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Uvod. Bolest rastuće prevalencije, hroničnu opstruktivnu bolest pluća (HOBP), karakteriše oštećenje funkcije pluća, nepotpuno reverzibilno na terapiju, uz prateće egzcerbacije na biološkom i kliničkom nivou. Ispoljava se sistemskom inflamacijom, koja izaziva posledice i u drugim organima, i pojavom komorbiditeta. Pušenje je najveći faktor rizika a ima dokaza da genetska predispozicija utiče na pojavu bolesti kod nekih osoba. Podložnost za HOBP nije do sada ispitivana testom homozigotno-recesivnih osobina (HRO-test). Cilj studije bila je analiza populaciono-genetičke strukture oboljelih od HOBP pomoću HROtesta, t.j. ispitivanje genetičke homozigotnosti oboljelih u odnosu na kontrolnu grupu i korelacije u odnosu na indeks tjelesne mase, stadijum HOBP, stepen ukupne izloženosti duvanskom dimu i drugim noksama, komorbiditet i distribuciju krvnih grupa sistema ABO oboljelih u odnosu na kontrolnu grupu i opštu populaciju. Materijal i metode. Studijsku grupu činilo je 394 ispitanika svrstanih u dvije grupe: 150 oboljelih od HOBP i 244 zdrava ispitanika kontrolne grupe (114 pušača i 130 nepušača). Kod svih je primijenjen HRO-test sa 21 morfo-fiziološkom osobinom i analizirano ukupno preko 8000 markera. Urađena je statistička analiza u skladu sa ciljevima studije. Rezultati. Utvrđen je značajno uvećani prosječan broj HRO u grupi oboljelih u odnosu na kontrolnu grupu, kao i među bolesnicima u odnosu na stadijum bolesti. Različita je distribucija krvnih grupa ABO sistema između oboljelih od HOBP i opšte populacije i u odnosu na stepen funkcijskog oštećenja pluća oboljelih. Zastupljenost komorbiditeta je značajno veća u grupi oboljelih. Zaključak. Oboljeli od HOBP imaju povećan stepen homozigotnosti u odnosu na zdrave osobe nezavisno od pušačkog statusa. Povećana homozigotnost oboljelih može se dovesti u vezu sa remećenjem homeostaze, što omogućava ispoljavanje prisutnih genskih lokusa, i time uvećava mogućnost nastanka bolesti., Introduction. Chronic obstructive pulmonary disease (COPD) is a disease of increasing prevalence characterized by impaired lung function, not fully reversible to treatment, with exacerbations at the biological and clinical levels. It manifests by systemic inflammation causing consequences in other organs, and comorbidities. Tobacco smoking is a major risk factor, and it is evidence based that genetic predisposition may play a role in its development in some individuals. Susceptibility to COPD has not yet been tested by the Homozygous Recessive Characteristics Test (HRC-test). The aim of the study was to analyze the population-genetic structure of patients with COPD by means of the HRC-test, i.e. to determine their genetic homozygosity in relation to the control group, and correlations with body mass index, COPD stage, total exposure to tobacco smoke ingredients and other noxae, comorbidities, and ABO system blood group distribution in relation to both the control group and general population they belong to. Material and methods. The study group consisted of 394 subjects: 150 COPD patients and 244 healthy subjects of the control group (114 smokers, 130 non-smokers). All participants were tested by HRC-test with 21 morpho-physiological markers. More than 8000 examined traits in total were analyzed. Statistical analysis was performed to meet the aims of the study. Results. A significantly increased mean number of HRCs is found in the group of patients compared to the control group, as well as in the group of patients when compared them according to the stages of the disease. The distribution of ABO blood groups between COPD patients and the general population is different, and correlates with lung function impairment. The prevalence of comorbidities is significantly higher in COPD patients. Conclusion. COPD patients have an increased degree of homozygosity compared to healthy individuals regardless of smoking status. The disturbance of homeostasis may enable the expres

Ishemijski moždani udar (IMU) nastaje usled okluzije krvnog suda embolusom, ili trombozom in situ u određenim regionima mozga. Centralna zona ishemije, sa terapijskog aspekta, od početka je izgubljena, ali oko nje se nalazi zona penumbre u kojoj su neuroni poremećene funkcije, ali strukturalno intaktni i gde je još uvek moguć oporavak njihove funkcije. Terapija izbora u akutnoj fazi IMU je intravenska primena rekombinovanog tkivnog aktivatora plazminogena (rtPA). Uprkos činjenici da samo mali broj pacijenata sa akutnim IMU primi rtPA, pacijenati u terapijskom prozoru za primenu iste, imaju veće dugoročno preživljavanje i niže stope mortaliteta, kao i bolji funkcionalni oporavak nakon IMU. Sa druge strane, kod određenog broja pacijenata koji su primili rtPA, dolazi do hemoragijske transformcije (HT) ili simptomatske intrakranijalne hemoragije (sICH), najozbiljnijih komplikacija ove terapije povezanih sa visokom stopom morbiditeta i mortaliteta. Razlozi zašto neki pacijenti bolje, a drugi lošije odgovore na rtPA terapiju su brojni, ali i dalje nisu do kraja razjašnjeni. Genski polimorfizmi mogu biti u osnovi različitog nivoa ekspresije gena, ili aktivnosti genskog produkta, pa posredno mogu uticati na fiziologiju i funkcionalnost ćelija, ali i na odgovor na primenjenu terapiju. Cilj ove disertacije bio je da se kod osoba sa IMU lečenim rtPA terapijom utvrdi učestalost genotipova i alela izabranih polimorfizama u genima koji regulišu fibrinolizu (PAI-1 i ACE) i intergritet vanćelijskog matriksa (MMP-2, MMP-9 i TIMP-2), kao i da se analizira povezanost ispitivanih polimorfnih genskih varijanti sa efikasnošću i pojavom hemoragijskih komplikacija nakon rtPA terapije. Metod: Istraživanje je sprovedeno po tipu hibridne panel studije. Studija je sprovedena od avgusta 2016. godine do avgusta 2018. godine u Specijalnoj bolnici za cerebrovaskularne bolesti ,,Sveti Sava’’ u Beogradu, dok su molekularno-genetička istraživanja obavljena na Institutu za humanu genetiku Medicinskog, Ischemic stroke (IS) occurs due to an embolus or thrombosis causing vascular occlusion in situ in certain brain parts. From the therapeutic point of view, the central zone of ischemia is irrelevant, since nerve cells cannot be saved. However, it is surrounded by a penumbra, an area where the neurons are functionally disturbed, but structurally intact, with the possibility for the recovery of their function. The therapy of choice in the acute phase of IS is an intravenous administration of recombined tissue plasminogen activator (rtPA). Even though only a small number of patients with acute IS receive rtPA, patients within the therapeutic window for its application have higher long-term survival and lower mortality rates, as well as better functional recovery. On the other hand, a certain number of patients who have received rtPA develop symptomatic intracranial hemorrhage (sICH) or hemorrhagic transformation (HT), as the most severe complications of this therapy - associated with high morbidity and mortality rates. The reasons why some patients respond to rtPA therapy better, and others worse are numerous, but still not fully elucidated. Gene polymorphisms could have different effects on gene expression, or the activity of a gene product, and can indirectly affect the physiology and functionality of cells, and also the response to applied therapy. This study aimed to determine the frequency of genotypes and alleles of selected polymorphisms in genes that regulate fibrinolysis (PAI-1 and ACE) and extracellular matrix integrity (MMP-2, MMP-9, and TIMP-2) in individuals with IS treated with rtPA therapy, as well as to analyze the association of the studied polymorphic gene variants with the rtPA efficacy and occurrence of hemorrhagic complications after rtPA therapy. Method: This is a hybrid panel study. It was conducted from August 2016 to August 2018 at the Special Hospital for Cerebrovascular Diseases "St. Sava" in Belgrade, while molecular genetic researches were p

Reumatoidni artritis (RA) je hronično, autoimunsko oboljenje sinovijalnih zglobova koje dovodi do invalidnosti i prerane smrti. Metotreksat (MTX) je zlatni standard u terapiji RA. Inhibicijom enzima adenozinskog ciklusa MTX povećava akumulaciju i izlučivanje adenozina, koji svoje antiinflamatorno dejstvo ostvaruje vezivanjem za adenozinske receptore (ADOR). Polimorfizmi u genima koji kodiraju enzime adenozinskog puta kao i ADOR mogli bi uticati na njihovu ekspresiju i funkciju, a posledično i na sam ishod terapije. Cilj ove doktorske disertacije bio je ispitivanje učestalost alala i genotipova polimorfizama ADORA2A gena (rs2298383, rs2236624, rs5751876, rs17004921), ADORA3 gena (rs2298191, rs1544223, rs3393) i ITPA gena (rs1127354), kao i njihove povezanosti sa efikasnošću i toksičnošću monoterapije MTXom. Metod: Naša studija je uključila 127 bolesnika sa RA koji su bili na monoterapiji MTXom. Efikasnost MTXa je procenjivana na osnovu EULAR kriteijuma koji se baziraju na promeni aktivnosti bolesti merene DAS28 indeksom nakon 6 meseci monoterapije. Oboleli sa dobrim i umerenim odgovorom su klasifikovani kao grupa bolesnika koja ,,pokazuju odgovor na terapiju’’, dok su oboleli bez odgovora činili grupu koja ,,ne pokazuju odgovor na terapiju’’. Neželjeni efekti (NE) su prikupljani tokom šestomesečnog praćenja bolesnika. Radiografska progresija bolesti se bazirala na praćenju pojave erozija na standardnim radiografskim snimcima šaka i stopala. Genotipizacija je izvedena primenom KASP eseja. Rezultati: Na terapiju je odgovor pokazalo 112 (88,2%) bolesnika. Erozije je razvilo 82 (64,6%) bolesnika. NE su bile prijavljene kod 31 (24,4%) bolesnika. Pojedinačni polimorfizmi nisu povezani sa efikasnošću i toksičnošću MTXa. ADORA3 TAA haplotip bio je češći kod obolelih sa erozijama kostiju (29% prema 15,6%, p = 0,023), kao i kod bolesnika sa hepatotoksičnošću (51,3% prema 21,6%, p = 0,013). Zaključak: Rezultati naše studije ukazuju da bi haplotipovi, pre nego pojedinačni polimo, Rheumatoid arthritis (RA) is a chronic, autoimmune disease that primarily affects synovial joints, leading to disability and premature death. Methotrexate (MTX) is the anchor treatment in RA. Via adenosine cycle enzymes inhibition, MTX leads to increased production and excretion of adenosine. Adenosine mediates its antiinflammatory effects by binding to adenosine receptors (ADOR). Polymorphisms within genes coding for adenosine pathway enzymes and ADOR could affect their expression and function, and consequently the outcome of MTX therapy. The aim of this doctoral dissertation was to assess the frequency of alleles and genotypes within ADORA2A (rs2298383, rs2236624, rs5751876, rs17004921), ADORA3 (rs2298191, rs1544223, rs3393) and ITPA (rs1127354) gene polymorphisms and their association with efficacy and toxicity of MTX monotherapy. Method: Our study included 127 RA patients on MTX monotherapy. MTX efficacy estimation was based on the changes in Disease activity score (DAS28) after 6 months of therapy, according to EULAR response criteria. Patients with good and moderate response were classified as ''responders'', while the patients with poor response were classified as ''nonresponders''. Adverse effects (AE) were collected during the six months follow-up period. Radiographic progression was based on the appearance of erosions on standard radiographic images of the hands and feet. Genotyping was performed using the KASP assays. Results: Among patients 112 (88.2%) were responders. We observed bone erosions in 82 (64.6%) of our patients. AE were reported in 31 patients (24.4%). We observed no association between analyzed individual polymorphisms and efficacy and toxicity of MTX. ADORA3 TAA haplotype was more frequent in patients with bone erosions (29% vs 15.6% p = 0.023), as well as in patients with hepatotoxicity (51.3% vs 21.6% p = 0.013). Conclusion: The results of our study suggest that haplotypes, rather than individual polymorphisms, could represent potential

Citohrom P450 genska superfamilija se u ljudskom genomu sastoji od 57 gena, koji se na osnovu aminokiselinske sličnosti razvrstavaju u 44 genske podfamilije i 18 familija. Geni koji pripadaju ovoj familiji se prevode u enzime sa raznovrsnim funkcijama, koji se nazivaju CYP enzimi i eksprimiraju se u različitim tkivima u ljudskom organizmu. Među najznačajnijim funkcijama CYP enzima su sposobnost katalize oksidacije, redukcije i hidroksilacije, zbog čega se ovi enzimi nazivaju i monooksigenazama i poznato je da učestvuju u fazi I metabolizma ksenobiotika. U širokom spektru ksenobiotika koji se metabolišu CYP enzimima se nalazi i veliki broj lekova koji su u kliničkoj upotrebi, što omogućava proučavanje uticaja genetičke varijabilnosti na farmakodinamiju i farmakokinetiku lekova. Uticaj genetičkih promena u CYP genima se prvenstvno ogleda u izmeni aminokiselinske sekvence, a posledično i u smanjenoj funkciji CYP enzima. Pored toga, izmene u DNK sekvenci koja reguliše ekspresiju CYP gena, mogu dovesti do umanjena ili povećanja kapaciteta CYP enzima da metabolišu lek. Izmene u CYP genima, koje najćešće dovode do promena u funkciji CYP enzima, se nazivaju funkcionalne varijante i mogu biti tačkaste izmene ili inserciono-delecione varijante u DNK sekvenci. Na osnovu genotipizacije funkcionalnih varijanti CYP gena, moguće je odrediti i funkcionalnost enzima, kao i metabolički kapacitet čovekovog organizma prema leku za koji je poznato da zavisi od funkcionalnosti tog enzima. Cilj je precizniji odabir vrste i doze leka, kao i izbegavanje neželjene reakcije na lek. Ovakav pristup se naziva farmakogenetikom i predstavlja osnovu na kojoj se razvija personalizovana medicina i molekularna autopsija. Od svih CYP genskih familija koje su bitne za metabolizam lekova, familije CYP1, CYP2 i CYP3 imaju najvećeg uticaja i najbolje su istražene, a unutar njih postoje genetičke varijante za koje je dokumentovano da dovode do izmena u metabolizmu lekova. Međutim, ciljana primena molekularn, The cytochrome P450 gene superfamily in the human genome consists of 57 genes, which are classified into 44 gene subfamilies and 18 families based on amino acid similarity. Genes belonging to this family are translated into enzymes with various functions, called CYP enzymes and are expressed in various tissues in the human body. Among the most important functions of CYP enzymes is the ability to catalyze oxidation, reduction and hydroxylation reactions, which is why these enzymes are also called monooxygenases and are known to participate in phase I metabolism of xenobiotics. The wide range of xenobiotics that are metabolized by CYP enzymes also includes a large number of drugs that are in clinical use, which enables the study of the influence of genetic variability on the pharmacodynamics and pharmacokinetics of drugs. The influence of genetic changes in CYP genes is primarily reflected in the change of the amino acid sequence, and consequently in the reduced function of CYP enzymes. Additionally, changes in the DNA sequence, that regulate CYP gene expression, may lead to a decrease or increase in the capacity of CYP enzymes to metabolize a drug. Changes in CYP genes, which most often lead to changes in the function of the CYP enzymes, are called functional variants and can be point changes or insertion-deletion variants in the DNA sequence. Based on the genotyping of functional variants of a CYP gene, it is possible to determine the functionality of the enzyme, as well as the metabolic capacity of the human body for a drug known to depend on the functionality of the enzyme. The goal is to accurately choose the type and dose of the drug, as well as to avoid an adverse reaction to it. This approach is called pharmacogenetics and is the basis for development of personalized medicine and molecular autopsy. Of all the CYP gene families important for drug metabolism, the CYP1, CYP2, and CYP3 families have the greatest impact, are most researched and encompass genetic va

Febrilni napadi (FN) predstavljaju najĉeńće neurolońko oboljenje u detinjstvu. Upravo zbog visoke incidence obolevanja, uzrasta koji obuhvataju i tendencije ponavljanja, predstavljaju svojevrstan izazov u pedijatrijskoj praksi. Etiologija FN je i dalje predmet brojnih istaņivanja i poznato je da moņe zavisiti od genetske predispozicije. Cilj Cilj istraņivanja je bio analizirati povezanost polimorfizama TRPV1 i KCC2 gena sa pojavom FN i odrediti stepen genetiĉke homozigotnosti i varijabilnosti kod dece sa FN i u kontrolnoj grupi ispitanika. Materijal i metode U studiju je bilo ukljuĉeno 150 pacijenata sa dijagnostikovanim FN koja su podeljena u ĉetiri grupe: jednostavni febrilni napadi (JFN), sloņeni febrilni napadi (SFN), deca sa epilepsijom (EFN) i deca bez epilepsije (BFN). Nakon kliniĉkog i neurolońkog pregleda, utvrĊivano je prisustvo homozigotno-recesivnih osobina (HRO) uz pomoć HRO testa. Kontrolnu grupu ĉinilo je 121 "zdravo " dete iz iste populacije, sliĉnog uzrast i pola. U ispitivanim grupama sprovedena je analiza genskih polimorfizama u genima KCC2 i TRPV1. Rezultati Genotip CC polimorfizma rs2297201 KCC2 gena je znaĉajno ĉeńće zastupljen u kontrolnoj grupi nego u grupi dece sa FN (p=0.003) kao i alel C ovog polimorfizma (p=0.045). TakoĊe, genotip CC rs2297201 polimorfizma KCC2 gena je statistiĉki znaĉajno vińe zastupljen u kontrolnoj grupi u odnosu na grupu dece sa SFN (p=0.000). Ustanovljeno je postojanje znaĉajnog uvećanja recesivne homozigotnosti i smanjene varijabilnosti za testirane genske lokuse ne samo u grupi pacijenata sa FN, već i u svim ispitivanim podgrupama dece (SFN, JFN, EPI, BFN) u poreĊenju sa kontrolnom grupom. Sa rastom stepena teņine ispoljenosti FN utvrĊeno je kako povećanje u stepenu recesivne homozigotnosti tako i smanjenje varijabilnosti za testirane lokuse. Zakljuĉak Dobijeni rezultati nam ukazuju da bi CT i CC genotipovi, kao i C alel rs2297201 polimorfizma KCC2 gena mogli biti predisponirajući faktor na nastanak FN, pre svega C, Febrile seizures (FN) are the most common neurological disease in childhood. It is precisely because of the high incidence of the disease, the age that includes the tendency of repetition, to pose a particular challenge in pediatric practice. The etiology of FN is still the subject of numerous studies and it is known that it can depend on genetic predisposition. The aim of the study was to determine the association of TRPV1 and KCC2 gene polymorphisms with the occurrence of FN and to determine the degree of genetic homozygity and variability in children with FN and in the control group of the examinees. Material and Methods. The study included 150 patients diagnosed with FN divided into four groups: simple febrile seizures (JFN), complex febrile seizures (SFN), children with epilepsy (EFN) and children without epilepsy (BFN). After clinical and neurological examination, the presence of homozygous-recessive characteristics (HRC) was determined using the HRC test. The control group consisted of 121 "healthy" children from the same population, of similar age and gender. In the examined groups, we analyzed genetic polymorphisms of KCC2 and TRPV1 genes. Results. The genotype CC polymorphism rs2297201 of the KCC2 gene is significantly more common in the control group than in the group of children with FN (p = 0.003) and allele C of this polymorphism (p = 0.045). Also, the genotype CC rs2297201 of the polymorphism of the KCC2 gene was statistically significantly higher in the control group compared to the group of children with SFN (p = 0.000). The existence of a significant increase in recessive homozygousness and reduced variability for the tested gene loci was established not only for a group of patients with FN, but also in all tested subgroups of children (SFN, JFN, EPI, BFN) compared to the control group. With the increase in the severity of FN expression, it was found that the increase in the degree of recessive homozygousness and the decrease in variability for the