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 f...

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Bibliographic Details
Published in:Genes 2021-07, Vol.12 (8), p.1174
Main Authors: Wang, Siqi, Said, M Abdullah, Groot, Hilde E, van der Most, Peter J, Thio, Chris H L, van de Vegte, Yordi J, Verweij, Niek, Snieder, Harold, van der Harst, Pim
Format: Article
Language:English
Subjects:
3' Untranslated regions
Adult
Biobanks
Blood & organ donations
Congestive heart failure
Creatinine
Diabetes
Diabetes mellitus
Excretion
Female
Gene expression
Gene frequency
Genetic diversity
Genetic Variation
Glucose
Glycated Hemoglobin A - metabolism
Hemoglobin
Humans
Informed consent
Kidneys
Male
Middle Aged
Mimicry
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Reabsorption
Regression analysis
Single-nucleotide polymorphism
Sodium
Sodium-Glucose Transporter 2 Inhibitors - pharmacology
Values
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Summary: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 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 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 . In conclusion, no genetic variant was found mimicking SGLT2i based on their location near and their association with sodium excretion or HbA1c and expression or function.
ISSN:2073-4425
2073-4425
DOI:10.3390/genes12081174