| | SLO | ENG | Cookies and privacy

Bigger font | Smaller font
First page > Show document

Show document Help

Title:Asociacijska analiza na celotnem genomu pri slovenskih bolnikih s kronično vnetno črevesno boleznijo
Authors:ID Mitrovič, Mitja (Author)
ID Potočnik, Uroš (Mentor) More about this mentor... New window
Files:.pdf DR_Mitrovic_Mitja_2013.pdf (74,81 MB)
MD5: EFA45BA9F4BBAB57CFCE9D285561D91C
PID: 20.500.12556/dkum/eddd6239-ec04-4396-8dfa-ad208e80d44b
 
Language:Slovenian
Work type:Dissertation
Organization:MF - Faculty of Medicine
Abstract:V preteklih desetletjih je bil v raziskave in razumevanje patogeneze KVČB vložen precejšen napor, vendar natančni vzroki nastanka bolezni še niso povsem pojasnjeni. Po zdaj najbolj uveljavljeni hipotezi se bolezen pojavi zaradi pretiranega imunskega odziva na normalno črevesno mikrofloro pri gensko dovzetnih posameznikih. Bolniki s KVČB zbolijo za eno od dveh precej podobnih oblik kroničnega vnetja črevesja: ulceroznim kolitisom (UK) ali Crohnovo boleznijo (CB). V 10−15 odstotkih primerov pa bolniki ne kažejo jasnih kliničnih, endoskopskih in histoloških značilnosti CB ali UK, in govorimo o intermediarnem kolitisu (IK). Največjo pogostost bolezni so ugotovili v Kanadi in Severni Evropi, najmanjšo pa v deželah v razvoju in v Aziji, pri čemer je UK pogostejši kot CB. Za slovensko populacijo sicer ni konkretnih epidemioloških podatkov, vendar je bilo ob koncu 90. let v Sloveniji 1150 bolnikov s KVČB, kar nas uvršča na dno evropske lestvice. Na nastanek bolezni vplivajo različni dejavniki okolja, iz epidemioloških raziskav družin in dvojčkov pa nedvomno izhaja, da k tveganju za KVČB prispevajo tudi genski dejavniki. Kljub številnim dokazom o genskem ozadju bolezni se je natančno določanje genskih determinant začelo šele v zadnjih petnajstih letih. Temeljilo je na številnih raziskovalnih pristopih. Asociacijske študije na celotnem genomu (GWAS) so z odkritjem povezav med KVČB in 99 lokusi največ prispevale k razumevanju genskega ozadja bolezni. Med pomembnejše izzive v obdobju po GWAS spadata odkrivanje vzročnih variant in analiza njihovih funkcionalnih posledic, s tem pa posledično tudi rešitev problema manjkajočega dednostnega deleža pri kompleksnih boleznih. Zaradi tega so bili predlagani številni pristopi, kot so npr. fino kartiranje, analiza eQTL-ov in GWAS pri družinah obolelih, vključno s preučevanjem učinkov starševskega izvora (angl. parent of origin − POO) na izražanje genov. Ob tem pa so številne raziskovalne skupine, ki se ukvarjajo z genetiko KVČB, pod okriljem konzorcija International Inflammatory Bowel Disease Consortium (IIBDGC) združile moči v projektu ImmunoChip (iCHIP), ki predstavlja tarčno mikromrežo DNK za analiziranje imunsko posredovanih bolezni. V raziskavi smo izvedli z iCHIP-om prvo tarčno študijo GWAS pri 227 bolnikih s KVČB in 210 zdravih posameznikih. Zaradi razmeroma omejenega števila preiskovancev sicer nismo imeli zadostne statistične moči za odkrivanje statistično značilnih povezav, vendar smo nakazali na nominalne povezave z boleznijo na kromosomih 1, 5, 8, 13 in 16. V sodelovanju z drugimi člani projekta iCHIP, ki je v metaanalizi vključeval približno 75.000 bolnikov s KVČB in zdravih posameznikov, smo prispevali k odkritju 71 novih statistično značilnih povezav z boleznijo, tako da se je skupno število bolezenskih lokusov z 99 povzpelo na 163. Glede odkrivanja skupnih mehanizmov kompleksnih bolezni je pomembna tudi ugotovitev, da je več kot dve tretjini lokusov KVČB impliciranih v patogenezi drugih imunsko posredovanih bolezni, kot so ankilizirajoči spondilitis, psoriaza in mikobakterijske okužbe. V raziskavi smo ločeno izvedli tudi asociacijsko analizo SNP-jev genov NOD2 in IL23R ter prvič povezali omenjena gena s patogenezo KVČB pri slovenskih bolnikih. Genotipske podatke smo pridobili z optimizacijo metode analize DNK s talilnimi krivuljami visoke ločljivosti (HRMA), ki se je izkazala kot hitra, preprosta, natančna in cenovno ugodna metoda za odkrivanje redkih mutacij in za gensko tipizacijo. V študiji smo s kartiranjem cis-eQTL-ov v regiji s tremi kandidatnimi geni ( ) ugotovili, da polimorfizma rs10178214, rs1041973 in redka varianta ccc-2-102248784-A-G statistično značilno vplivajo na izražanje gena IL1RL1 v periferni venski krvi. Nismo pa opazili statistično značilnega izražanja tarčnih genov v črevesnih biopsijah bolnikov s CB. V raziskavi smo pri nizozemskih bolnikih s KVČB odkrili omejen učinek POO genov IL12B, PRDM1 in NOD2, ki pa nam ga v večji neodvisni kohorti ni uspelo replicirati.
Keywords:kronična vnetna črevesna bolezen, asociacijska analiza na celotnem genomu, ImmunoChip
Place of publishing:Maribor
Year of publishing:2013
PID:20.500.12556/DKUM-40169 New window
COBISS.SI-ID:512280632 New window
NUK URN:URN:SI:UM:DK:0T67MRBE
Publication date in DKUM:08.05.2013
Views:4711
Downloads:467
Metadata:XML DC-XML DC-RDF
Categories:MF
:
MITROVIČ, Mitja, 2013, Asociacijska analiza na celotnem genomu pri slovenskih bolnikih s kronično vnetno črevesno boleznijo [online]. Doctoral dissertation. Maribor. [Accessed 30 March 2025]. Retrieved from: https://dk.um.si/IzpisGradiva.php?lang=eng&id=40169
Copy citation
  
Average score:
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
(0 votes)
Your score:Voting is allowed only for logged in users.
Share:Bookmark and Share


Hover the mouse pointer over a document title to show the abstract or click on the title to get all document metadata.

Secondary language

Language:English
Title:Genome-wide association analysis of Slovenian inflammatory bowel disease patients
Abstract:Crohn’s disease (CD) and ulcerative colitis (UC) are the two main forms of chronic relapsing inflammatory bowel diseases (IBD). The etiology of IBD has been extensively studied in the past few decades however, disease pathogenesis is not fully understood. It is a chronic disease characterized by recurring inflammation of the gut, and is thought to arise in response to the commensal microflora in a genetically susceptible host. IBD is believed to be associated with industrialization of nations, with the highest incidence rates and prevalence of IBD in North America and Northern Europe. There are no precise epidemiological data available for Slovenians, yet in the late 90. there were 1.190 individuals affected with IBD. The abundance of epidemiological data is suggesting influence of different environmental and genetic determinants in the disease pathogenesis. Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes to date. One of the future challenges in this post-GWAS era is to identify potential sources of the remaining heritability. Such sources may include common variants with limited effect size, rare variants with higher effect sizes, or even more complicated mechanisms such as epistatic and epigenetic interactions. Many approaches to meet these challenges have been suggested, including fine-mapping, eQTL mapping and family studies, focused on parent of origin (POO) analysis. To fully unravel the hidden heritability of IBD, collaborations between genome research centers are crucial, since the solutions to identify the hidden heritability are either costly or require a huge number of cases and controls. The IIBDGC is a good example of what can be achieved by performing large meta­analyses, and it is currently joining forces in the ImmunoChip project (iCHIP), a custom made array encompasing loci from GWAS of 12 immune-mediated diseases. We conducted iCHIP based association analysis on 227 IBD patients and 210 healthy controls. Unfortunately, due to small sample size we did not have sufficient power to detect significant associations. However we show a trend towards association on chromosomes 1, 5, 8, 13 and 16. In collaboration with other IIBDGC members we expanded on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. We also conducted a separate association analysis for SNPs in genes NOD2 and IL23R, which were associated with Slovenian IBD patients for the first time. Genotypes were obtained by high-resolution melting analysis (HRMA). The results of this study suggest that HRMA yields significant savings on analysis time and costs and has proven as a simple high-throughput technique for screening for polymorphisms. In this study, we also conducted eQTL mapping of IL18RAP locus, which contains 3 candidate genes IL18R1, IL18RAP in IL1RL1. Polymorphisms rs10178214, rs1041973 and a rare variant ccc- 2-102248784-A-G, were influencing expression of IL1RL1 in whole-blood samples. We did not observe any changes of gene expression of the candidate genes when intestinal biopsies were taken into consideration. We identified POO effects for NOD2 for Dutch CD trios; these results could not be replicated in an independent cohort. A POO effect in IBD was observed for IL12B and PRDM1. In the Indian trios the IL10 locus showed a nominal POO effect.
Keywords:inflammatory bowel disease, targeted genome-wide association analysis, ImmunoChip


Comments

Leave comment

You must log in to leave a comment.

Comments (0)
0 - 0 / 0
 
There are no comments!

Back
Logos of partners University of Maribor University of Ljubljana University of Primorska University of Nova Gorica