Projects / Programmes
Genetics and pharmacogenomics of inflammatory bowel diseases and genetically related chronic immune diseases
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| B220 |
Biomedical sciences |
Genetics, cytogenetics |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
genetics, pphramacogenomics, chronic immune diseases, complex diseases
Researchers (22)
Organisations (3)
Abstract
Together with our partners in the "International Inflammatory Bowel Disease Genetics Consortium« (IIBDGC), we have recently performed Genome Wide Association Study (GWAs) using custom designed genotyping Immunochip (iCHIP) in 75,000 Inflammatory bowel diseases (IBD) patients (Crohn disease, ulcerative colitis) and controls and discovered 163 IBD associated loci, yet the highest number of identified loci associated to particular disease (Nature, 2012 Nov 1;491(7422):119-24 ). Using our genetic data for bioinformatic and in silico functional analysis we 1. revealed more than 80% of single nucleotide polymorphisms (SNPs) associated with IBD was located in non-coding or even “gene desert” regions; 2. discovered that host-microbe interactions have shaped genetic architecture of IBD. 3. discovered that similar chronic immune diseases share many genes and pathways.
Linking disease associated non-coding SNPs to genes they affect, identification of causal variants and explaining molecular mechanism by which non-coding SNPs affect disease genes is due to high linkage disequilibrium among SNPs in disease regions, the major challenge for post GWAs genetic studies of IBD and other complex diseases for the next few years and aim of our project. Breakthrough in this field will facilitate functional studies that will enhance our understanding of molecular pathways involved in IBD pathogenesis, discovery of molecular targets for novel biological drug design, discovery of biomarkers and development of predictive models for better diagnosis, disease monitoring and personalized therapy.
Considering gene expression as quantitative phenotype and correlating gene expression of candidate genes in the disease associated region to disease associated SNPs (eQTL analysis) proved to be efficient approach for identification of best disease candidate genes.
Most eQTL studies so far used expression data obtained from lymphoblastic cell lines which may not represent the natural gene expression state in vivo. Most eQTL studies obtained gene expression data using microarray technology which could not de novo identify new splice variants (isoforms).
Within this project we will provide significant improvement in eQTL analysis by measuring gene expression leucocytes and colon tissue biopsies obtained directly from IBD patients, , using next generation sequencing (NGS) for RNA (RNA-seq) that will enable us to identify and quantify new splice variants (isoforms) with biological importance in disease pathogenesis. Moreover, integration of genetic (NGS, genotyping), gene expression (RNAseq), epigenetics (methylation, ChIP) and gene regulation (miRNA profiling, splicing mechanism) data and bioinformatic tools (GO) ensure identification and description of biological pathways important in molecular pathogenesis.
Our project is fully feasible as our biobank includes one of the worldwide largest number of paired DNA/RNA samples from Slovenian patients with chronic immune diseases, including 600 IBD patients (1200 RNA samples taken during adalimumab therapy), 500 asthma patients (800 RNA samples taken during treatment with antileukotriens and corticosteroids), 250 rheumatoid arthritis, and 250 patients with multiple sclerosis. Particularly, part of our biobank representing RNA samples taken from the subgroup of Crohn disease patients refractory to standard treatment and developing severe form of the disease, before and during adalimumab treatment (after 2, 4, 8, 12 weeks) represents unique and most promising part to provide new discoveries. In addition, the access to genotype data within consortium databank necessary for the successful completion of our project is ensured as our project was already approved by IIBDGS consortium managing committee.
Finaly, corellation of molecular genetic patients data with Clostridium difficile strains ribotypeing and toxinotyping data obtained from IBD patients will contribute to understanding of host-microbe interations in IBD.
Significance for science
• The first fine mapping GWA pharmacogenomic study in adalimumab treatment in Crohn disease discovered new SNPs that could be used in personalized treatment. Patients could suffer for less adverse side effects if therapy is personalized based on molecular and genetic biomarkers dicovered in our project. • The first comprehensive eQTL analysis in blood lymphocytes and tissue samples from patients with different immune diseases identified new eQTL loci and linked noncoding SNPs to new genes that were previously not considered to be disease genes • The progress beyond the state of art and scientific impact is ensured by identification of causal variants and true disease genes that will facilitate functional studies and development of biomarkers and predicitve models for personalized medicine • Results of our eQTL, gene regulation and epigenetic studies will progress our understand of the mechanism of cisacting elements and SNPs in »gene deserts« in different cell types which will contribute to better understanding of regulation of gene expression. We will also beter understand the role of variability in noncoding regions in human genome. • Results of our eQTL, gene regulation and epigenetic studies will result in linking the noncoding IBD and other chronic diseases associated SNPs with genes and proteins they affect. This is essential for dicovery of molecular targets (proteins) for new drug desing and for discovery of molecular and biological patways important in IBD and other chronic immune diseases pathogenesis
Significance for the country
• The results of this project will provide essential experience, exprertise and knowhow which will be directly used in setting up the »Center for genome analysis and personalized medicine«, operating withnin IP-0029 Infrastructure center at University of Maribor, unit CORE@UM, finnancialy supported by ARRS. Our Center: 1. provide genetic diagnostic services and research&development and implementation of new diagnostic protocols for the University Clinical Center Maribor and University Clinical Center Ljubljana and other clinical and non-clinical national health related institutions such as National instute of Public Health; selected R&D projects include IRP-2016/01 »Development of next generation sequencing protocols for diagnosis of monogenetic (Mendelian) syndromes at University Clinical Center Maribor, Division of Paediatrics«, IRP-2014/01-30 2. Collaboration with industry • Development of pharmacogenomics field in Slovenia. Patients could suffer for less adverse side effects if therapy is personalized based on molecular and genetic biomarkers dicovered in our project. The health care budged could benefit from more efficient individualized therapy. • biotech company providing jobs with highly added value could be started based on results of our project: Different sets of biomarkers will result from the biochemical, genetic and microarray data, which can be offered as service or sold as diagnostic kits. Kits will be attractive for academic and industrial research. Genes related to adverse drug reactions and SNPs in these genes (so called safety targets) can be patented. The intellectual property can be utilized for own drug development through partners from the institute or more likely can be licensed to pharmaceutical companies for drug development. • Descriptions of genetic diversity, such as location in the genome, the type and frequency of polymorphisms in the control population are directly applicable to a number of research groups in Slovenia, which carried out association studies in various complex diseases. Experience and knowledge of statistical and bioinformatics analysis of a vast number of genetic data obtained NGS for genotyping SNP can offer a support to Slovenian research teams, using association studies in the whole genome to identify genetic risk factors for complex diseases and other complex phenotypes in humans and other organisms.
Most important scientific results
Annual report
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
2015,
final report
