# Exploring the relationship between serum magnesium levels, genetic variants and chronic kidney disease: a prospective study

## TL;DR

Low magnesium levels are linked to a higher risk of chronic kidney disease, but no strong genetic evidence supports a direct cause.

## Contribution

This study explores the interplay between magnesium levels, genetic variants, and CKD risk using mediation and Mendelian randomization analyses.

## Key findings

- Hypomagnesemia was associated with a 73% higher risk of CKD.
- Four SNPs showed indirect effects on CKD risk through magnesium levels.
- MR analyses found no strong causal link between magnesium and CKD.

## Abstract

Recent evidence suggests that magnesium deficiency may play a role in the development and progression of chronic kidney disease (CKD). We assessed the association between genetic variations, serum magnesium levels and CKD risk in the general population.

In this population-based prospective study (n = 4047; mean age 53 years; 54% female; mean follow-up 12.5 years), Cox regression models evaluated the effects of hypomagnesemia on CKD risk. Genetic risk scores and mediation analyses were used to assess the direct and indirect effects of single-nucleotide polymorphisms (SNPs) on CKD development through magnesium levels. One-sample and two-sample Mendelian randomization (MR) analyses were conducted to examine the causal relationship between genetically predicted serum magnesium levels and CKD risk.

Multivariable Cox regression analyses identified that hypomagnesemia was significantly associated with an increased risk of CKD, with a hazard ratio of 1.73 (95% confidence interval 1.14–2.61, P = .010). Analyses based on single SNPs and SNP scores did not reveal direct effects on CKD risk. Mediation analyses demonstrated that four SNPs exerted significant indirect effects on CKD risk through serum magnesium levels. However, the proportion of the total effect mediated by magnesium was low and not statistically significant. MR analyses did not provide strong evidence for a significant causal relationship between genetically predicted magnesium levels and CKD risk.

Hypomagnesemia was significantly associated with an increased risk of long-term CKD. Genetic analysis suggests that serum magnesium levels may play an indirect role in CKD risk, but no clear causal relationship was found.

Graphical Abstract