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.

Are SGLT2 polymorphisms linked to diabetes mellitus and cardiovascular disease? Prospective study and meta-analysis

Inhibition of the sodium glucose co-transporter 2 (SGLT2) reduces cardiovascular morbidity, and mortality in patients with type 2 diabetes mellitus (T2DM) with atherosclerotic, cardiovascular disease. So far, a link between common genetic variations of the SGLT2 encoding gene SLC5A2 and glucose homeostasis as well as cardiovascular disease has not been established. The present study, therefore, aimed to investigate SLC5A2 single nucleotide polymorphisms (SNPs) in relation to type 2 diabetes and coronary artery disease (CAD) and prospectively the incidence of cardiovascular events. We genotyped the SLC5A2 tagging SNPs rs9934336, rs3813008, and rs3116150 in a total of 1684 high risk cardiovascular patients undergoing coronary angiography, including 400 patients with T2DM. Additionally, we performed a meta-analysis combining results from the present study and the literature. Variant rs9934336 was significantly associated with decreased HbA1c (P = 0.023). Further, rs9934336 was significantly inversely associated with the presence of T2DM in univariate (OR = 0.82 [0.68–0.99]; P = 0.037) as well as in multivariate analysis (OR = 0.79 [0.65–0.97]; P = 0.023). The association between rs9934336 and T2DM was confirmed in a meta-analysis including results from two previous observations which by themselves had failed to show a significant association of the polymorphism with T2DM (OR = 0.86 [0.78–0.95]; P = 0.004). Polymorphisms rs3813008 and rs3116150 were associated neither with glycemic parameters nor with T2DM. None of the SNPs tested was significantly associated with the baseline presence of CAD or the incidence of cardiovascular events. We conclude that genetic variation within the SLC5A2 gene locus is significantly related to the manifestation of T2DM.