Causal Effect of Genetically Determined Blood Copper Concentrations on Multiple Diseases: A Mendelian Randomization and Phenome-Wide Association Study

Exposures to copper have become a health concern.We aim to explore the broad clinical effects of blood copper concentrations.A total of 376,346 Caucasian subjects were enrolled.We performed a Mendelian randomization and phenome-wide association study(MR-PheWAS)to evaluate the causal association between copper and a wide range of outcomes in UK Biobank,and we constructed a protein-protein interaction network.We found association between blood copper concentrations and five diseases in the overall population and nine diseases in male.MR analysis implicated a causal role of blood copper in five diseases(overall population),including prostate cancer(OR=0.87,95%CI 0.77-0.98),malignant and unknown neoplasms of the brain and nervous system(OR=0.58,95%CI 0.38-0.89),and hypertension(OR=0.94,95%CI 0.90-0.98),essential hypertension(OR=0.94,95%CI 0.90-0.98)and cancer of brain and nervous system(OR=0.63,95%CI 0.41-0.98).For male,except for dysphagia being newly associated with blood copper(OR=1.39,95%CI 1.18-1.63),other MR results were consistent with the overall population.In addition,the PPI network showed possible relationship between blood copper and four outcomes,namely brain cancer,prostate cancer,hypertension,and dysphagia.Blood copper may have causal association with prostate cancer,malignant and unknown neoplasms of the brain and nervous system,hypertension,and dysphagia.Considering that copper is modifiable,exploring whether regulation of copper levels can be used to optimize health outcomes might have public health importance.

Causal Relationship Between Complement C3,C4,and Nonalcoholic Fatty Liver Disease:Bidirectional Mendelian Randomization Analysis

The complement system is activated during the development of nonalcoholic fatty liver disease(NAFLD).We aimed to evaluate the causal relationship between serum C3 and C4 levels and NAFLD.After exclusion criteria,a total of 1600 Chinese Han men from the Fangchenggang Area Male Health and Examination Survey cohort were enrolled in cross-sectional analysis,while 572 participants were included in the longitudinal analysis(average follow-up of 4 years).We performed a bidirectional Mendelian randomization(MR)analysis using two C3-related,eight C4-related and three NAFLD-related gene loci as instrumental variables to evaluate the causal associations between C3,C4,and NAFLD risk in cross-sectional analysis.Per SD increase in C3 levels was significantly associated with higher risk of NAFLD(OR=1.65,95%CI 1.40,1.94)in cross-sectional analysis while C4 was not(OR=1.04,95%CI 0.89,1.21).Longitudinal analysis produced similar results(HR_(C3)=1.20,95%CI 1.02,1.42;HR_(C4)=1.10,95%CI 0.94,1.28).In MR analysis,there were no causal relation-ships for genetically determined C3 levels and NAFLD risk using unweighted or weighted GRS_C3(β_(E_unweighted)=−0.019,95%CI−0.019,−0.019,p=0.202;β_(E_weighted)=−0.019,95%CI−0.019,−0.019,p=0.322).Conversely,serum C3 lev-els were significantly effected by the genetically determined NAFLD(β_(E_unweighted)=0.020,95%CI 0.020,0.020,p=0.004;β_(E_weighted)=0.021,95%CI 0.020,0.021,p=0.004).Neither the direction from C4 to NAFLD nor the one from NAFLD to C4 showed significant association.Our results support that the change in serum C3 levels but not C4 levels might be caused by NAFLD in Chinese Han men.