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P-glycoprotein (Pgp) is a drug efflux transporter and is the encoded product of the human multidrug resistance gene ABCB1 (MDR1). Pgp is expressed in the blood-brain barrier (BBB) and blood- cerebrospinal fluid (CSF) barrier, and reduces the brain penetration of antiepileptic drugs (AEDs). Functional polymorphism or overexpression of Pgp in the BBB of patients with epilepsy may play a role in pharmacoresistance. The aim of this study was to investigate the possible association of ABCB1 gene polymorphisms C1236T in exon 12, G2677T in exon 21, and C3435T in exon 26 with the development of resistance to antiepileptic therapy. All patients enrolled in the study had an established diagnosis of partial complex epilepsy with or without secondary generalisation and have been suffering from it for more than two years. Patients were devided into two groups. The first group comprised 57 patients refractory to the current therapy, while group 2 consisted of 48 patients with well-controled seizures. Results of our study showed statistically significant difference in the allele and genotype frequency of ABCB1 G2677T between resistant and nonresistant patients. Haplotype G2677/C3435/C1236 was overrepresented among resistant patients. According to our results, ABCB1 variants C1236T, G2677T and C3435T might be associated with therapeutic response to AED in patients with partial epilepsy with or without secondary generalization and represent a possible predictive factor for pharmacoresistance.

Background. It appears that atrial fibrillation (AF) may have genetic determinants. Estrogen regulates expression of many genes through estrogen receptor  (gene ESR1) and β (ESR2). ESR1 polymorphisms alter expression of different genes, including those of eNOS and L-type Ca2+ channel gene. The long allele of ESR1 variant has been associated with increased cardiovascular risk profile. Association of ESR1 gene polymorphism with AF in patients without gross structural cardiac abnormality. Those patients were selected to avoid the smothering of inheritance by dominant exogenous factors. Methods. We analyzed TA polymorphism of long-L ( ≥19 TA repeats ; 178-194 bp) and short-S (0.02). Logistic regression analysis revealed male gender and LL allele as the significant risk factors for AF. Conclusions. Functional activity of estrogen receptors may be more critical in males than in females with abundance of circulating estrogen. These preliminary results point at the need for further research of ESR1 role in AF.

The aim of this study was to determine if insertion-deletion polymorphism of angiotensin-converting enzyme is a risk factor for the development of preeclampsia. Sixty women with preeclampsia and 50 normotensive pregnant women were included in this study. Preeclampsia was defined as blood pressure >140/90 mmHg in a previously normotensive women with proteinuria >300 mg/L in a 24-hours. Twelve women also had preeclampsia in previous pregnancy. The genotyping of polymorphism in the intron 16 of the angiotensin-converting enzyme was performed by the polymerase chain reaction followed by the agarose electrophoresis. The patients were divided into three groups according to the presence (I) or absence (D) of insertional polymorphism (II, ID, and DD). Genotype distribution and allele frequencies were compared by Mantel-Haenszel chi2 testing. The frequency of DD genotype was not significantly higher in women with preeclampsia (26/60) than in the control group (14/50, p=0.096). The D allele frequency was significantly higher in 17 women with preeclampsias who required delivery before 34 weeks of pregnancy (0.735), than in 43 women in whom obstetric complications took place after 34 weeks of pregnancy (0.56, p=0.036). The D allele frequency was 0.83 in women having recurrent preeclampsia, i.e. significantly higher compared with women, who were for the first time, experienced preeclampsia (0.57, p=0.013). This study showed a significantly positive association between D allele frequency and risk of recurrent preeclampsia and preterm delivery before 34 weeks of pregnancy. The deletion genotype could be an important contributing factor for an early onset and recurrent preeclampsia.

The LDL-receptor is a cell surface glycoprotein that regulates the plasma cholesterol level by specific uptake of LDL particles. Mutations in LDL-receptor gene cause an elevation of plasma LDL and clinical phenotype of familial hypercholesterolemia (FH). More than 700 of different mutations have been identified worldwide and are heterogeneous in most populations. The aim of the study was to determine the presence and delineate the mutation spectrum of FH patients in Croatia. 249 hypercholesterolemic patients were selected (LDL-cholesterol level above 4.0 mmol/L). Promoter region and all 18 exons of the LDL-receptor gene were screened for changes by SSCP. Detected changes were than additionally characterized by DNA sequencing method. Molecular changes in the LDL-receptor gene were found in 68% of the patients. Six different LDL-receptor gene mutations were observed in 30 of them. Four mutations were found in the ligand-binding domain while the remaining two were located in the epidermal growth factor homology domain that mediates receptor recycling. Mutation in LDL receptor gene that results in Cys127Arg change, named FH-Zagreb, is newly found defect of this gene. In the rest of the patients with molecular changes, genetic polymorphisms 81 T>C, 1413 G>A, 1773 T>C and 1959 C>T were detected. 26% of these patients showed two or more of these polymorphisms simultaneously. Our results offer better insight into the molecular basis of FH in Croatia and shown its heterogeneous nature. They give further understanding of FH pathogenesis and facilitate the selection of the most appropriate diagnostic approach for genetic hypercholesterolemia.

As part of teh ApoEurope project, apolipoprotein E (apo E) common polymorphism and serum concentration were determined in 489 Alzheimer's disease patients and 429 controls. Patients and controls were recruited through nine centres in eight European countries. Age, sex ratios and education levels of both case and control populations were similar, although discrete differences appeared between centres. The prevalence of the e4 allele was higher in Alzheimer's disease than in controls (increased by 140%), while serum apo E concentration was lower by 11.2% (p

Aim. Apolipoprotein E (ApoE) gene is found to be polymorphic with three common alleles (e2, e3, e4) coding for three isoforms (E2, E3, E4) differing from each other by a single amino acid substitution at positions 112 and 158, thus causing different binding affinity of ApoE containing lipoproteins for the corresponding receptors. The common apoE isoforms E2 (Arg158-Cys) and E4 (Arg112-Cys) are found to be responsible for the variations in plasma cholesterol and triglyceride concentrations and hyperlipidemic conditions. ApoE genotypes determine the concentration of plasma ApoE. The aim of this study of ApoE genotypes was to assess their role in the pathogenesis of vascular and Alzheimer's dementia. Methods used in the study include determination of serum lipids and lipoproteins by standard methods, plasma ApoE concentration by immunoturbidimetric method and ApoE genotyping by polymerase chain reaction isotyping. Altogether in the study patients and control subjects were analysed. Results of the study of epidemiological and clinical significance of ApoE genotyping in diseased patients groups presented in comparison with healthy population and corresponding control groups revealed E4/4 genotype to be associated with Alzheimer's disease, E3/4 genotype with vascular dementia, E2/2 genotype with a reduced risk of Alzheimer's dementia but positively linked to longevity.

Deletion insertion polymorphism of the angiotensin converting enzyme gene in patient with cerebral artery disease

Angiotensin-converting enzyme gene polymorphism and cerebral atherosclerosis

Estrogeni štite od endotelne disfunkcije te djeluju na metabolizam lipida, a određeni su polimorfizmi u genu ERα u ranijim studijama povezivani s koronarnom bolešću. IL-6 pak ima centralnu ulogu u procesu upale, te je polimorfizam gena za IL-6 kao i plazmatske koncentracije IL-6 i CRP-a ranije povezivan s ACS-om. Funkcija endotela se može procijeniti neinvazivno i na perifernim arterijama, pomoću ultrazvučnog testa FMD. Cilj ovog istraživanja bio je analizirati povezanost polimorfizma gena ERα (duljina T/A ponavljanja) i polimorfizma gena IL-6 (174G>C) u potomaka bolesnika s ranom koronarnom bolešću s endotelnom disfunkcijom korištenjem FMD metode. Pritom je analizirana i prevalencija ovih polimorfizama u obje populacije, povezanost polimorfizma gena ERα i patoloških vrijednosti lipidograma, kao i povezanost polimorfizma gena IL-6 i patoloških vrijednosti plazmatskog CRP-a. Rezultati ovog rada su pokazali visoku pojavnost heterozigotne i homozigotne „duge“ alelne forme polimorfizma ERα u bolesnika s ranom koronarnom bolesti - u čak 76% njih te visoku pojavnost heterozigotne i homozigotne alelne forme polimorfizma IL-6, prisutne u 56% bolesnika. Pritom je prvi puta istražena učestalost ovih polimorfizama u djece potomaka ranih koronarnih bolesnika, koja je nađena u 78% za polimorfizam ERα i 66% za polimorfizam IL-6. Također, „kratka“ alelna forma polimorfizma ERα („divlji“ tip) u ovom radu imala je utjecaj na vrijednosti plazmatskih lipida u muških bolesnika i muških potomaka koji su imali statistički značajno više vrijednosti LDL-a. Isto tako, prisustvo homozigotne i heterozigotne alelne forme polimorfizma IL-6 bilo je povezano s povišenim vrijednostima CRP-a u 32% bolesnika s ranom koronarnom bolešću naspram njih 18% s „divljim“ tipom. Potomci bolesnika s ranom koronarnom bolešću s nasljeđene obje homozigotne forme polimorfizma ERα i IL-6 su imali najniže izmjerene vrijednosti FMD-a s dvostruko nižim medijanom od potomaka s „divljim“ tipom oba polimorfizma. Zaključno, ova studija govori u prilog moguće uloge polimorfizma gena ERα i IL-6 u endotelnoj disfunkciji prema pokazateljima dobivenim FMD metodom, no potrebna su dodatna istraživanja kako bi se procijenila njihova potencijalna upotreba kao biomarkera rane koronarne bolesti., Estrogens protect from endothelial dysfunction as well as affect lipid metabolism and certain polymorphisms in the ERα gene have been associated with coronary disease in earlier studies. IL-6 plays a central role in the inflammation process, and polymorphism of the IL-6 gene as well as plasma concentrations of IL-6 and CRP, were also associated with ACS in previous studies. Endothelial function can be assessed non-invasively on peripheral arteries, using the FMD test. The aim of this research was to analyze the association of ERα gene polymorphism (T/A repeat length) and IL-6 gene polymorphism (174G>C) in the offspring of patients with early coronary disease and endothelial dysfunction using the FMD method. This study analyzed the prevalence of these polymorphisms in both populations, as well as the association of ERα gene polymorphism with pathological lipidogram values, as well as the association of IL-6 gene polymorphism with pathological plasma CRP values. Study showed a high incidence of heterozygous and homozygous "long" allelic forms of the ERα polymorphism in patients with early coronary disease - in as many as 76% of them, and a high incidence of heterozygous and homozygous allelic forms of the IL-6 polymorphism, present in 56% of patients. This study is the first to investigate the frequency of these polymorphisms in the children early coronary patients, and found them in 78% for the ERα polymorphism and 66% for the IL-6 polymorphism. Also, the "short" allelic form of the ERα polymorphism ("wild" type) in our study had an impact on plasma lipid values in male patients and male offsprings, who had significantly higher LDL values. Likewise, the presence of homozygous and heterozygous allelic forms of the IL-6 polymorphism was associated with increased CRP values in 32% of patients with early coronary disease compared to 18% with the "wild" type. The offspring of patients with early coronary disease who inherited both homozygous forms of the ERα and IL-6 polymorphisms had the lowest measured FMD values with a median twice as low as the offspring with the "wild" type of both polymorphisms. In conclusion, this study supports the possible role of ERα and IL-6 polymorphism in the endothelial dysfunction detected with FMD, but additional studies are needed in order to investigate their potential use as a biomarker of early coronary disease.

Uvod: Juvenilni idiopatski artritis (JIA) najčešća je reumatska bolest dječje dobi. Rana kontrola upalnog procesa u JIA korelira s povoljnijim ishodima liječenja. Odgovor na primjenu metotreksata (MTX), prvog lijeka druge linije liječenja djece s JIA je heterogen, s udjelom većim od 30 % djece u koje navedeni lijek nema učinka u smislu postizanja remisije. Kako je za procjenu učinka MTX nužan period od 3 do 6 mjeseci kontinuirane primjene, u djece u koje navedeni lijek neće djelovati gubi se mogućnost ranog postizanja remisije, odnosno smanjuje vjerojatnost povoljnog ishoda liječenja. Cilj rada bio je istražiti vrijednost određivanja delecijskih polimorfizama GSTM1 i GSTT1 kao predskazatelja učinkovitosti MTX u liječenju JIA. ----- Ispitanici i metode: U istraživanje je uključeno 109 JIA bolesnika: 46 bolesnika u kojih je tijekom terapije MTX postignuta stabilna klinička remisija u trajanju od minimalno 6 mjeseci i 63 bolesnika u kojih tijekom liječenja metotreksatom nije postignuta stabilna klinička remisija. U svih bolesnika uključenih u studiju određeni su delecijski polimorfizmi gena GSTM1 i GSTT1. ----- Rezultati: Između ispitivanih skupina JIA bolesnika nije nađeno statistički značajnih razlika u raspodjeli pojedinih delecijskih polimorfizama gena GSTM1 i GSTT1. Delecijski polimorfizam gena GSTM1 detektiran je u 40/63 (63,5 %) ispitanika u kojih tijekom terapije MTX nije postignuta remisija te u 27/46 (58,7 %) ispitanika u kojih je tijekom terapije MTX postignuta remisija. Delecijski polimorfizam gena GSTT1 detektiran je u 14/63 (22,2 %) ispitanika u kojih tijekom terapije MTX nije postignuta remisija te u 8/46 (17,4 %) ispitanika u kojih je tijekom terapije MTX postignuta remisija. Kombinacija delecijskih polimorfizama gena GSTM1 i GSTT1 detektirana je u 8/63 (12,7 %) ispitanika u kojih tijekom terapije MTX nije postignuta remisija te u 6/46 (13,0 %) ispitanika u kojih je tijekom terapije MTX postignuta remisija. Nije nađeno statistički značajnih razlika u raspodjeli pojedinih delecijskih polimorfizama niti njihove kombinacije između ispitivanih skupina. Dodatno su analizirane razlike delecijskih polimorfizama gena GSTM1 i GSTT1 u skupini djece u koje tijekom liječenja MTX nije postignuta remisija, odnosno u koje je bilo potrebno liječenje bDMARD u odnosu na broj bDMARD potrebnih za postizanje remisije. U podskupini oboljele djece u kojoj je za postizanje remisije bila potrebna jedna ili više zamjena bDMARD u odnosu na podskupinu djece u kojoj je za postizanje remisije bio dostatan jedan bDMARD, statistički je značajno zastupljeniji nalaz pozitivnog genotipa polimorfizma gena GSTM1: 64,3 % naprema 28,6 %; P = 0,026. ----- Zaključak: Određivanje delecijskih polimorfizama gena GSTM1 i GSTT1 prema ovom istraživanju ne pomaže u detekciji djece oboljele od JIA u koje se neće postići remisija tijekom terapije MTX. No, statistički značajno češća pojavnost pozitivnog genotipa polimorfizma gena GSTM1 u podskupini oboljele djece u kojoj je za postizanje remisije bila potrebna jedna ili više zamjena bDMARD u odnosu na skupinu djece u koje je remisija postignuta jednim bDMARD, otvara nove horizonte u istraživanjima polimorfizama gena GSTs u sklopu JIA i drugih upalnih reumatskih bolesti., Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood. Early control of the inflammatory process in JIA correlates with more favourable treatment outcomes. The effectiveness of the MTX, the first- line drug in JIA treatment is heterogeneous, with a proportion of more than 30% of children without effect in terms of achieving remission. Since an assessment of the MTX effects requires a period of 3–6 months of continuous administration, in more than 30% of children the possibility of early remission and favourable outcome of treatment is reduced. The aim of the research was to investigate the value of the determination of GSTM1 and GSTT1 genes deletion polymorphisms as the predictor of the MTX treatment effectiveness in JIA patients. ----- Subjects and methods: The study included 109 JIA patients: 46 patients who had achieved stable clinical remission for a minimum of 6 months during MTX therapy and 63 patients who did not achieve stable clinical remission during MTX therapy. In all patients enrolled in the study, the deletion polymorphisms of the GSTM1 and GSTT1 genes were determined. ----- Results: No statistically significant differences in the distribution of deletion polymorphisms were found between the JIA patient study groups. Deletion polymorphism of the GSTM1 gene was detected in 40/63 (63.5%) subjects who did not achieve remission during MTX therapy and 27/46 (58.7%) subjects who achieved remission during MTX therapy. Deletion polymorphism of the GSTT1 gene was detected in 14/63 (22.2%) subjects in whom remission was not achieved during MTX therapy and in 8/46 (17.4%) subjects in whom remission was achieved during MTX therapy. The combination of deletion polymorphisms for the GSTM1 and GSTT1 genes was detected in 8/63 (12.7%) subjects in whom remission was not achieved during MTX therapy and in 6/46 (13.0%) subjects in whom remission was achieved during MTX therapy. No statistically significant differences were found in the distribution of deletion polymorphisms or their combinations between the investigated groups. The differences between the deletion polymorphisms of the GSTM1 and GSTT1 genes in the group of children in whom remission was not achieved during MTX therapy were further analyzed. In a subgroup of affected children in which one or more bDMARD changes were needed to achieve remission, positive genotype GSTM1 gene polymorphism was statistically significantly more frequently detected: 64.3% to 28.6%; P = 0.026. ----- Conclusion: According to this study, the determination of GSTM1 and GSTT1 gene deletion polymorphisms does not help in the distinction of JIA patients who will not achieve remission during MTX therapy. However, the statistically significantly more frequent occurrence of positive polymorphism of GSTM1 gene in a subgroup of children in which one or more changes of bDMARD were needed to achieve remission compared with the subgroup of children in whom remission was achieved by initial bDMARD, opens new horizons in GST gene polymorphism research in JIA and other inflammatory rheumatic diseases.

Kronična upala povezana je sa nastankom karcinoma, a Toll-like receptori (TLR) ključni su sudionici u regulaciji upalnog odgovora. Kronična opstruktivna plućna bolest (KOPB) se smatra najvećim neovisnim čimbenikom rizika za nastanak karcinoma pluća (KP), što ukazuje da u razvoju obje bolesti postoji preklapajuća genetska podloga. Obzirom na važnu ulogu TLR-a u aktivaciji i regulaciji imunološkog odgovora, u ovom istraživanju pretpostavljeno je da bi njihova genetička varijabilnost mogla biti povezana s razvojem KOPB-a i karcinoma pluća. Rezultati ovog istraživanja pokazuju da poremećeni procesi regulacije upale, u kontekstu smanjene aktivnosti TLR-a, doprinose razvoju karcinoma pluća kod pacijenata s dijagnosticiranim KOPB-om. U istraživanje je bilo uključeno 940 pacijenata, podijeljenih u tri skupine: KOBP vs KOPB + KP, KOPB vs KP, KOPB + KP vs KP. Obuhvaćeno je 13 polimorfizama jednog nukelotida (SNP-ova) smještenih u 6 različitih gena koji kodiraju za TLR-e. Genetska povezanost procijenjena je logističkom regresijom, te je prilagođena dobi i spolu. Razina IL-6 u serumu određena je ELISA-om. Rezultati su pokazali povezanost između C/G genotipa TLR1 rs5743611 i povećanog rizika za razvoj karcinoma pluća, dok su genotipovi polimorfizama TLR5 G/G (rs2072493) i C/C (rs725084) povezani s razvojem karcinoma pluća u bolesnika sa KOBP-om. Nakon prilagodbe na dob i spol, pokazano je da je polimorfizam rs2072493 statistički značajno povezan s rizikom za razvoj karcinoma pluća u prisutnosti KOBP-a. Također, polimorfizam rs2072493 povezani je sa statistički značajnim smanjenjem koncentracije IL-6 u serumu ispitanika. Rezultati ovog istraživanja mogli bi pridonijeti razumijevanju povezanosti promijenjenog imunološkog odgovora i veze između karcinoma pluća i KOBP-a. Također, ovi bi rezultati možda mogli predstavljati u literaturi još neopisanu, novu povezanost između karcinoma pluća i KOBP-a u kontekstu promijenjenog imunološkog odgovora, a koja bi mogla omogućiti predviđanje rizika za razvoj bolesti, bolje razumijevanje mehanizama nastanka bolesti i razvoj novih strategija u liječenju ovih teških bolesti., Chronic inflammation is associated with cancer development, and Toll-like receptors (TLRs) are key participants in the regulation of the inflammatory response. Chronic obstructive pulmonary disease (COPD) is considered to be the largest independent risk factor for lung cancer (LC), indicating there is an overlapping genetic background in the development of both diseases. Given the important role of TLRs in the activation and regulation of the immune response, it was hypothesized in this study that their genetic variability could be associated with the development of COPD and lung cancer. The results of this study show that impaired inflammatory regulation processes, in the context of decreased TLR activity, contribute to the development of lung cancer in patients diagnosed with COPD. The study included 940 patients, divided into three groups: COPD vs COPD + KP, COPD vs KP, COPD + KP vs KP. It included 13 polymorphisms of one nucleotide (SNP) located in 6 different genes encoding TLRs. Genetic associations were estimated using logistic regression and adjusted for age and gender. Serum IL-6 levels were determined by ELISA. The results showed an association between C/G genotype TLR1 rs5743611 and an increased risk of developing lung cancer, while G/G genotype of TLR5 rs2072493 and C/C genotype of TLR5 rs725084 polymorphism were associated with the development of lung cancer in patients with COPD. After age and gender adjustment, the TLR5 rs2072493 polymorphism showed statistically significant association with risk of lung cancer development in the presence of COPD. Also, the rs2072493 polymorphism was associated with a statistically significant decrease in the serum IL-6 concentration. The results of this study could contribute to an understanding of the association between altered immune response and the link between lung cancer and COPD. Also, these results might represent an as yet undescribed, new association between lung cancer and COPD in the context of altered immune response, which could also allow risk prediction, better understanding of disease mechanisms and development of new strategies in the treatment of these serious diseases.