Copper is a trace element that is nutritionally necessary for the body to obtain, and this trace element is primarily obtained from foods such as shellfish, organ meats, whole grain products, seeds, and nuts, but recent studies have shown that circulating copper concentrations are also determined to some extent by genes. Alterations in circulating trace elements in many body organs, including the brain, heart, kidneys, and liver, have been linked to trauma-related deaths. Excessive dietary copper intake will lead to copper deposition in the kidney and nephrotoxicity through oxidative stress, cellular damage causing proximal tubular necrosis, and decreased renal function.

However, the interaction between copper and renal disease is bidirectional, as homeostatic imbalances in circulating copper levels may also occur in patients with chronic kidney disease（CKD） due to impaired renal excretion and altered protein metabolism. Indeed, the regulation of copper levels in patients with chronic kidney disease is important for the prevention of complications. In previous observational studies, elevated circulating copper levels were associated with chronic kidney disease. Whether higher levels of copper in the blood lead to kidney injury, more rapid decline in kidney function and increased risk of chronic kidney disease remain to be confirmed, as traditional observational epidemiological studies tend to confound and reverse causality.

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Mendelian randomization is one of the methods to infer causal relationships between lifestyle factors and disease outcomes. Mendelian randomization is a framework for testing causal relationships between modifiable exposures associated with different phenotypes, where genetic variants associated with exposure are used as instrumental variables. Given the random combination of genetic variants during conception, genetic variants are generally not associated with potential confounders in exposure-outcome associations. No previous studies have explored the causal relationship between circulating copper levels and CKD.

We hypothesized that elevated circulating copper levels would increase the risk of CKD. To confirm this hypothesis, we performed a series of preliminary analyses of the association between genetically predicted circulating copper levels and CKD. In a secondary analysis, we investigated whether genetically predicted high circulating copper levels were associated with lower estimated glomerular filtration rate (eGFR), increased rapid kidney decline, and kidney injury.

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This study was designed according to MR. the MR approach was based on three assumptions. First, genetic instrumental variables should be correlated with exposure. Second, genetic instrumental variables should be correlated with potential confounders. Finally, genetic instrumental variables should influence outcome variables through exposure. The hypothesis was tested by a two-sample MR approach using genetic variation associated with copper as an instrumental variable. In addition, because genetic variation cannot be altered by disease state, MR studies do not easily reverse causality.

Genetic association estimates for circulating copper were derived from a genome-wide association meta-analysis of three population-based cohorts (including 6937 individuals of European descent). In this meta-analysis study, we measured circulating copper levels in both plasma and serum. This study identified two genome-wide significant genetic variants positively associated with circulating copper levels (rs17564336 for SELENBP1 and rs34951015 for CP). Both variants were used as genetic tools for MR studies

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To assess the potential causal association between circulating copper levels and CKD risk, we obtained genetic association estimates for CKD from a genome-wide association study (GWAS) meta-analysis containing 12,385 CKD cases and 104,780 non-European [8] cases. cKD was defined as serum creatinine based on a 60 mL-min - 1 / 1.73 m2 eGFR. eGFR genetic association estimates (as continuous variables) were obtained from the GWAS containing 312,468 multiple ancestry individuals (discovery dataset) [9], and the CKDGEN consortium and the UK Biosample Repository cohort (n = 1,004,040) (replication dataset).

To assess the potential causal relationship between circulating copper levels and creatinine risk based on rapid glomerular filtration rate decline (eGFRcrea), we obtained genetic association estimates for eGFRcrea from Gorski et al. eGFRcrea was assessed based on samples from the CKDGEN consortium and the UK Biosample Repository cohort. Rapid eGFRcrea cases (also known as CKDi25, including n cases = 19,901 and n controls = 175,244) were defined as having a baseline eGFR ≥ 60 mL/min / 1.73 m2 and a 25% decrease in eGFR from baseline. 60 mL/min / 1.73 m2, CKDi25 group were those with normal baseline eGFR and gt;60 mL/ (min-1.73 m2) and did not meet these parameters of renal function decline (no 25% decline in eGFR). The duration of follow-up for the mean eGFR decline varied among the cohorts participating in the study (1 ~ 15 years). Serum creatinine was measured in all study subjects using enzymatic and Jaffe reaction-based serum creatinine assays. The chronic kidney disease epidemiology collaborative study (CKD-EPI) formula was used to estimate eGFR.

To investigate the potential causal relationship between circulating copper levels and renal damage, Teumer et al [12] obtained a genetic association estimate for markers of renal damage in a GWAS meta-analysis. Renal damage was reflected by the urinary albumin/creatinine ratio (n = 48,589) and normoalbuminuria vs. micro/large albuminuria (n = 48,255) [12]. All included study samples were of European descent, age >18 years, and included both men and women. All included studies followed the Declaration of Helsinki criteria.

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9. Morris, A.P.; Le, T.H.; Wu, H.; Akbarov, A.; van der Most, P.J.; Hemani, G.; Smith, G.D.; Mahajan, A.; Gaulton, K.J.; Nadkarni, G.N.; et al. Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies. Nat. Commun. 2019, 10, 29.

10. Stanzick, K.J.; Li, Y.; Schlosser, P.; Gorski, M.; Wuttke, M.; Thomas, L.F.; Rasheed, H.; Rowan, B.X.; Graham, S.E.; Vanderweff, B.R.; et al. Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals. Nat. Commun. 2021, 12, 4350.

11. Gorski, M.; Jung, B.; Li, Y.; Matias-Garcia, P.R.; Wuttke, M.; Coassin, S.; Thio, C.H.L.; Kleber, M.E.; Winkler, T.W.; Wanner, V.; et al. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. Kidney Int. 2021, 99, 926–939.

12. Teumer, A.; Tin, A.; Sorice, R.; Gorski, M.; Yeo, N.C.; Chu, A.Y.; Li, M.; Li, Y.; Mijatovic, V.; Ko, Y.A.; et al. Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes. Diabetes 2016, 65, 803–817.

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