The causal effects of blood iron and copper on lipid metabolism diseases: Evidence from phenome-wide mendelian randomization study

Jingqi Zhou, Chang Liu, Michael Francis, Yitang Sun, Moon Suhn Ryu, Arthur Grider, Kaixiong Ye

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number3174
Pages (from-to)1-17
Number of pages17
JournalNutrients
Volume12
Issue number10
DOIs
StatePublished - Oct 2020

Bibliographical note

Funding Information:
JZ is supported by Shanghai Jiao Tong University (YG2017QN69, KJ3-0221-18-4403). AG is supported by the United States Department of Agriculture, National Institute of Food and Agriculture Hatch Funds. MSR is supported by the Allen Foundation Inc., the United States Department of Agriculture, and National Institute of Food and Agriculture Hatch Funds. KY is supported by the University of Georgia Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study was conducted using the UK Biobank Resource under project 48818. The authors would like to thank all UK Biobank participants. We also want to thank other members of the Ye lab for stimulating discussions.

Funding Information:
Funding: JZ is supported by Shanghai Jiao Tong University (YG2017QN69, KJ3-0221-18-4403). AG is supported by the United States Department of Agriculture, National Institute of Food and Agriculture Hatch Funds. MSR is supported by the Allen Foundation Inc., the United States Department of Agriculture, and National Institute of Food and Agriculture Hatch Funds. KY is supported by the University of Georgia Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords

  • Copper
  • Iron
  • Lipid metabolism disorder
  • Mendelian randomization
  • Phenome-wide association study

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