Marijana Janković Danolić

Ime i prezime: dr. sc. MARIJANA JANKOVIĆ DANOLIĆ, mag. pharm.
 
Naslov disertacije: „ULOGA ADROPINA I HOMOCISTEINA U ATEROGENEZI BOLESNIKA S PRIMARNIM SJÖGRENOVIM SINDROMOM”
 
Mentorica: izv. prof. dr. sc. DIJANA PERKOVIĆ 


Datum obrane: 26. lipnja 2023.
 
Poveznnica: https://neuron.mefst.hr/docs/graduate_school/ebm/Pred%20obranom/DOKTORSKA%20DISERTACIJA_MARIJANA%20JANKOVIC%20DANOLIC_.pdf?vel=1950080
 
Kvalifikacijski znanstveni radovi za doktorsku disertaciju:


Danolić MJ, Perković D, Petrić M, Barišić I, Gugo K, Božić J. Adropin Serum Levels in Patients with Primary Sjögren's Syndrome. Biomolecules. 2021;11(9):1296.
doi: 10.3390/biom11091296.
 
 
SAŽETAK:
Uvod: Bolesnici s pSS-om imaju povećanu prevalenciju endotelne disfunkcije i preuranjene ateroskleroze, a posljednjih godina je u fokusu istraživanja subklinička ateroskleroza u bolesnika s autoimunim bolestima. Nedavno je otkriven adropin, sekretorni protein koji ima značajnu ulogu u regulaciji metabolizama lipida i inzulinskoj rezistenciji, a isto tako ispoljava pozitivan učinak na funkciju endotelnih stanica te ima protuupalni učinak. Povišene razine homocisteina pokazale su se kao jak i neovisan čimbenik kardiovaskularnog rizika u zdravoj populaciji. Homocistein se pokazao i kao neovisan faktor rizika za razvoj subkliničke ateroskleroze. Korištenje CIMT-a, valjanog markera generalizirane ateroskleroze i rizika od vaskularne bolesti, može pomoći u identificiranju visokorizičnih bolesnika sa subkliničkom aterosklerozom. Cilj: Cilj ovog istraživanja bio je odrediti razine adropina i homocisteina te CIMT-a u bolesnika s pSS-om u usporedbi s kontrolnom skupinom. Nadalje, ciljevi su bili istražiti povezanoti između adropina, homocisteina i CIMT-a s imunološkim parametarima u pSS-u, uključujući protutijela specifična za bolest, EULAR-ov indeks aktivnosti bolesti u Sjögrenovom sindromu (ESSDAI) i indeks oštećenja bolesti u Sjögrenovom sindromau (SSDDI). Metode: U ovom presječnom istraživanju uključeno je 52 bolesnika s pSS-om i 52 ispitanika u kontrolnoj skupini usporedni s ispitivanom grupom po dobi, spolu, pušenju i ITM-u. Za dio istraživanja o homocisteinu uključeno je 48 bolesnika s pSS-om i 46 ispitanika u kontrolnoj skupini. Demografske varijable i klasični čimbenici kardiovaskularnog rizika: hipertenzija, dislipidemija, pretilost i navika pušenja procijenjeni su u obje skupine, a također su kliničkim pregledom i intervjuem prikupljene značajke povezane s bolešću u bolesnika s pSS-om. Za procjenu aktivnosti bolesti i kroničnog oštećenja su koristeni ESSDAI te SSDDI. Za analizu adropina je korištena enzimatska imunoanaliza (ELISA). Koncentracija homocisteina u serumu mjerena je korištenjem kemiluminiscentnog imunološkog testa mikročestica (CMIA). Prisutnost subkliničke ateroskleroze određena je CIMT-om procijenjenim ultrazvukom karotida.
Rezultati: Bolesnici s pSS-om imaju značajno više razine adropina u usporedbi s kontrolnom skupinom (3,76 ± 0,68 naspram 3,14 ± 0,69 ng/mL, p < 0,001). Razine adropina u bolesnika s pSS-om su pozitivno povezane s HDL-om (r = 0,290, p = 0,036) i anti SSA/Ro52 antitijelima (r = 0,307, p = 0,026) te negativno povezane sa SSDDI ( r = −0,401, p = 0,003). Multivarijantna linearna regresija pokazala je da su razine adropina neovisno povezane s HDL-om (β ± SE, 0,903 ± 0,283, p = 0,002) i SSDDI (β ± SE, -0,202 ± 0,073, p = 0,008). Arterijski tlak je bio viši u bolesnika s pSS-om (p = 0,007) za sistolički krvni tlak (SBD) i ()p = 0,018 za dijastolički krvni tlak (DBP). Suprotno od očekivanog, ukupni kolesterol (TC) bio je veći u kontrolnoj skupini (p = 0,047). Vrijednosti homocisteina bile su značajno veće u pacijenata s pSS-om (p=0,015), kao i CIMT (p=0,0372). Homocistein je pozitivno korelirao s trigliceridima (TG) (r=0,204, p=0,048) i CIMT-om (r= 0,231, p=0,046). CIMT je pozitivno povezan s dobi (r=0,416, p p<0,0001), SBP (r=0,293, r=0,004) i s indeksom oštećenja u Sjögrenovom sindromu (SSDDI) (r=0,351, p=0,014). Također je negativno korelirao s autoantitijelima specifičnim za Sjögrenov sindrom anti SSA/Ro60 (r= -0,431, p=0,002) i anti SSB/La (r= -0,346, p=0,016).
Zaključak: Naše istraživanje ukazuje da bolesnici s pSS-om imaju povećani rizik za subkliničku aterosklerozu te da bi adropin mogao biti uključen u patofiziologiju pSS-a i navedene procese djelujući protektivno na endotel. Također smo pokazali da postoji značajna povezanost između subkliničkog aterosklerotskog procesa i homocisteina. Homocistein bi mogao biti jeftini i dostupan marker za stratifikaciju rizika razvoja subkliniče ateroskleroze u asimptomatskih bolesnika. Ovi rezultati upućuju da bi uključivanje određivanja razina adropina i homocisteina u plazmi u protokole za smanjenje rizika moglo biti relevantno za identifikaciju pojedinaca s većim rizikom od aterosklerotskih događaja. U konačnici bi to omogućilo pravovremeno poduzimanje preventivnih mjera kojima bi se navedeni rizici smanjili.
Ključne riječi: primarni Sjögren-ov sindrom, subklinička ateroskleroza, endotelna disfunkcija, adropin, homocistein, CIMT, anti SSA/Ro antitijela, anti SSB/La antitijela, SSDDI, ESSDAI
 
SUMMARY:
Background: Patients with pSS have an increased prevalence of endothelial dysfunction and premature atherosclerosis, and in recent years the focus of research has been on subclinical atherosclerosis in patients with autoimmune diseases. Recently, adropin was discovered, a secretory protein that plays a significant role in the regulation of lipid metabolism and insulin resistance, and also has a positive effect on the function of endothelial cells and has an antiinflammatory effect. Elevated homocysteine levels have been shown to be a strong and independent cardiovascular risk factor in a healthy population. Homocysteine has also been shown to be an independent risk factor for the development of subclinical atherosclerosis. The use of CIMT, a valid marker of generalized atherosclerosis and risk of vascular disease, may help identify high-risk patients with subclinical atherosclerosis.
Objective: The aim of this study was to determine the level of adropin and homocysteine and CIMT values in patients with pSS compared to healthy controls. Additional objectives were to investigate the correlation between adropin, homocysteine and CIMT with immunological parameters in pSS as disease-specific antibodies, EULAR Sjögren's syndrome disease activity index (ESSDAI) and Sjögren's syndrome disease damage index (SSDDI).
Methods: In this cross-sectional study, 52 patients with pSS and 52 subjects in the control group were included, comparable in terms of age, sex, smoking and BMI. For the homocysteine part of the study, 48 patients with pSS and 46 subjects in the control group were included. Demographic variables and classic cardiovascular risk factors: hypertension, dyslipidemia, obesity and smoking habits were assessed in both groups, and features associated with the disease in the pSS group were also collected through clinical examination and interviews. ESSDAI and SSDDI were used to assess disease activity and chronic disease damage. Enzyme immunoassay (ELISA) was used to analyze adropin. Serum homocysteine concentration was measured using a chemiluminescent microparticle immunoassay (CMIA). The presence of subclinical atherosclerosis was determined by CIMT assessed by carotid ultrasound.
Results: Patients with pSS have significantly higher adropin levels compared to controls (3.76 ± 0.68 vs. 3.14 ± 0.69 ng/mL, p < 0.001). Adropin levels in patients with pSS are positively correlated with HDL (r = 0.290, p = 0.036) and anti SSA/Ro52 antibodies (r = 0.307, p = 0.026) and negatively correlated with SSDDI (r = −0.401, p = 0.003). Multivariate linear regression showed that adropin levels were independently associated with HDL (β ± SE, 0.903 ± 0.283, p = 0.002) and SSDDI (β ± SE, -0.202 ± 0.073, p = 0.008).
Arterial pressure was higher in patients with pSS (p = 0.007) for systolic blood pressure (SBP) and (p = 0.018) for diastolic blood pressure (DBP). Contrary to expectation, total cholesterol (TC) was higher in the control group (p = 0.047). Homocysteine values were significantly higher in patients with pSS (p=0.015), as well as CIMT (p = 0.0372). Homocysteine positively correlated with triglycerides (TG) (r = 0.204, p = 0.048) and CIMT (r= 0.231, p=0.046). CIMT was positively correlated with age (r = 0.416, p < 0.0001), SBP (r=0.293, r=0.004) and with Sjögren's syndrome impairment index (SSDDI) (r = 0.351, p = 0.014). It also negatively correlated with Sjögren's syndrome-specific autoantibodies anti SSA/Ro60 (r = -0.431, p = 0.002) and anti SSB/La (r = -0.346, p = 0.016).
Conclusion: Our findings are implying that patients with pSS have an increased risk for subclinical atherosclerosis and that adropin could be involved in the pathophysiology of pSS and the in mentioned processes by acting protectively on the endothelium. We also showed that there is a significant association between the subclinical atherosclerotic process and homocysteine. So, homocysteine could be a cheap and available marker for risk stratification of the development of subclinical atherosclerosis in asymptomatic patients. These results suggest that the inclusion of determination of plasma adropin and homocysteine levels in risk reduction protocols may be relevant to identify individuals at higher risk of atherosclerotic events. Ultimately, this would enable timely taking of preventive measures that would reduce the mentioned risks.
Key words: primary Sjögren’s syndrome, subclinical atherosclerosis, endothelial dysfunction, adropin, homocysteine, CIMT, anti SSA/Ro antibodies, anti SSB antibodies, SSDDI, ESSDAI
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