Uloga alelnih varijanata MDR1 gena u patogenezi upalnih bolesti crijeva i odgovoru na liječenje glukokortikoidima

Brinar, Marko (2011) Uloga alelnih varijanata MDR1 gena u patogenezi upalnih bolesti crijeva i odgovoru na liječenje glukokortikoidima. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Inflammatory bowel diseases are chronic diseases of unknown etiology and pathogenesis in which genetic factors contribute to development of disease. MDR1/ABCB1 is an interesting candidate gene in inflammatory bowel disease for several reasons. First, mdr1a knock out mice develop colitis that resembles ulcerative colitis. Second, it is located in the region of chromosome 7 associated with inflammatory bowel disease. Finally, high levels of its protein product Pgp, functioning as an ATP-dependant membrane efflux pump, are found on apical surfaces of intestinal epithelial cells. Initial reports confirmed association of polymorphisms of MDR1 and IBD. However, results of subsequent studies were contradictory making the role of MDR1 gene in IBD pathogenesis and susceptibility unclear. Additional interest in these gene arose from the fact that glucocorticoids are know substrates of Pgp. The fact that certain polymorphisms influence expression levels of Pgp leads to the possibility that different expression levels might influence outcome of glucocorticoid therapy. However, results of current studies are contradictory. Thus, the aims of this research were to investigate the association of MDR1polymorphisms and inflammatory bowel disease and to investigate the association of these polymorphisms with certain clinical characteristics. We also aimed to investigate the association of MDR1 polymorphisms with outcome of glucocorticoid therapy with an attempt to identify aleles or genotypes risk conffering for therapy failure. A total of 310 inflammatory bowel disease patients, 199 Crohn's disease and 109 ulcerative colitis patients, and 120 healthy controls were included in the study. All subjects were genotyped for G2677T/A i C3435T polymorphism using RT-PCR. In IBD patients review of medical records was performed and patients were meticulously phenotyped according to the Montreal classification. Additionaly, data regarding exposure to glucocorticoids and therapy outcome were recorded and patients were categorised as having good response, dependant or refractory to glucocorticoids. We report association of MDR1 gene polymorphisms and inflammatory bowel disease on the level of alleles, genotypes and two locus haplotypes. Based on our findings, the observed association of MDR1 polymorphisms and IBD is modest. We also report an association of investigated polymorphisms and phenotypic characteristics of Crohn's disease patients. Furthermore, we found an association with outcome of glucocorticoid therapy. The observed effect is also modest but is somewhat more prononced in ulcerative colitis patients. In conclusion, MDR1 gene polymorphisms are associated with inflammatory bowel disease. Apart from their effect on disease susceptibility they also exhibit a disease-modifying effect in Crohn's disease. Furthermore, MDR1 gene has a modest impact glucocorticoid therapy outcome that is more pronounced in ulcerative colitis.

Abstract in Croatian

Upalne bolesti crijeva kronične su bolesti nepoznate etiologije i patogeneze u kojih postoji doprinos genetskih čimbenika pojavi bolesti. MDR1/ABCB1 gen zanimljiv je kandidat gen za upalne bolesti crijeva iz nekoliko razloga. Prvo, knock out miševi za mdr1a gen razvijaju kolitis nalik ulceroznom kolitisu. Nadalje, smješten je na 7 kromosomu u regiji povezanoj s pojavom upalnih bolesti crijeva. Konačno, postoje visoke razine ekspresije Pgp-a, proteinskog produkta MDR1 gena koji funkcionira kao o ATP-u ovisna membranska transportna pumpa, na apikalnim površinama crijevnih epitelnih stanica. Nakon inicijalnih istraživanja koja su uputila na povezanost polimorfizama MDR1 gena i upalnih bolesti crijeva, kasnija istraživanja ponudila su oprečne rezultate te je uloga MDR1 u patogenezi upalnih bolesti crijeva nejasna. Dodatno zanimanje za MDR1 pobudila je i činjenica da su glukokortikoidi supstrat Pgp-a, proteinskog produkta MDR1. Spoznaja da pojedini polimorfizmi MDR1 gena utječu na ekspresiju proteina otvorila je mogućnost da različite razine ekspresije mogu utjecati na uspjeh terapije glukokortikoidima. Međutim, rezultati dosadašnjih istraživanja također su proturječni. Stoga su ciljevi ovog istraživanja bili dokazati povezanost između polimorfizama MDR1 gena i upalnih bolesti crijeva te pronaći povezanost između prisutnosti određenog genotipa i pojedinih kliničkih karakteristika bolesti. Nadalje, cilj istraživanja bilo je dokazati povezanost polimorfizama MDR1 gena i učinka terapije glukokortikoidima s krajnjim ciljem identificiranja rizičnih faktora na razini alela odnosno genotipova za terapijski neuspjeh. U istraživanje smo uključili ukupno 308 bolesnika s upalnim bolestima crijeva, 199 s Crohnovom bolesti i 109 s ulceroznim kolitisom, te 120 zdravih kontrola. U svih bolesnika učinjena je genotipizacija za G2677T/A i C3435T polimorfizma metodom RT-PCR. U bolesnika s upalnim bolestima crijeva učinjen je studiozan pregled dosadašnje medicinske dokumentacije te su bolesnici fenotipizirani prema Montrealskoj klasifikaciji. Također, učinjen je i pregled dosadašnjeg načina liječenja posebno u pogledu uzimanja glukokortikoida u tijeku bolesti te su bolesnici grupirani u skupinu s dobrim odgovorom, ovisne ili refraktorne na glukokortikoide. Dokazali smo povezanost polimorfizama MDR1 gena i upalnih bolesti crijeva na razini alela, genotipova i haplotipova dva lokusa. Na temelju naših rezultata povezanost polimorfizama MDR1 gena i upalnih bolesti crijeva je skromna. Također smo dokazali povezanost ispitivanih polimorfizama i fenotipskih karakteristika u bolesnika s Crohnovom bolesti. Nadalje, dokazali smo utjecaj ovih polimorfizama na uspjeh terapije glukokortikoidima. Opaženi utjecaj na ishod terapije je skroman te je nešto izraženiji u bolesnika s ulceroznim kolitisom. Zaključno, polimorfizmi MDR1 gena igraju ulogu u patogenezi upalnih bolesti crijeva. Izuzev učinka na predispoziciju na pojavu bolesti modificiraju i tijek Crohnove bolesti. Također, MDR1 gen ima skroman utjecaj na uspjeh liječenja glukokortikoidima posebno u bolesnika s ulceroznim kolitisom.

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