendelian randomizationlipid metabolism disorder |
| spellingShingle | Jingqi Zhou Chang Liu Michael Francis Yitang Sun Moon-Suhn Ryu Arthur Grider Kaixiong Ye The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study Nutrients iron copper phenome-wide association study Mendelian randomization lipid metabolism disorder |
| title | The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study |
| title_full | The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study |
| title_fullStr | The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study |
| title_full_unstemmed | The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study |
| title_short | The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study |
| title_sort | causal effects of blood iron and copper on lipid metabolism diseases evidence from phenome wide mendelian randomization study |
| topic | iron copper phenome-wide association study Mendelian randomization lipid metabolism disorder |
| url | https://www.mdpi.com/2072-6643/12/10/3174 |
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