Genetically determined blood lead is associated with reduced renal function amongst individuals with type 2 diabetes mellitus: insight from Mendelian Randomisation

ABSTRACT: Some observational studies indicate a link between blood lead and kidney function although results remain controversial. In this study, Mendelian randomisation (MR) analysis was applied to obtain unconfounded estimates of the casual association of genetically determined blood lead with estimated glomerular filtration rate (eGFR) and the risk of chronic kidney disease (CKD). Data from the largest genome-wide association studies (GWAS) on blood lead, eGFR and CKD, from predominantly ethnically European populations, were analysed in total, as well as separately in individuals with or without type 2 diabetes mellitus. Inverse variance weighted (IVW) method, weighted median (WM)-based method, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier (PRESSO) as well as the leave-one-out method were applied. In a general population, lifetime blood lead levels had no significant effect on risk of CKD (IVW: p = 0.652) and eGFR (IVW: p = 0.668). After grouping by type 2 diabetes status (no diabetes vs. diabetes), genetically higher levels of blood lead had a significant negative impact among subjects with type 2 diabetes (IVW = Beta: −0.03416, p = 0.0132) but not in subjects without (IVW: p = 0.823), with low likelihood of heterogeneity for any estimates (IVW p > 0.158). MR-PRESSO did not highlight any outliers. Pleiotropy test, with very negligible intercept and insignificant p-value, indicated a low likelihood of pleiotropy for all estimations. The leave-one-out method demonstrated that links were not driven by a single SNP. Our results show, for the first time, that among subjects with type 2 diabetes, higher blood lead levels are potentially related to less favourable renal function. Further studies are needed to confirm our results. KEY MESSAGES: What is already known about this subject? Chronic kidney disease is associated with unfavourable lifestyle behaviours and conditions such as type 2 diabetes. Observational studies have reported an association between blood lead and reduced estimated glomerular filtration rate, but the relationship between lead exposure and renal function remains controversial. What is the key question? Using Mendelian randomisation with data from 5433 individuals from the UK and Australian populations, does genetically determined blood lead have a potentially causal effect on estimated glomerular filtration rate and the risk of chronic kidney disease? What are the new findings? Blood lead levels have a potentially causal effect on reduced renal function in individuals with type 2 diabetes. In subjects without diabetes, no such causal relationship was identified. How might this impact on clinical practice in the foreseeable future? This highlights the risk of elevated blood lead, for example, due to environmental exposure, amongst those with type 2 diabetes, which may predispose them to impaired renal function. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00109-021-02152-5.