We used inverse variance weighting (IVW) methods to estimate the causal relationship between genetically predicted copper and renal outcomes. We could not exclude potential pleiotropic effects by applying other MR methods (e.g. weighted median and MR- Egger regression methods) because the minimum number of genetic variants required for these MR methods should be at least 3, and we only had 2 genetic variants associated with copper.

Higher circulating copper levels predicted by the gene were significantly associated with CKD prevalence (ratio 1.17; 95% confidence interval (CI) 1.04, 1.32; p-value= 0.009).

Genetic prediction of association of circulating copper with chronic kidney disease CI, confidence interval; IVW, inverse variance weighting; OR, dominance ratio; SNP, single nucleotide polymorphism.

In the discovery study, genetically predicted higher circulating copper levels were significantly correlated with lower eGFR (β -0.88 mL min-1 / 1.73 m2; 95% ci -1.72, -0.03; p-value = 0.043) [9], but not in the replication study (β -0.0001 mL min-1 / 1.73 m2; 95% ci -0.0023, 0.0023; assumed value = 0.91).

Our MR analysis provided evidence that genetically predicted higher circulating copper levels were slightly associated with an increase in decreased glomerular function rate (dominance ratio 1.10; 95% ci 0.99, 1.23; assumed value = 0.076). When the urinary albumin-creatinine ratio was modeled as a continuous variable, the genetically predicted copper levels were not significantly correlated with renal injury (beta 0.03; 95% ci-0.03, 0.06; p-value = 0.36) when comparing normoalbuminuria with micro/large albuminuria (beta 0.05; 95% ci-0.34, 0.44; p = 0.80).

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In the current study, we investigated the causal relationship between genetically predicted circulating copper and the risk of CKD, eGFR, decreased renal function, urinary albumin-creatinine ratio, and microalbuminuria. To the best of our knowledge, this is the first study to use MR methods to explore the causal relationship between circulating copper intake and CKD-related outcomes. Our two-sample MR analysis confirmed the observed association between high circulating copper levels and increased risk of CKD. High circulating copper levels were also associated with reduced eGFR, rapid decline in renal function, and higher levels of urinary albumin, creatinine ratio, and microalbuminuria. However, by MR analysis, we observed a nominally significant correlation between genetically predicted copper levels and reduced eGFR and rapid decline in renal function, but not with proteinuria.

Our important finding is that circulating copper is causally associated with a higher prevalence of CKD and reduced eGFR. Copper is an important transition metal in the human body, a cofactor for many enzymes, and involved in many physiological pathways. Circulating copper is controlled to some extent by genes, but humans are also exposed to copper through dietary intake and reach the kidneys through blood circulation. In the kidney, copper catalyzes the production of highly reactive hydroxyl radicals, and thus this oxidative stress can lead to proximal tubular necrosis. Previously, through observational epidemiological studies, higher copper intake was found to be associated with abnormal eGFR and end-stage CKD.

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Our study also proposed a causal association of circulating copper with higher CKD prevalence and reduced eGFR. In the replicated study (Stanzick et al.), the eGFR-GWAS analysis was also corrected for confounding factors, including a sex*age interaction term, and age2 *sex. This may explain why the magnitude of the single nucleotide polymorphism- eGFR estimates in the analysis based on replication studies was very small and not comparable to the estimates obtained by Morris et al. based on GWAS, where the regression estimates were not corrected for any interaction term.

The strength of the present MR study is that circulating copper levels were measured by plasma and serum and genetic association estimates for copper and CKD was measured in independent samples, thus avoiding bias in the direction of the observed associations. A limitation of this study is that only two genetic variants were used as instrumental variables. Therefore, it was not possible to exclude potential pleiotropic effects using other MR methods that are more robust to such effects. Circulating copper levels were assessed by whole blood, serum, and red blood cells, and by different transformations of copper values (including different model adjustments in different cohorts of copper genome-wide association studies). Our study may not be sufficient to detect a weak causal relationship between copper and renal biomarkers.

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In addition, we examined many of the outcome characteristics in our MR analysis. However, our results on genetically predicted circulating copper levels associated with CKD risk remained statistically significant even when we applied multiple corrections. In replicate samples from CKDGEN and the UK Biosample Repository, we observed similar directions of circulating copper- CKD estimates. We used only GWAS pooled data and could not use both GFR and albuminuria to define CKD. finally, our study sample was based on individuals of European ancestry, which limits the generalizability to another ancestry.

In conclusion, the results of this MR study suggest that genetically predicted elevated circulating copper levels may be a pathogenic risk factor for CKD and may be associated with reduced eGFR and rapid decline in renal function. Additional studies are needed to assess the potential underlying mechanisms and clinical relevance of these findings.

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