Diabetes, Metabolic Syndrome and Obesity (Jun 2020)
Intronic Variants in OCT1 are Associated with All-Cause and Cardiovascular Mortality in Metformin Users with Type 2 Diabetes
Abstract
Natascha Schweighofer,1,2 Bernd Genser,3,4 Winfried Maerz,5,6 Marcus E Kleber,5 Olivia Trummer,1 Thomas R Pieber,1,2 Barbara Obermayer-Pietsch1,2 1Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Graz, Austria; 2CBmed GmbH, Center for Biomarker Research in Medicine, Graz, Austria; 3BG Stats Consulting, Vienna, Austria; 4Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany; 5Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; 6SynLaboratory Academy, SynLaboratory Holding Deutschland GmbH, Mannheim and Augsburg, GermanyCorrespondence: Barbara Obermayer-PietschDepartment of Internal Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Auenbruggerplatz 15, Graz A-8036, AustriaTel +43 316 385 80253Fax +43 316 385 13428Email [email protected]: Organic cation transporters (Octs) use cations like endogenous compounds, toxins, and drugs, such as metformin, as substrates. Therefore, these proteins determine the pharmacokinetics and -dynamics of metformin and thus its efficacy. Of note, metformin is today the most commonly used pharmaceutical in the treatment of type 2 diabetes (T2DM) with nevertheless a great variability in clinical response, which attributes to genetic variances. The aim of this study was to determine the influence of intronic OCT1 SNPs on prevalence of all-cause and cardiovascular death.Patients and Methods: Genotypes of 27 intronic SNPs in OCT1 were investigated in the LURIC study, a prospective cohort of 3316 participants scheduled for coronary angiography. We investigated whether these variants were associated with all-cause and cardiovascular death in 73 individuals with T2DM under metformin therapy, in individuals without diabetes, individuals with T2DM and individuals with T2DM without metformin therapy.Results: In a multivariate Cox regression analysis adjusted for classical cardiovascular risk factors, 4 intronic OCT1 SNPs were significantly associated with all-cause and cardiovascular mortality in individuals with T2DM on metformin therapy.Conclusion: According to their OCT1 genotype, some individuals with T2DM on metformin therapy might be prone to an increased risk of cardiovascular death.Keywords: organic cation transporter 1, SNP, T2DM, cardiovascular death, metformin
