Dissertation shows how genomic information can be used in drug development

The PhD thesis discovered genetic trigger points that can be used for the development of diabetes and potentially also cancer medication.
The PhD thesis discovered genetic trigger points that can be used for the development of diabetes and potentially also cancer medication. Source: (Victoria Pickering/Creative Commons)

Silva Kasela, who recently defended her PhD thesis at the University of Tartu, has discovered molecules that could be suitable for the treatment of type-1 diabetes, and others that could be suitable for fighting cancer.

In her thesis, Kasela studied the tissue and cell-type-specific regulation of gene expression. The study revealed that genetic variants in the adult liver affect the expression of genes that are involved in both general and drug metabolism. 

“For genes responsible for drug metabolism, both genetic and epigenetic variations play an important role, which means that variable drug response among individuals results from both heritable and environmental factors, for example concomitant medication, smoking, and even one’s diet,” Kasela’s supervisor, Lili Milani explained.

In collaboration with drs. Urmo Võsa and Tarmo Annilo, they also investigated the relationship between small non-coding microRNAs and genetic markers. They found several cancer-associated markers that influenced gene expression levels, supporting the significant role of microRNAs in the regulation of gene expression.

The most significant study in the thesis, carried out in cooperation with immunologists Dr. Kai Kisand and Prof. Pärt Peterson of UT Biomedicum (the university’s Centre for Disease Models and Biomedical Imaging) revealed mechanisms for several disease-related genes and cell types associated with disease development. This was made possible by an in-depth study of different immune cells from 300 participants of the Estonian Biobank of the university’s Estonian Genome Centre, and advances the understanding of the pathways of different diseases. The result is a potential drug target for type-1 diabetes.

Kasela writes that over the past ten years, genome-wide association studies have unravelled tens of thousands of genetic variants linked to complex traits and diseases.  All these studies have provided knowledge about disease causes and heritability. 

However, the identified associations do not point directly to a causal genetic variant, but rather mark the region of the genome that influences the risk for a certain disease or phenotypic expression. 

Genetic variants that modulate gene expression levels, the intermediate trait between DNA variation and phenotypes, help to leverage the information gathered so far. 

“It is important to describe the genetic regulation of gene expression in as many different cells and tissues as possible, because the effect of genetic variants on gene expression is dependent on both cell types and environmental impacts,” Kasela pointed out. 

Together with other similar studies, Kasela’s research is leading the way to the main task facing geneticists in the next ten years: to study disease-associated genetic variants and find out in which cell types and through which molecular mechanisms and pathways they affect people’s well-being. 

“Answers to these questions should take us one step closer to applying the gathered information on the human genome in drug development and clinical practice,” Kasela said.

Editor: Dario Cavegn

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