genes G C A T T A C G G C A T Article Search for a Functional Genetic Variant Mimicking the Effect of SGLT2 Inhibitor Treatment Siqi Wang 1,† , M. Abdullah Said 1,† , Hilde E. Groot 1 , Peter J. van der Most 2 , Chris H. L. Thio 2 , Yordi J. van de Vegte 1 , Niek Verweij 1 , Harold Snieder 2 and Pim van der Harst 1,3, *   Citation: Wang, S.; Said, M.A.; Groot, H.E.; van der Most, P.J.; Thio, C.H.L.; van de Vegte, Y.J.; Verweij, N.; Snieder, H.; van der Harst, P. Search for a Functional Genetic Variant Mimicking the Effect of SGLT2 Inhibitor Treatment. Genes 2021, 12, 1174. https://doi.org/10.3390/ genes12081174 Academic Editor: Giuseppe Limongelli Received: 5 July 2021 Accepted: 27 July 2021 Published: 29 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; s.wang01@umcg.nl (S.W.); m.a.said@umcg.nl (M.A.S.); h.e.groot@umcg.nl (H.E.G.); y.j.van.de.vegte@umcg.nl (Y.J.v.d.V.); n.verweij@umcg.nl (N.V.) 2 Department of Epidemiology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; p.j.van.der.most@umcg.nl (P.J.v.d.M.); c.h.l.thio@umcg.nl (C.H.L.T.); h.snieder@umcg.nl (H.S.) 3 Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands * Correspondence: P.vanderHarst@umcutrecht.nl; Tel.: +31-(0)5-0361-2355 † These authors are equally contributed. Abstract: 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. Keywords: SGLT2 inhibitor; heart failure; UK Biobank; genetic variants 1. Introduction Sodium-glucose co-transporter-2 (SGLT2) is the primary transporter in the proximal tubule of the kidney [1] and reabsorbs over 90% of the glucose from the glomerular filtrate [2]. SGLT2 is encoded by the SLC5A2 gene, which is located on chromosome 16 (16p11.2)[3]. SGLT2 inhibitors (SGLT2i) block renal glucose reabsorption, resulting in increased urinary glucose excretion, but also between a 30% and 60% increase in urinary sodium excretion [4], and blood glucose reduction [5]. Originally used for the treatment of type 2 diabetes (T2D), SGLT2i was the first anti-diabetic drug shown to reduce the risk of hospi- talization for heart failure (HF) in these patients [6]. HF is a complex clinical syndrome in which the heart is unable to pump a sufficient amount of blood for the body’s requirements and is caused by a structural or functional impairment of the contractility or filling of the ventricles. HF is a major cause of cardiovascular morbidity and mortality worldwide, leading to a heavy economic burden on society [7]. A recent study reported that the use of SGLT2i was associated with a lower risk of worsening HF or death from a cardiovascular cause among patients with HF with a reduced ejection fraction, regardless of their diabetic Genes 2021, 12, 1174. https://doi.org/10.3390/genes12081174 https://www.mdpi.com/journal/genes