Search for a Functional Genetic Variant Mimicking the Effect of SGLT2 Inhibitor Treatment

SGLT2 inhibitors (SGLT2i) block renal glucose reabsorption. Due to the unexpected beneficial observations in type 2 diabetic patients potentially related to increased natriuresis, SGLT2i are also studied for heart failure treatment. This study aimed to identify genetic variants mimicking SGLT2i to further our understanding of the potential underlying biological mechanisms. Using the UK Biobank resource, we identified 264 SNPs located in the SLC5A2 gene or within 25kb of the 5' and 3' flanking regions, of which 91 had minor allele frequencies >1%. Twenty-seven SNPs were associated with glycated hemoglobin (HbA1c) after Bonferroni correction in participants without diabetes, while none of the SNPs were associated with sodium excretion. We investigated whether these variants had a directionally consistent effect on sodium excretion, HbA1c levels, and SLC5A2 expression. None of the variants met these criteria. Likewise, we identified no common missense variants, and although four SNPs could be defined as 5' or 3' prime untranslated region variants of which rs45612043 was predicted to be deleterious, these SNPs were not annotated to SLC5A2. In conclusion, no genetic variant was found mimicking SGLT2i based on their location near SLC5A2 and their association with sodium excretion or HbA1c and SLC5A2 expression or function.