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

BackgroundBlood levels of iron and copper, even within their normal ranges, have been associated with a wide range of clinical outcomes. Available epidemiological evidence on blood iron and copper association with potential clinical effects, such as lipid metabolism disorder, is inconsistent and scarce. This study aims to examine and disentangle the causal clinical effects of iron and copper. MethodsGenetic instruments for the blood level 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 multiple phenotypes in 310,999 unrelated individuals of European ancestry from the UK Biobank. All signals passing stringent correction for multiple testing were followed by Mendelian randomization (MR) analyses, with replication in independent data sources where possible. ResultsGenetically predicted higher blood levels of iron and copper are both associated with lower risks of iron deficiency anemia (OR = 0.75, 95% CI:0.67-0.85, p =1.90x10-06 for iron; OR= 0.88, 95% CI: 0.78-0.98, p =0.03 for cooper), lipid metabolism disorders and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI:0.85-0.96, p =6.44x10-04 for iron; OR = 0.92, 95% CI:0.87-0.98, p = 5.51x10-03 for cooper) and hypercholesterolemia (OR = 0.90, 95% CI:0.84-0.95, p = 5.34x10-04 for iron; OR = 0.93, 95% CI:0.89-0.99, p =0.02 for cooper). 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 pleiotropy and stability of the estimation, and consistent evidence across different approaches was obtained. Additionally, unique clinical effects of each blood mineral were also pinpointed, and sex-stratified MR analysis further revealed the clinical implication of iron and copper exhibits some degree of sex differences. ConclusionsOur comparative PheWAS-MR study of iron and copper comprehensively characterized their shared and unique clinical effects, highlighting their novel causal roles in hyperlipidemia and hypercholesterolemia. Given the modifiable and variable nature of blood mineral status, these findings warrant further investigation.