Genetic determinants of endogenous arginine derivatives and their role in cardiometabolic diseases

Event start date
Event start time
12.00
Place

Arvo building, auditorium F115, address: Lääkärinkatu 1.

Doctoral defence of Lic.Med., M.Sc. (Tech.) Ilkka Seppälä

Genetic determinants of endogenous arginine derivatives and their role in cardiometabolic diseases : With special emphasis on ADMA, SDMA and L-homoarginine

The field of science of the dissertation is Clinical Chemistry.

The opponent is docent Leo Niskanen (University of Eastern Finland). Professor Terho Lehtimäki acts as the custos.

The language of the dissertation defence is Finnish.

Genetic determinants of endogenous arginine derivatives and their role in cardiometabolic diseases

Cardiometabolic disease are the leading cause of morbidity and mortality worldwide. In this thesis, we investigated the genetics of three endogenous dimethylarginines and the associations of newly identified genetic variants with different cardiometabolic disease and their risk factors. It has been shown in numerous prospective population and patient cohorts that blood levels of asymmetric and symmetric dimethylarginine (ADMA and SDMA) as well as homoarginine (hArg) predict cardiovascular and overall mortality. However, the mechanisms underlying these associations as well as the genes and their variants affecting the blood concentrations are not completely known.

Using genome-wide association studies, we found several genetic variants associated with ADMA, SDMA and hArg levels in the blood. The newly identified functional variants within the AGXT2 gene were associated with SDMA levels, heart rate variability in young healthy adults and atrial fibrillation in patients with coronary artery disease. High hArg predicted future hyperglycaemia and abdominal obesity in young men and type 2 diabetes mellitus in young women. However, based on analyses utilizing the hArg associated genetic variants, hArg levels do not seem to causally alter cardiometabolic disease risk. Whether hArg could be used as a biomarker for identification of individuals at risk developing cardiometabolic abnormalities merits further investigation.

Based on the results of this thesis, it might be possible to identify high risk patients that would benefit from early interventions aimed to modify their cardiometabolic risks. On the other hand, better knowledge of the metabolism of arginine derivatives might aid to develop pharmacological therapies that reduce the risks for cardiometabolic diseases or improve the prognosis of the patients who have already developed a cardiometabolic disease.

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The dissertation is published in the publication series of Acta Universitatis Tamperensis; 2282, Tampere University Press, Tampere 2017. The dissertation is also published in the e-series Acta Electronica Universitatis Tamperensis; 1784, Tampere University Press 2017.

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