Naslov (srp)

Povezanost varijanti gena za receptore slične Toll-u, njihovih regulatornih mikro RNK i retinoidnog receptora (RXR) sa rizikom za nastanak i kliničkim parametrima osteoartritisa : doktorska disertacija

Autor

Mišić, Debora, 1991-

Doprinosi

Šupić, Gordana, 1973-
Petković-Ćurčin, Aleksandra, 1971-
Obradović, Ana, 1981-
Lunić, Tanja, 1995-
Božić Nedeljković, Biljana, 1975-

Opis (eng)

Osteoarthritis (OA) is a progressive degenerative disease of all structures of the joint. Hereditary and environmental factors play a significant role in the development and progression of OA. Inflammatory reaction and immune-mediated mechanisms represent the basis of the disease pathogenesis. Genes associated with the inflammatory process, including Toll-like receptor (TLR) genes, are tightly controlled by several micro RNAs. Micro RNAs play a key role in the regulation of TLR-signaling in the inflammatory process by controlling TLRs themselves, as well as by controlling adapter and regulatory molecules, transcription factors and cytokine signaling. Retinoid X receptor (RXR), a member of the nuclear receptor family, is involved in the regulation of the inflammatory process as a regulator of the main procatabolic mediators involved in the inflammatory reaction in the joints.The study evaluated the association between genetic variants in TLRs, their regulatory micro RNAs (miR-196a-2, miR-146, miR-155) and RXRα and clinical parameters of OA, as well as OA risk in 95 surgically treated OA patients and control group of 104 healthy individuals. Adjusted logistic regression analysis demonstrated that polymorphisms in TLR4 rs4986790 (p=0.006), rs4986791 (p=0.00001), and TLR7 rs385389 (p=0.012) increased OA risk, while miR-196a-2 rs11614913 (p=0.034) was significantly associated with decreased OA risk. Both analyzed RXRα variants are associated with the risk of OA-rs7864987 variant with an increased (p=0.012), while the rs3118523 variant is a protective factor for OA (p=0.030). A statistically significant difference was observed in the distribution of genotypes in OA cases and controls for both investigated TLR4 gene variants-rs4986790 (p=0.004), and rs4986791 (p=0.0001), TLR7 variant-rs3853839 (p=0.033), miR-196a-2 variant rs11614913 (p=0.010), as well as for the rs7864987 variant of the RXRα gene (p=0.008). The rs5743708 variant of the TLR2 gene was associated with menopause (p=0.03). The rs11614913 variant of the miR-196a2 gene was associated with gender and previous joint injury (p=0.014), while the rs767649 variant of the miR-155 gene was associated with early menopause (p=0.036). RXRα variant rs7864987 is associated with age (p=0.035). TLR4 (rs4986790; rs4986791) and TLR7 (rs385389) gene variants represent potential risk factors for OA, while miR-196a-2 gene variant rs11614913 represents a protective factor for this disease. Analyzed RXRα variations are both associated with OA susceptibility, one as protective (rs3118523) and other as risk factor for OA (rs7864987). The identification of new genetic biomarkers associated with the inflammatory process in the joint microenvironment provides insight into the immunopathological mechanisms of the disease. Modulation of TLRs, micro RNAs and RXR-α can be successfully applied in designing an individualized approach not only in the treatment of patients who have developed this disease, but also in patients susceptible to developing OA.

Opis (srp)

Osteoartritis (OA) je progresivna degenerativna bolest svih struktura zlobnog aparata. U razvoju i progresiji OA značajnu ulogu imaju nasledni faktori i faktori životne sredine. Zapaljenska reakcija i imunski posredovani mehanizmi su osnova patogeneze bolesti. Geni koji su povezani sa zapaljenskim procesom, uključujući gene za receptore slične Toll-u (TLR), su strogo kontrolisani od strane nekoliko mikro RNK. Mikro RNK igraju ključnu ulogu u regulaciji TLR signalizacije u zapaljenskom procesu kontrolom samih TLR, kao i kontrolom adapterskih i regulatornih molekula, faktora transkripcije i citokinske signalizacije. Retinoidni X receptor (RXR), član porodice nuklearnih receptora, je uključen u regulaciju zapaljenskog procesa kao regulator glavnih prokataboličkih medijatora uključenih u zapaljensku reakciju u zglobovima.Ispitivana je povezanost varijanti gena za TLR, njihovih regulatornim mikro RNK (miR-196a-2, miR-146, miR-155) i RXRα sa kliničkim parametrima, kao i rizikom od OA kod 95 hirurški lečenih pacijenata sa primarnim OA i kontrolnoj grupi od 104 zdrava pojedinca.Logistička regresiona analiza prilagođena za pol i godine je pokazala da varijante gena za TLR4 rs4986790 i rs4986791 značajno povećavaju rizik od OA (p=0,006; p=0,00001), kao i varijanta gena za TLR7 rs385389 (p=0,012). Varijanta rs11614913 u genu za miR-196a2 je povezana sa smanjenim rizikom od OA (p=0,034). Obe analizirane RXRα varijante dovedene su u vezu sa rizikom od OA, i to varijanta rs7864987 sa povećanim rizikom za OA (p=0,012), dok rs3118523 varijanta predstavlja protektivni faktor za OA (p=0,030). Uočena je statistički značajna razlika u distribuciji genotipova kod ispitanika sa primarnim OA i kontrola i to za obe ispitivane varijante gena za TLR4-rs4986790 (p=0,004) i rs4986791 (p=0,0001), gena za TLR7-rs3853839 (p=0,033), gena za miR-196a2-rs11614913 (p=0,010), kao i za varijantu rs7864987 gena za RXRα (p=0,008). Varijanta rs5743708 gena za TLR2 dovedena je u vezu sa menopauzom (p=0,03). Varijanta rs11614913 gena za miR-196a2 povezana je sa polom i prethodnom povredom zgloba (p=0,014), dok je varijanta rs767649 gena za miR-155 povezana sa ranom menopauzom (p=0,033). RXRα varijanta rs7864987 povezana je sa starošću (p=0,035).Varijante gena za TLR4 (rs4986790; rs4986791) i TLR7 (rs385389) su potencijalni faktor rizika za OA, dok varijanta gena za miR-196a-2 rs11614913 predstavlja potencijalni zaštitni faktor za ovu bolest. Analizirane varijante gena za RXRα su takođe povezane sa predispozicijom za razvoj OA, jedna kao zaštitna (rs3118523), a druga kao faktor rizika (rs7864987). Identifikacija novih genetičkih biomarkera povezanih sa zapaljenskim procesom u mikrosredini zgloba omogućava uvid u imunopatološke mehanizme bolesti. Modulacija TLR-a, mikro RNK i RXR-α može se uspešno primeniti u dizajniranju individualizovanog pristupa ne samo u lečenju pacijenata koji su razvili ovu bolest, već i kod pacijenata koji su podložni razvoju OA.

Opis (srp)

Biologija - Genetika/Imunogenetika / Biology- Genetics/Immunogenetics Datum odbrane: 20.12.2024.

Jezik

srpski

Datum

2024

Licenca

Ovo delo je licencirano pod uslovima licence
Creative Commons CC BY-NC-ND 3.0 AT - Creative Commons Autorstvo - Nekomercijalno - Bez prerada 3.0 Austria License.

http://creativecommons.org/licenses/by-nc-nd/3.0/at/legalcode

Predmet

OSNO - Opšta sistematizacija naučnih oblasti, Molekularna imunologija

osteoartritis, TLR, mikro RNK, varijante gena, RXR, zapaljenska reakcija

577.27:616-097(043.3)

OSNO - Opšta sistematizacija naučnih oblasti, Molekularna imunologija

osteoarthritis, TLR, micro RNA, RXR, gene variants, inflammation