Projects / Programmes
Decoding polygenic background of endocrine disorders using advanced DNA sequencing techniques and bioniformatics
| Code |
Science |
Field |
Subfield |
| 3.05.00 |
Medical sciences |
Human reproduction |
|
| Code |
Science |
Field |
| B660 |
Biomedical sciences |
Pediatrics |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
hypercholesterolemia, obesity, next generation sequencing, epistasis, paediatric population
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
32181 |
PhD Jernej Kovač |
Medical sciences |
Head |
2016 - 2017 |
207 |
Organisations (1)
Abstract
The aim of this postdoctoral project is the polygenic background analysis of two different health issues where instruments of mendelian genetics cannot completely explain the clinical presentation. Consequently developed methodological and analytical solutions, will be adopted in everyday genetic diagnostics routine. Understanding of polygenic factors influencing the presentation of complex clinical phenotype is crucial for understanding of complex disorders ethology and improved patient’s management.
Genetic disease are classified into two groups: medelian diseases and polygenic diseases. Single causative genetic variant is responsible for the development of Mendelian diseases (for example phenylketonuria) and combination of multiple independent genetic variants contributes to the development of polygenic diseases (for example obesity, cardiovascular diseases and neurological disorders) [1-5]. Number of polygenic diseases is much bigger compared to mendelian disorders [1].
Next generation DNA sequencing enables a high-throughput analysis of multitude of genetic variants of an individual [6], while the bioinformatics development is accelerating complex analysis of causality [7].
Obesity is one of mayor global public health issues [8]. Obese children are prone for development of complications in later age including insulin resistance and type 2 diabetes [9]. Genome wide association studies (GWAS) identified many genes influencing obesity development. FTO andMC4R genes are the most recognized in that group, but only a fraction of obese population can be explained by genetic variants in both of them [10, 11]. The increasing issue of rising incidence of paediatric population is a valid argument for in depth analysis of polygenic background of obesity [12].
Increased level of plasma cholesterol is characteristic feature of Hypercholesterolemia (HH) increasing risk of atherosclerosis and cardiovascular complications for 100-fold [13]. The HH prevalence is estimated at around 1/500 with most patients having mutation in LDLR, APOB orPCSK9 genes. Nevertheless the genetic cause for HH cannot be identified for around 25% of the patients [14]. Those patients represent ideal group research on polygenic background of HH. Slovenia is currently the only country implementing universal national screening for HH at the age of 5 with the aim of early detection of individuals with HH [15]. Between 17.000 and 20.000 children is screened annually and systematic genetic testing of positive individuals for LDLR, APOB andPCSK9 mutations is performed since 2011. Identification of additional genetic factors influencing development of HH would improve the quality of clinical counselling for risk-prone population.
Literature:
1. Lvovs D et al. Acta Naturae. 2012;4: 59–71.
2. Groselj U et al. Mol Genet Metab. 2012;106: 142–148.
3. Hinney A et al. Eur Child Adolesc Psychiatry. 2010;19: 297–310. 6
4. Sasidhar MV et al. Indian Heart J. 2014;66: 663–671.
5. Wray NR et al. J Child Psychol Psychiatry. 2014;55: 1068–1087.
6. Xuan J et al. Cancer Lett. 2013;340: 284–295.
7. Greene CS et al. J Cell Physiol. 2014;229: 1896–1900.
8. King BM Am Psychol. 2013;68: 88–96.
9. Park MH et al. Obes Rev Off J Int Assoc Study Obes. 2012;13: 985–1000.
10. Winter Y et al. Vitam Horm. 2013;91: 29–48.
11. Valette M et al. Int J Obes 2005. 2013;37: 1027–1035.
12. Hebebrand J et al. Dtsch Ärztebl Int. 2013;110: 338–344.
13. Scientific Steering Committee. Atherosclerosis. 1999;142: 105–112.
14. Goldberg AC et al. J Clin Lipidol. 2011;5: 133–140.
15. Kusters DM et al. Arch Dis Child. 2012;97: 272–276.
Significance for science
Published data have importantly contributed to the understanding of insulin resistance aetiology in obese paediatric population. Scientific articles were successfully published in important scientific journals from the specific field of research. All three journals (International Journal of Obesity, Pediatric Obesity and Pediatric Diabetes) are among the most important in their specific fields. The identification of novel candidate genes (DEPTOR and PYGB) will promote future work on the mechanisms of obesity and insulin resistance as well as the development of specific pharmacological molecules with specific action on the reported genes to reverse or slow down the development of clinical complications associated with the obesity. The identification of MC4R associated obesity prevalence was important for the adequate clinical management of obese children and adolescents. The analysis of HH genetic background has revealed the important role of genetic variants. The research of these variants is important to reduce the risk of CVD development in the population with elevated cholesterol level and the development of pharmacological specific molecules targeting mutated genes as was the case in the PCSK9 associated hypercholesterolemia. At the same time the results are a good starting point for the future research projects.
Significance for the country
It is crucial to properly address the increasing problem of paediatric obesity. Together with the preventative measures directly addressing the disproportionate body mass of the individual, it is important to identify potential genetic cause of the obese phenotype to be able to offer appropriate clinical management of the disease. The identification of MC4R associated obesity prevalence in Slovenian paediatric population was important to improve the established clinical protocols. At the same time the development of advanced laboratory procedures will improve clinical management and diagnostics of obese population. Implementing the patient’s risk stratification based on newly discovered associations between genes DEPTOR and PYGB and waist to height ratio will improve established clinical practice and potentially patient’s quality of life. A fraction of this discoveries have already been transferred into practical use at University Children’s hospital. The establishment of quick genetic diagnostics will improve the quality of life in patients. Additionally, the screening of patient’s family members for identified causative genetic mutation enable us to identify whole families at risk of elevated cholesterol levels and premature CVD events. Most of the results of postdoctoral project has been or will be relatively soon implemented in clinical practice. Additionally, the cooperation in the international project researching mIR-122 and its role in NAFLD established important international connections that will further facilitate the future growth of Slovenian science. And non-the-least the published articles and contributions will positively affect the international recognition of Slovenian science.
Most important scientific results
Interim report,
final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
