Assessment of the effect of the SLC5A2 gene on eGFR: a Mendelian randomization study of drug targets for the nephroprotective effect of sodium-glucose cotransporter protein 2 inhibition

TL;DR

This study uses genetic data to show that the SLC5A2 gene affects kidney function, supporting the protective effects of SGLT2 inhibitors on the kidneys.

Contribution

The study provides novel genetic evidence linking SLC5A2 gene activity to eGFR decline and supports the nephroprotective role of SGLT2 inhibitors.

Findings

SLC5A2 gene-regulated HbA1c levels are negatively correlated with eGFR in multi-ancestry and European populations.

Genetic inhibition of SLC5A2 is associated with higher eGFR, supporting the renoprotective effect of SGLT2 inhibitors.

Results were validated using GWAS data from the CKDGen consortium, reinforcing the causal relationship.

Abstract

Sodium-glucose cotransporter protein 2 (SGLT2) inhibitors have been shown to have renoprotective effects in clinical studies. For further validation in terms of genetic variation, drug-targeted Mendelian randomization (MR) was used to investigate the causal role of SGLT2 inhibition on eGFR effects.

Genetic variants representing SGLT2 inhibition were selected as instrumental variables. Drug target Mendelian randomization analysis was used to investigate the relationship between SGLT2 inhibitors and eGFR. The IVW method was used as the primary analysis method. As a sensitivity analysis, GWAS pooled data from another CKDGen consortium was used to validate the findings.

MR results showed that hemoglobin A1c (HbA1c) levels, regulated by the SLC5A2 gene, were negatively correlated with eGFR (IVW β -0.038, 95% CI -0.061 to -0.015, P = 0.001 for multi-ancestry populations; IVW β -0.053, 95% CI -0.077 to -0.028, P = 2.45E-05 for populations of European ancestry). This suggests that a 1-SD increase in HbA1c levels, regulated by the SLC5A2 gene, is associated with decreased eGFR. Mimicking pharmacological inhibition by lowering HbA1c per 1-SD unit through SGLT2 inhibition reduces the risk of eGFR decline, demonstrating a renoprotective effect of SGLT2 inhibitors. HbA1c, regulated by the SLC5A2 gene, was negatively correlated with eGFR in both validation datasets (IVW β -0.027, 95% CI -0.046 to -0.007, P=0.007 for multi-ancestry populations, and IVW β -0.031, 95% CI -0.050 to -0.011, P=0.002 for populations of European origin).

The results of this study indicate that the SLC5A2 gene is causally associated with eGFR. Inhibition of SLC5A2 gene expression was linked to higher eGFR. The renoprotective mechanism of SGLT2 inhibitors was verified from the perspective of genetic variation.

Figures