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Projects / Programmes source: ARIS

Biogenetic and epigenetic markers of obesity and metabolic syndrome in children and adolescents

Research activity

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 
Keywords
obesity, prediabetes, genetics, pharmacogenetics, child, adolescent
Evaluation (rules)
source: COBISS
Researchers (24)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  23435  PhD Magdalena Avbelj Stefanija  Human reproduction  Researcher  2014 - 2017  177 
2.  13023  PhD Tadej Battelino  Medical sciences  Head  2014 - 2017  1,246 
3.  35553  PhD Sara Bertok  Human reproduction  Researcher  2015 - 2017  86 
4.  01314  MSc Nevenka Bratanič  Human reproduction  Researcher  2014 - 2015  279 
5.  13409  PhD Nataša Bratina  Human reproduction  Researcher  2014 - 2017  433 
6.  15657  PhD Maruša Debeljak  Oncology  Researcher  2014 - 2017  248 
7.  11711  PhD Vita Dolžan  Biochemistry and molecular biology  Researcher  2014 - 2017  766 
8.  22251  Jurka Ferran    Technical associate  2014 - 2017 
9.  32515  Nevenka Flis Šlibar    Technical associate  2014 - 2017 
10.  33110  PhD Katja Goričar  Oncology  Researcher  2014 - 2017  290 
11.  33868  PhD Urh Grošelj  Human reproduction  Researcher  2014 - 2017  485 
12.  10412  PhD Simon Horvat  Biotechnical sciences  Researcher  2014 - 2017  564 
13.  28512  PhD Tinka Hovnik  Medical sciences  Researcher  2014 - 2017  107 
14.  34575  PhD Gašper Klančar  Oncology  Junior researcher  2014 - 2015  74 
15.  31947  PhD Tilen Konte  Biochemistry and molecular biology  Researcher  2014  33 
16.  21358  PhD Primož Kotnik  Human reproduction  Researcher  2014 - 2017  247 
17.  32181  PhD Jernej Kovač  Medical sciences  Researcher  2014 - 2015  210 
18.  29097  Brigita Mali    Technical associate  2014 - 2017 
19.  26462  PhD Simona Murko  Metabolic and hormonal disorders  Researcher  2014  64 
20.  29991  Alja Oblak  Biochemistry and molecular biology  Technical associate  2014  60 
21.  36427  PhD Andraž Šmon  Metabolic and hormonal disorders  Junior researcher  2014 - 2017  41 
22.  37490  PhD Tine Tesovnik  Human reproduction  Junior researcher  2015 - 2017  65 
23.  20253  PhD Katarina Trebušak Podkrajšek  Human reproduction  Researcher  2014 - 2017  407 
24.  15440  PhD Mojca Žerjav Tanšek  Human reproduction  Researcher  2014 - 2017  318 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,092 
2.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  77,757 
3.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  48,536 
Abstract
Obesity in children and adolescents is one of the most important public healthcare problems in the world and in Slovenia.   Genetic background has an important influence on body mass index (BMI). Polygenic obesity in children is associated with genetic variants in several genes and some are specific for children (FTO, MC4R in TMEM18). To-date identified genetic variants explain a relatively minor proportion in the variability of BMI. Undetermined genetic variants and also epigenetic variants e.g. methylation pattern variants and miRNA molecules, probably have an important role. Candidate regions where methylation variants could influence the development of obesity are promotor regions in genes associated with energy intake and consumption (e.g. POMC, MC4R) and genes associated with adipogenesis as DEPTOR, a new gene associated with obesity that was first described by a part of the proposed project group and is to date unexplored in children. Determining epigenetic mechanisms involved in obesity is also important in the evaluation of interventions.   Fat accumulation in the liver and muscle and adipose tissue dysfunction lead to systemic insulin resistance and hyperinsulinism, that is not only associated with the development of type 2 diabetes (T2D) but independently with the development of atherosclerosis and cardiovascular diseases. Therefore we allocated an important part of the proposed project to determining differences between children and adolescent with and without hyperinsulinism. Variants in the genes related to actions and excretion of insulin are candidate genes for prediabetes – hyperinsulinism (INSR, TCF7L2, IGF2BP2, CDKAL1, HHEX, HNF1A). Association between methylation patterns and obesity and obesity complications are described (PGC1alfa). Role of miRNA in the development of prediabetes in children and adolescents is poorly researched.   Metformin is the main medication for T2D in adolescents. It increases tissues sensitivity for insulin and thereby lowers circulating insulin levels, which is an important effect in the treatment of obesity complications. Organic cation transporters (OCT1, OCT 2, MATE) have an important role in metformin transport. Genetic variants in these genes are associated with decreased efficacy of metformin in T2D adults. Inter-individual variability in genetic variants in these genes could influence metformin treatment outcome in adolescents with prediabetes.   In regard to the extent of the discussed problem and its long-term consequences it is imperative to immediately develop preventive and therapeutic strategies to lower prevalence of obesity and early find subjects at an increased risk of early complications. From this aspect it is imperative to determine population specific pathogenesis of obesity and its complications. Aims of the study are (1) to determine genetic and epigenetic predisposition for obesity and (2) prediabetes – hyperinsulinism in Slovenian children and adolescents and (3) to determine genetic markers of the efficacy of metformin treatment in obese adolescents with prediabetes.   All methods to be used are already implemented or are in the process of implementation in the participating institutions (1) high resolution melting analysis (HRM) and Sanger sequencing (2) genome-wide association study (GWAS) of pooled samples (3) bisulfite sequencing for determination of DNA methylation patterns (4) next generation sequencing (NGS) and real-time PCR of selected miRNA and (5) allele-specific real-time PCR.   Results would be used to produce clinical algorithms that would be directly implemented in clinical use, significantly improving healthcare of children and adolescents at an increased risk.
Significance for science
Results of the research project significantly contributed to the basic knowledge in the fild of childhood obesity and its complications, especially insulin resistance that is considered one of the most important. By project conclusion we managed to publish 3 research articles in important scientific journals that cover fields of childhood obesity and paediatric diabetes (International Journal of Obesity, Pediatric Obesity in Pediatric Diabetes). Further article is in the process of revision. Based on the results of the project 2 diplomas in the master degree programme BIOCHEMISTRY were successfully defended. By determining the prevalence of mutations in the MC4R gene that is most frequently affected in monogenic forms of obesity and FTO gene that is most frequently affected in poligenec obesity we corroborated the role of genetic testing in morbidly obese children. Using the next generation sequencing method in individuals with morbid obesity we confirmed the role of this type of diagnostics in determination of novel genes associated with certain traits. We were among the first to determine INPP5E as a novel candidate gene for further studies on appetite disregulation and obesity. Most significant scientific contribution was in the field of insulin resistance aetiology. SNPs in the promotor region of DEPTOR gene were for the first time associated with an increased risk of insulin resistance in obese children. By this DEPTOR become a novel candidate gene not only for obesity but also its complication insulin resistance. This will have important consequences not only for the diagnostic purposes, but possibly also for development of type 2 diabetes treatment. Furthermore we were the first to use genome wide association study on pooled DNA samples for the determination of novel genes associated with insulin resistance. By further analysis we determined PYGB gene as a novel candidate gene. By further data analysis we expect to determine further novel candidate genes. Significant part of the project was also devoted to the development of metodologies for methylation patters which is one of the main epigenetic mechanisms influencing gene expression. We studied methylation patterns in known genes associated with obeisty and insulin resistanece and in the promotor region of gene DEPTOR. Significant contribution was done by investigating the role of non-coding RNA in obeisty complications namelly non-alcoholic liver steatosis. In cooperation with two internationa research teams role of miR-122 was linked to pathogenesis of this complication in obese prepubertal children.
Significance for the country
Childhood obesity and its complications are a mayor public health problem in Slovenia. Due to the high prevalence of childhood obesity and its long-term health complications it is imperative to develop mechanisms for early identification and treatment of those at an increased risk for obesity and its complications. To this effect it’s of paramount importance to determine population specific pathogenesis of obesity and its complications. Prevalence of mutations in the gene that is most frequently associated with monogenic form of obesity and prevalence of SNP in the gene most frequently associated with polygenic form of obesity was determined. Metodology that was developed will be further used in the diagnostic procedures of the Department of Endocrinology, Diabetes and Metabolism at the University Children’s hospital in Ljubljana that it the terciary c3nter for management of childhood obesity and its complications. Of importance for Slovenia is also the that the biochemical methods for the determination of genetic and epigenetic mechanism of insulin resistance, that is one of the fundamental pathophysiological mechanisms of obesity complications, were developed. Based on the results of the project we are able to better predict predisposition for obesity complication in obese children. This enables us to provide more intense conservative and medicamentous treatment to those at an increased risk with the goal of preventing early complications of obesity which should decrease long-term morbidity of this population. In addition, scientific publications and lectures at international meeting contributes to better recognition of Slovenia and creates opportunities for further scientific collaboration and possible foreign investments in the development of services and products with high added value.
Most important scientific results Annual report 2014, 2015, final report
Most important socioeconomically and culturally relevant results Annual report 2014, 2015, final report
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