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Equipment at the Genome Center of Eastern Finland.

Doctoral defence of Rowmika Ravi, 31 March 2023: Novel biomarkers may play an important role in simvastatin metabolism

The doctoral dissertation in the field of Metabolomics and Genomics will be examined at the Faculty of Health Sciences at Kuopio campus.

What is the topic of your doctoral research? Why is it important to study the topic?

Cardiovascular diseases (CVDs) are a worldwide burden, the leading cause of death. ‘Multi-omics’ has facilitated scientific research in understanding disease state at a molecular level. This doctoral thesis explores the application of metabolomics (study of metabolites that are a part of chemical reactions in our body) and genomics (study of genes) to investigate CVDs.

We applied metabolomics approach to examine the metabolic changes in individuals on simvastatin therapy. High cholesterol is a leading risk factor for atherosclerosis and coronary artery disease. Simvastatin belongs to a major class of cholesterol-lowering drugs called statins. It has several beneficial cardiovascular effects and, in some cases, adverse side-effects like statin-induced muscle disorder and type 2 diabetes. The aim was to understand metabolites that may play an important role in simvastatin metabolism. The efficacy of statin therapy also depends on the genetic profile of an individual. The genetic variant c.521T>C in SLCO1B1 gene is known to be associated with increased simvastatin concentration in blood and decreased drug efficacy. Since genome influences the metabolome, we integrated genomics and metabolomics to study the metabolic changes in c.521T>C carriers during simvastatin therapy.

We further investigated the metabolites associated with pathogenic variant carriers in the rare genetic disorders, hypertrophic and dilated cardiomyopathy (HCM/DCM). In HCM and DCM, family members with the same gene variant may have different disease characteristics. It is also possible for a pathogenic variant carrier to not show any symptoms. Multi-omics methodology can provide valuable information to elucidate disease pathophysiology for risk stratification and disease management.

What are the key findings or observations of your doctoral research?

The studies show for the first time a comprehensive metabolic signature of simvastatin treatment, SLCO1B1 variant carriers during simvastatin therapy and pathogenic variant carriers of HCM and DCM. We report changes in several novel metabolite concentrations in the individuals on simvastatin treatment indicating that simvastatin exerts profound pleiotropic effects on different metabolite pathways, including lipids, steroids, degradation of branched chain amino acids, disturbances in the gamma-glutamyl cycle, folate, glutamate, and proline metabolism. We further report that simvastatin lowers LDL-cholesterol through several distinct pathways in the carriers of SLCO1B1 c.521C>T variant, including steroid, bile acid, dicarboxylic acid, and glycerophospholipid pathways.

This is also the first study to report that SLCO1B1 c.521C>T variant does not play a role in causing simvastatin-induced diabetes, suggesting a direct role of simvastatin in risk for type 2 diabetes.

Investigation of HCM pathogenic variant carriers indicated that the hypertrophy of cardiac cells is regulated not only by factors predisposing cardiac hypertrophy (left ventricle wall thickening), but also by factors that attempt to counteract hypertrophy. In the carriers of DCM genetic variants, the pathophysiology could be elucidated with identification of a metabolite profile compatible with vascular endothelial dysfunction, decreased antioxidant precursors, increased reactive oxygen species generation, an increase in cardiac remodelling, and an indication of a disturbed collagen metabolism.

How can the results of your doctoral research be utilised in practice?

High cholesterol is a modifiable risk factor for CVDs. Simvastatin is a widely prescribed LDL-cholesterol lowering medication whose multiple beneficial and adverse effects needs to be elucidated to improve its efficiency. This thesis demonstrates the high potential of metabolomics and genomics in identifying novel biomarkers that may play an important role in mediating drug metabolism. Furthermore, quantifying the metabolite concentrations in the carriers of a pathogenic variant of HCM and DCM helps to explain the phenotype and report new vital information about the pathophysiology of cardiomyopathies. Investigations on novel biomarkers to predict the risk of HCM and DCM onset and prognosis in the pathogenic variant carriers may lead to new ways of disease management and development of novel drugs. Together, this thesis aids in accelerating precision medicine in the management of CVDs, where drugs are given based on an individual’s metabolic and genetic profile.

What are the key research methods and materials used in your doctoral research?

The major strength of this doctoral research is the large size of our population-based study cohort-the METSIM study, with a detailed analyses of genetic variants and metabolites. The METSIM study consists of 10,197 Finnish men aged 45-73, randomly selected from Eastern Finland in the years 2005-2010. The Finnish population represents an isolated community having a unique geography and two bottlenecks in its history. Applying multi-omics methodology to a homogenous population-based cohort provides advantages like increased chances of identifying the enriched rare genetic variants and elimination of confounding effects. The METSIM study including only men is advantageous for studies of metabolic disorders for coronary artery disease as it is more prevalent in men.

A non-targeted liquid chromatography- tandem mass spectroscopy (LC-MS/MS) was used in our metabolomics studies to quantify the metabolite profile of the METSIM participants. LC-MS/MS is a highly sensitive method for detection of several metabolites in one measurement with precision. Gene variants were identified using whole exome sequencing data of the METSIM participants, targeting the protein coding region of the genome. This thesis describes the application of ‘omics’ methodology in studies of CVDs using a large-scale population-based study. The studies indicate the high potential of ‘omics’ in determining novel biomarkers and elucidating molecular mechanisms related to a phenotype.

The doctoral dissertation of Rowmika Ravi, entitled Metabolomics and genomics approach in cardiovascular diseases will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Professor Risto Kaaja of the University of Turku, and the Custos will be Professor Markku Laakso of the University of Eastern Finland.

Doctoral defence



For further information, please contact:

Rowmika Ravi, rowmika.ravi(a),