Naslov (srp)

Značaj određivanja serumskog vitamina 25(OH)D i polimorfizmi gena CYP2R1, CYP27B1, DBP i VDR kod obolelih od sarkoidoze : doktorska disertacija

Autor

Stjepanović, Mihailo, 1980-, 15368295

Doprinosi

Mihailović-Vučinić, Violeta, 1956-, 12471399
Pavlović, Sonja, 1960-, 13797991
Milenković, Branislava, 1959-, 12527975
Škodrić-Trifunović, Vesna, 1959-, 11856231
Lazić, Zorica, 1956-, 13568615

Opis (eng)

Sarcoidosis is a rare multisystem granulomatous disease of unknown etiology. It is characterized by the formation of granulomas, which can occur in any part of the body, most commonly occurring in the lungs and lymph nodes. Patients often suffer from coughing, shortness of breath, chest pain, and severe fatigue and are at risk of developing lung fibrosis or irreversible damage to other organs. In many patients, the disease resolves spontaneously, often without clinical diagnosis, while in 10-30% of cases, sarcoidosis becomes chronic and progressive, sometimes leading to death. Mortality is relatively low, from 1-8%, depending on the intensity of the disease, the patient’s age, gender and ethnicity. According to numerous studies, vitamin D and sarcoidosis are in close relationship. Sarcoidosis most commonly occurs in the winter months when vitamin D levels are low. Further, sarcoidosis is more common in areas beyond the equator. Vitamin D deficiency and the risk of sarcoidosis are common in dark pigmented individuals and are particularly high in African Americans living in northern latitudes and with a higher incidence of vitamin D. For those individuals sarcoidosis is a serious multisystemic disease with a chronic course. The role of molecular markers in vitamin D deficiency, that is, variants in genes encoding for proteins involved in vitamin D metabolism, has not been sufficiently investigated in the etiology of sarcoidosis. A number of proteins, including CYP2R1, DBP, CYP27B1, and VDR, are thought to play a role in the metabolism and signaling pathways of vitamin D. Namely, after primary activation of vitamin D in the skin, pro-vitamin D undergoes double hydroxylation. The first one is taking place in the liver by the CYP2R1 enzyme and the other one is in the kidney by the CYP27B1 enzyme. Vitamin D-binding protein (DBP) is a major carrier of vitamin D, which binds all vitamin D metabolites and transports them through the circulation to the cells. The vitamin D receptor (VDR) belongs to the nuclear receptor family and, after ligand binding, the active form of vitamin D creates a heterodimer with the retinoid X receptor and regulates the biological activity of vitamin D. VDR is present on dendritic cells, lymphocytes and marcophages – key immune effector cells involved in sarcoidosis. Therefore, it is thought that these proteins, which play a significant role in the metabolism of vitamin D, its conversion to the active form, as well as signal transduction and activation of target genes, may also act as susceptibility factors and also influence the clinical course of sarcoidosis. Aim: The aim of this associative study was to examine the level of vitamin D in sarcoidosis patients and the influence of variants in genes CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588) and VDR (rs2228570) on serum vitamin D. Additionally, the predisposing influence of these genetic variants on the onset and clinical course of sarcoidosis was examined. Material and methods: The study included 86 patients with sarcoidosis and 50 healthy subjects, who comprised the control group. Serum vitamin D levels were determined by the ELISA method, and detection of variants in the genes tested was performed using the PCR-RFLP method. Results: Our results showed that vitamin D levels correlated with calcium levels as well as with pulmonary function parameters. Also, the results showed that the allele A of the rs4588 of DBP gene was significantly associated with lower levels of 25(OH)D vitamin D in patients with sarcoidosis (p=0.046). Additionally, the AA genotype of DBP rs4588 gene was shown to be a risk factor, as individuals with this genotype were eight times more likely to develop sarcoidosis (OR 8.856, p=0.049). Subjects carrying the CC genotype in the CYP27B1 gene (rs10877012) were ten times less likely to develop sarcoidosis (OR 0.116, p=0.001). Conclusion: These results show that the level of serum vitamin D in patients depends on the genotype of the rs4588 DBP gene, and that this genetic variant represents a risk factor for vitamin D hypovitaminosis. Also, variants in the tested genes influence the risk of sarcoidosis, because the genotypes in rs10877012 CYP27B1 and rs4588 DBP were statistically different in the patient group compared to the control group. This is a significant result, not only for sarcoidosis, but also for other diseases resulting from immune system dysfunction. Additional studies, as well as different approaches, which will monitor the expression of these genes, as well as their functional characterization, will contribute to a better understanding of the complex role that vitamin D plays in health and disease.

Opis (srp)

Sarkoidoza je retka multisistemska granulomatozna bolest nepoznate etiologije. Karakteriše je stvaranje granuloma, koji se mogu javiti u bilo kom delu tela, a najčešće se javljaju u plućima i limfnim čvorovima. Pacijenti često pate od kašlja, nedostatka daha, bolova u grudima i izraženog umora i preti im rizik od razvoja fibroze pluća ili nepovratnog oštećenja drugih organa. Kod mnogih pacijenata bolest spontano prođe, često i bez kliničke dijagnoze, dok kod 10–30% slučajeva sarkoidoza postaje hronična i progresivna, i ponekad dovodi do smrti. Smrtnost je relativno mala, od 1-8%, zavisno od intenziteta bolesti, starosti pacijenta, pola i etničke pripadnosti. Prema brojnim studijama, vitamin D i sarkoidoza su u bliskoj vezi. Sarkoidoza se najčešće javlja u zimskim mesecima kada je nivo vitamina D nizak. Dalje, sarkoidoza je češća u oblastima koje su dalje od ekvatora. Nedostatak vitamina D i rizik od razvoja sarkoidoze je uobičajen kod tamno pigmentiranih pojedinaca i posebno je visok kod Afro-Amerikanaca koji žive na severnim geografskim širinama i koji imaju veću učestalost nedostatka vitamina D. Kod njih je sarkoidoza ozbiljna multisistemska bolest sa hroničnim tokom. Uloga molekularnih markera u deficijenciji vitamina D, odnosno varijanti u genima koji kodiraju za proteine uključene u metabolizam vitamina D, je nedovoljno istražena u etiologiji sarkoidoze. Smatra se da brojni proteini, među kojima su CYP2R1, DBP, CYP27B1 i VDR imaju ulogu u metabolizmu i signalnim putevima vitamina D. Naime, nakon primarne aktivacije vitmina D u koži, pro- vitamin podleže dvostrukoj hidroksilaciji. Prava se odigrava u jetri posredstvom enzima CYP2R1, a druga u bubrezima, posredstvom CYP27B1 enzima. Vitamin D-vezujući protein (DBP) je glavni nosač vitamina D, koji vezuje metabolite vitamina D i transportuje ih kroz cirkulaciju do ćelija. Receptor za vitamin D (VDR) pripada familiji nuklearnih receptora i nakon vezivanja liganda – aktivne forme vitamina D, stvara heterodimer sa retinoidnim X receptorom i reguliše biološku aktivnost vitamina D. VDR je prisutan na dendričnim ćelijama, limfocitima i markofagama – ključnim ćelijama imuno- efektora kod sarkoidoze. Stoga se smatra da ovi proteini, koji igraju značajnu ulogu u metabolizmu vitamina D, njegovoj konverziji u aktivan oblik, kao i signalnoj transdukciji i aktivaciji ciljnih gena mogu imati uticaj i na predispoziciju i uticati na klinički tok sarkoidoze. Cilj: Cilj ove asocijativne studije bio je da se ispita nivo vitamina D kod pacijenata, kao uticaj varijanti u genima CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588) i VDR (rs2228570) na nivo serumskog vitamina D. Takođe, ispitivan je i predisponirajući uticaj ovih genetičkih varijanti na nastanak i klinički tok sarkoidoze. Materijal i metode: Studija je obuhvatila 86 pacijenata sa sarkoidozom i 50 zdravih ispitanika, koji su činili kontrolnu grupu. Serumski nivo vitamina D određen je ELISA metodom, a detekcija varijanti u ispitivanim genima vršena je korišćenjem PCR-RFLP metode. Rezultati: Dobijeni rezultati su pokazali da nivo vitamina D koreliše sa nivoom kalcijuma, kao i sa parametrima plućne funkcije. Takođe, rezultati su pokazali da je alel A rs4588 DBP gena značajno povezan sa nižim nivoima 25(OH)D vitamina D kod pacijenata sa sarkoidozom (p=0.046). Dodatno, Za genotip AA gena DBP rs4588 je pokazano da je faktor rizika, jer su osobe sa ovim genotipom imale osam puta veću verovatnoću za razvoj sarkoidoze (OR 8.856, p=0.049). Ispitanici nosioci CC genotipa u genu CYP27B1 (rs10877012) imaju deset puta manju verovatnoću da obole od sarkoidoze (OR 0.116, p=0.001). Zaključak: Ovi rezultati pokazuju da nivo serumskog vitamina D kod pacijenata zavisi od genotipa u rs4588 DBP gena, i da ova genetička varijanta predstavlja faktor rizika za hipovitaminozu vitamina D. Takođe, varijante u ispitivanim genina utiču na rizik od oboljevanja od sarkoidoze, jer su genotipovi CYP27B1 rs10877012 i DBP rs4588 statistički različito zastupljeni u grupi pacijenata u odnosu na kontrolnu grupu ispitanika. Ovo je značajan podatak, ne samo za sarkoidozu, već i za druge bolesti koje su posledica disfunkcije imunskog sistema. Dodatne studije, kao i drugačiji pristupi, u kojima će se pratila ekspresija ovih gena, kao i njihova fukcionalna karakterizacija, doprineće boljem razumevanju kompleksne uloge koju vitamin D ima u zdravlju i bolesti.

Opis (srp)

MEDICINA - PULMOLOGIJA / Medicine- Pulmology Datum odbrane: 30.09.2020.

Jezik

srpski

Datum

2020

Licenca

Ovo delo je licencirano pod uslovima licence
Creative Commons CC BY-NC 2.0 AT - Creative Commons Autorstvo - Nekomercijalno 2.0 Austria License.

http://creativecommons.org/licenses/by-nc/2.0/at/legalcode

Predmet

OSNO - Opšta sistematizacija naučnih oblasti, Pulmologija

sarkoidoza, vitamin D, CYP27B1, VDR, DBP, CYP2R1

616.24:577.2(043.3)

OSNO - Opšta sistematizacija naučnih oblasti, Pulmologija

sarcoidosis, vitamin D, CYP27B1, VDR, DBP, CYP2R1