Association of potentially regulatory variants in genes IL2RA, IFI30, IKZF3 and expression of selected target genes with onset and severity of multiple sclerosis

[M. Stefanović]

76 str.

Molekularna biomedicina - Molekularna biologija multiple skleroze / olecular biomedicine - Genetics of multiple sclerosis

Prethodne studuje i analiza algoritmima za poboljšanje procene uzročnosti genetičkih varijanti su ukazale da su varijante IL2RA rs2104286, IFI30 rs11554159 i IKZF3 rs12946510 najverovatnje uzročne varijante, u hromozomskim lokusima u kojima se nalaze, za nastanak multiple skleroze (MS). Ciljevi doktorske disertacije su obuhvatili analizu asocijacije navedenih varijanti i ekspresije odabranih ciljnih gena sa nastankom i težinom MS kao i procenu efekta genetičkih varijanti na regulaciju ekspresije ciljnih gene kod pacijenata i zdravih ispitanika iz populacije Srbije. Za ostvarivanje ciljeva primenjene su eksperimentalne metode za genotipizaciju genetičkih varijanti i ekpresije gena koje koriste TaqMan® tehnologiju, a naknadnom statističkom analizom su ispitane asocijacije i korelacije genetičkih i kliničkih podataka. Od tri ispitane varijante, IL2RA rs2104286 je povezana sa nastankom MS-a, gde ređi alel G ispoljava protektivan efekat. Detektovan je kombinovani efekat varijante HLA-DRB1*15:01 i IFI30 rs11554159 ređeg homozigotnog genotipa AA na progresiju MS-a. Ekspresija gena ORMDL3 i GSDMB u MĆPK je smanjena kod pacijenata sa relapsno remitentnim tokom MS u odnosu na zdrave ispitanike. Utvrđena je asocijacija varijante IKZF3 rs12946510, koja je prethodno definisana kao ona koja modifikuja nivo transkripcije određenih gena u različitim tkivima, sa ekpresijom gena ORMDL3 i GSDMB u MĆPK pacijenata sa relapsno remitentim tokom MS. Rezultati ukazuju na kombinovane efekte genetičkih varijanti i imunomodulatorne terapije na promene u ekspresiji gena u MĆPK pacijenata sa relapsno remitentnim MS-om. Diskusijom rezultata sugerisani su molekularni mehanizmi koji potencijalno objašnjavaju detektovane asocijacije i predloženi pravci za buduća istraživanja.

Previous studies and algorithm analysis for improved assessment of genetic variant causality have pointed to variants IL2RA rs2104286, IFI30 rs11554159 and IKZF3 rs12946510 as the most probable causal variants, in their chromosomal loci, for the development of multiple sclerosis (MS). Goals of the doctoral dissertation encompass the analysis of the association of specified variants and expression of the selected target genes with MS development and severity, as well as the assessment of genetic variant’s effect on the expression of target genes in patients and healthy controls from Serbian population. To achieve the dissertation goals, experimental methods for genotyping and gene expression analysis based on TaqMan® technology were applied, and subsequent statistical analysis was used to asses association and correlations of genetic and clinical data. Of the three investigated variants, IL2RA rs2104286 is associated with MS risk, with the rare G allele being protective. A combined effect of variant HLA-DRB1*15:01 and rare IFI30 rs11554159 homozygote, AA, on MS progression was detected. Expression of genes ORMDL3 and GSDMB in PBMCs is diminished in relapsing remitting MS patients in comparison to healthy controls. The variant IKZF3 rs12946510, which was previously defined as a gene expression modifying variant in different tissues, was associated with expression of ORMDL3 and GSDMB in PBMCs of MS patients with relapsing remitting MS. Results show combined effects of genetic variants and immunomodulatory therapy on gene expression changes in PBMCs of patients with relapsing remitting MS. Discussion of the results suggests molecular mechanisms which potentially explain the detected associations and future directions of scientific research were proposed.

Multipla skleroza, tačkasti polimorfizmi, uzročne varijante, ekspresija gena, IL2RA, IFI30, IKZF3, ORMDL3, GSDMB, IKZF3, HLA-DRB1*15:01

Multiple sclerosis, SNP, causal variants, gene expression, IL2RA, IFI30, IKZF3, ORMDL3, GSDMB, IKZF3, HLA-DRB1*15:01

577.2:616.832-004.2(043.3)

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