Identification of Novel Intronic SNPs in Transporter Genes Associated with Metformin Side Effects

Natascha Schweighofer; Moritz Strasser; Anna Obermayer; Olivia Trummer; Harald Sourij; Caren Sourij; Barbara Obermayer-Pietsch

doi:10.3390/genes14081609

Identification of Novel Intronic SNPs in Transporter Genes Associated with Metformin Side Effects

Genes (Basel). 2023 Aug 11;14(8):1609. doi: 10.3390/genes14081609.

Authors

Natascha Schweighofer^{1

2}, Moritz Strasser^{1

3}, Anna Obermayer^{1

4}, Olivia Trummer¹, Harald Sourij^{1

4}, Caren Sourij⁵, Barbara Obermayer-Pietsch¹

Affiliations

¹ Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
² Center for Biomarker Research in Medicine, CBmed, 8010 Graz, Austria.
³ Department of Health Studies, Institute of Biomedical, FH Joanneum University of Applied Sciences, 8020 Graz, Austria.
⁴ Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, 8036 Graz, Austria.
⁵ Division of Cardiology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

Abstract

Metformin is a widely used and effective medication in type 2 diabetes (T2DM) as well as in polycystic ovary syndrome (PCOS). Single nucleotide polymorphisms (SNPs) contribute to the occurrence of metformin side effects. The aim of the present study was to identify intronic genetic variants modifying the occurrence of metformin side effects and to replicate them in individuals with T2DM and in women with PCOS. We performed Next Generation Sequencing (Illumina Next Seq) of 115 SNPs in a discovery cohort of 120 metformin users and conducted a systematic literature review. Selected SNPs were analysed in two independent cohorts of individuals with either T2DM or PCOS, using 5'-3'exonucleaseassay. A total of 14 SNPs in the organic cation transporters (OCTs) showed associations with side effects in an unadjusted binary logistic regression model, with eight SNPs remaining significantly associated after appropriate adjustment in the discovery cohort. Five SNPs were confirmed in a combined analysis of both replication cohorts but showed different association patterns in subgroup analyses. In an unweighted polygenic risk score (PRS), the risk for metformin side effects increased with the number of risk alleles. Intronic SNPs in the OCT cluster contribute to the development of metformin side effects in individuals with T2DM and in women with PCOS and are therefore of interest for personalized therapy options.

Keywords: metformin; polygenic risk score; side effects; single nucleotide polymorphisms; transporter proteins.

Publication types

Systematic Review
Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2* / drug therapy
Diabetes Mellitus, Type 2* / genetics
Drug-Related Side Effects and Adverse Reactions*
Female
Humans
Introns / genetics
Membrane Transport Proteins
Metformin* / adverse effects
Polycystic Ovary Syndrome* / drug therapy
Polycystic Ovary Syndrome* / genetics
Polymorphism, Single Nucleotide

Substances

Metformin
Membrane Transport Proteins

Grants and funding

GIRO was supported by unrestricted research grants by Novo Nordisk, Eli Lilly, Böhringer Ingelheim and CBmed (Center for Biomarker Research). Work done in “CBmed” was funded by the Austrian Federal Government within the COMET K1 Centre Program (Project number 844609), Land Steiermark and Land Wien.