Povezanost polimorfizma u genu za receptor vitamina D sa genskom predispozicijom i kliničkim parametrima obolelih od osteoartritisa velikih zglobova

Abstract

Uvod. Osteoartritis je degenerativna, hronična i ireverzibilna bolest koja pogađa milione ljudi širom sveta. Uzroci i mehanizmi osteoartritisa nisu do kraja razjašnjeni. Vitamin D je bitan faktor u metabolizmu kostiju. Njegovo delovanje posreduje vitamin D receptor, faktor transkripcije koji kontroliše ekspresiju gena, održavajući na taj način homeostazu kalcijuma i fosfata. Hipoteza o vitaminu D je da igra ključnu ulogu u brojnim mišićnokoštanim bolestima, uključujući osteoartritis, a njegov nedostatak preovlađuje među pacijentima s osteoartritisom. Polimorfizmi gena za receptor vitamina D (VDR) mogli bi da igraju značajnu ulogu u genetskoj predispoziciji i patogenezi osteoartritisa (OA), najčešćeg degenerativnog poremećaja zglobova kod ljudi. Cilj. Cilj ove doktorske disertacije bilo je utvrđivanje postojanja povezanosti između polimorfizama FokI, TaqI, ApaI i EcoRV u VDR genu s rizikom za nastanak i progresiju osteoartritisa u domaćoj populaciji. Urađen je veliki broj studija u vezi s efektima vitamina D na patogenezu i progresiju osteoartritisa, kao i njegovom upotrebom kao terapeutskog sredstva. Do sada su studije dale kontroverzne rezultate i nije postignut konsenzus po tom pitanju. Našim radom želimo da istražimo trenutne podatke o mogućoj ulozi vitamina D i njegovog receptora u patogenezi osteoartritisa, i procenimo efikasnost suplementacije vitamina D kao terapijske strategije. Materijal i metode. Studijska grupa ispitanika je obuhvatila ukupno 94 pacijenta s OA, a kontrolna grupa 100 zdravih, asimptomatskih osoba odgovarajuće polne i starosne distribucije. Polimorfizmi FokI (rs2228570), TaqI (rs731236), ApaI (rs7975232) i EcoRV (rs4516035) u VDR genu su određivani pomoću metode PCR-a u realnom vremenu (Realtime PCR). Rezultati. Analiza prilagođenog odnosa šansi (OR) pokazala je da su polimorfizmi VDR TaqI i FokI značajno povezani s predispozicijom za OA (OR = 1,986, p = 0,001, odnosno OR = 1,561, p = 0,017). Analiza specifična za tip zglobova pokazala je da je polimorfizam VDR TaqI povezan s rizikom nastanka OA kuka (OR = 1,930, p = 0,005) i OA kolena (OR = 1,916, p = 0,028), dok je polimorfizam VDR FokI povezan s višim rizikom pojave OA kolena (OR = 2,117, p = 0,012). Polimorfizmi VDR TaqI i FokI povezani su s pojavom trajnog bola (p = 0,005, odnosno p = 0,027), dok je ApaI povezan s porodičnom istorijom OA (p = 0,004). Zaključak. Genetske varijante VDR FokI i TaqI bi mogle značajno doprinositi riziku za nastanak osteoartritisa, pojavi trajnog bola i potencijalno riziku za pojavu OA specifičnog za tip zgloba.

Introduction. Osteoarthritis is a degenerative, chronic and irreversible disease that affects millions of people around the world. The causes and mechanisms of osteoarthritis are not fully understood. Vitamin D is an important factor in bone metabolism. Its action is mediated by the vitamin D receptor, a transcription factor that controls gene expression, thus maintaining the homeostasis of calcium and phosphate. The vitamin D hypothesis is that it plays a key role in a number of musculoskeletal diseases, including osteoarthritis, and its deficiency is prevalent among patients with osteoarthritis. Vitamin D receptor (VDR) gene polymorphisms could play a significant role in the susceptibility and pathogenesis of osteoarthritis (OA), the most common degenerative joint disorder in humans. Aim. The aim of the doctoral dissertation was to determine the association between polymorphisms FokI, TaqI, ApaI and EcoRV in VDR gene, with risk for the onset and progression of osteoarthritis in the local population. A large number of studies have been done regarding the effects of vitamin D on the pathogenesis and progression of osteoarthritis, as well as its use as a therapeutic agent. So far, studies have yielded controversial results and no consensus has been reached on the issue. Our work aims to investigate current data on the possible role of vitamin D and its receptor in the pathogenesis of osteoarthritis and to evaluate the efficacy of vitamin D supplementation as a therapeutic strategy. Material and methods. The current study involved 94 OA patients, and 100 healthy, asymptomatic controls. VDR variants FokI (rs2228570), TaqI (rs731236), ApaI (rs7975232) and EcoRV (rs4516035) were genotyped using the TaqMan based Real-Time PCR. Results. Adjusted Odds Ratio (OR) analysis showed that VDR TaqI and FokI polymorphisms are significantly associated with the susceptibility to OA (OR=1.986, p=0.001, and OR=1.561, p=0.017, respectively). The joint-specific analysis showed that VDR TaqI polymorphism was associated with a risk of hip OA (OR=1.930, p=0.005) and the knee OA (OR=1.916, p=0.028), while VDR FokI polymorphism was associated with the higher risk of knee OA (OR=2.117, p=0.012). VDR TaqI and FokI polymorphisms are associated with the occurrence of persistent pain (p=0.005, and p=0.027, respectively), while ApaI was associated with a family history of OA (p=0.004). Conclusion. The VDR FokI and TaqI genetic variants significantly contribute to osteoarthritis susceptibility, the occurrence of persistent pain, and potentially to jointspecific OA risk.