Using rare coding variants in SLC5A2 to explore the impact of SGLT2 inhibitors on cardiorenal outcomes

Aims Sodium-glucose cotransporter-2 (SGLT2) inhibitors are agents originally developed as glucose-lowering drugs but now widely used to improve cardiorenal outcomes, including in patients with heart failure and chronic kidney disease regardless of diabetes status. However, their exact mode of action remains unclear. Here, we investigated the association of loss-of-function (LoF) and other rare coding variants in the SLC5A2 gene, as a genetic model of altered SGLT2 function, with 13 cardiometabolic and renal traits and clinical outcomes. Methods and results A total of 442 570 European ancestry participants from the UK Biobank with exome sequence and phenotype data were included. We applied SAIGE-GENE+ for gene-based and single-variant association tests in the full study population and in individuals with heart failure, renal failure, and type 2 diabetes (T2D). A total of 52 LoF variants in SLC5A2 were identified. Rare variants in SLC5A2 were associated with decreased uric acid (PCauchy = 4.98 × 10−13) and with increased haematocrit (PCauchy = 1.67 × 10−5), haemoglobin (PCauchy = 1.60 × 10−5), and estimated glomerular filtration rate (PCauchy = 9.88 × 10−4). One frameshift variant (rs267607067) was significantly associated with increased haemoglobin (β = 0.33 [95% CI 0.15–0.51]; P-value = 2.40 × 10−4) and another (rs768095044) with decreased uric acid (β = −0.31 [95% CI −0.49 to −0.13]; P-value = 4.22 × 10−4). In patients with T2D, the rare variants within SLC5A2 were also associated with a lower probability of having heart failure (PCauchy = 4.00 × 10−4). Conclusion Rare genetic variants in SLC5A2 were associated with increased haemoglobin and decreased uric acid. These variants were also associated with a lower probability of heart failure among participants with T2D, providing tentative genetic support for a cardioprotective effect of SGLT2 inhibition.