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

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.

Causal Effects of Genetically Predicted Iron Status on Sepsis: A Two-Sample Bidirectional Mendelian Randomization Study

“…In contrast with the previous MR studies of iron status (29,30), the number of IVs in our study was more conservative. Previous research confirmed that rs1800562 and rs855791 were the primary determinants of variation associated with HFE and TMPRSS6 in serum iron status (31,32).…”

“…Previous research confirmed that rs1800562 and rs855791 were the primary determinants of variation associated with HFE and TMPRSS6 in serum iron status (31,32). Searching the GWAS Catalog and PubMed, we found that rs1800562 and rs1495741 were associated with low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), or triglyceride (30,33), but there is currently no evidence to confirm the above lipid metabolism biomarkers as risk factors for sepsis susceptibility (34,35).…”

Blood copper and risk of cardiometabolic diseases: a Mendelian randomization study

“…In this regard, a previous MR found inverse associations between copper levels and different disorders of lipid metabolism (hyperlipidemia, hypercholesterolemia) and lipid biomarkers (low-density lipoprotein (LDL), total cholesterol) using instruments from Evans et al . ( 7 ) and outcome data from the Global Lipids Genetics Consortium ( 13 ). Similar to our results, the latter associations of copper and lipid biomarkers could not be observed when using data from the UK Biobank ( 13 ).…”

“…( 7 ) and outcome data from the Global Lipids Genetics Consortium ( 13 ). Similar to our results, the latter associations of copper and lipid biomarkers could not be observed when using data from the UK Biobank ( 13 ). Another important risk factor for CAD is elevated blood pressure/hypertension.…”

A novel hydrophilic fluorescent probe for Cu2+ detection and imaging in HeLa cells

“…Even when present in trace amounts, copper, a mineral micronutrient, has been associated with a wide range of cellular processes; it plays a vital role as a coenzyme in free-radical scavenging and is involved with mitochondrial respiration, collagen and elastin synthesis, iron metabolism, erythropoiesis, and leukopoiesis. [1][2][3][4][5][6] The average concentration of copper in human blood is 100-150 mg dL À1 (ref. 46) and the recommended intake of copper for humans is 0.9 mg each day.…”