Zsolt B. Nagy

Cholesterol diet‐induced hyperlipidemia influences gene expression pattern of rat hearts: a DNA microarray study

To profile gene expression patterns involved in the direct myocardial effect of cholesterol‐enriched diet‐induced hyperlipidemia, we monitored global gene expression changes by DNA microarray analysis of 3200 genes in rat hearts. Twenty‐six genes exhibited significant up‐regulation and 25 showed down‐regulation in hearts of rats fed a 2% cholesterol‐enriched diet for 8 weeks as compared to age‐matched controls. The expression changes of 12 selected genes were also assessed by real‐time quantitative polymerase chain reaction. Genes with altered expression in the heart due to hyperlipidemia included procollagen type III, cofilin/destrin, tensin, transcription repressor p66, synaptic vesicle protein 2B, Hsp86, chaperonin subunit 5ϵ, metallothionein, glutathione S‐transferase, protein kinase C inhibitor, ATP synthase subunit c, creatine kinase, chloride intracellular channel 4, NADH oxidoreductase and dehydrogenase, fibronectin receptor β chain, CD81 antigen, farnesyltransferase, calreticulin, disintegrin, p120 catenin, Smad7, etc. Although some of these genes have been suspected to be related to cardiovascular diseases, none of the genes has been previously shown to be involved in the mechanism of the cardiac effect of hyperlipidemia.

Genetic Background of Anticyclic Citrullinated Peptide Autoantibody Production in Hungarian Patients with Rheumatoid Arthritis

Abstract:  Polymorphisms of the peptidylarginine deiminase 4 (PADI4) gene encoding for the isoenzyme that converts arginyl into citrullyl residues have been shown to contribute to susceptibility to rheumatoid arthritis (RA), depending on the population studied. We aimed at determining whether PADI4 single nucleotide polymorphisms (SNPs) are associated with RA in a Hungarian population. The relationship between anticyclic citrullinated peptide (anti‐CCP) production and HLA‐DRB1 alleles encoding the shared epitope (SE) was also investigated. DNA samples were obtained from RA (n= 261) patients and from control donors (n= 120). HLA‐DRB1 genotyping was carried out by polymerase chain reaction (PCR) with sequence‐specific priming. PAD4_92 G/C and PAD4_104 T/C SNPs were genotyped using real‐time PCR allele discrimination. Autoantibodies against CCP were detected by ELISA. All healthy controls tested anti‐CCP negative, whereas 171 (66%) RA patients were anti‐CCP positive. No significant difference in allele or genotype frequencies were found between RA patients and controls for any of the PADI4 SNPs. Anti‐CCP seropositivity was unrelated to these two SNPs. No association was found between any of the PADI4 SNPs and HLA‐DRB1 subtypes. Presence of the HLA‐RB1 SE alleles was significantly associated with anti‐CCP seropositivity; HLA‐DRB1*0401 and HLA‐DRB1*1001 carriers showed the strongest association. In conclusion, our data suggest that polymorphisms of the PADI4 gene are not associated with rheumatoid arthritis and are unlikely to be responsible for the presence of anti‐CCP autoantibodies in a white Hungarian population. HLA‐DRB1 SE alleles, however, may significantly contribute to the genetic determination of anti‐CCP production in Hungarian patients with RA.

Gene expression patterns of the 11β-hydroxysteroid dehydrogenase 2 enzyme in human placenta from intrauterine growth restriction: the role of impaired feto-maternal glucocorticoid metabolism

OBJECTIVE To assess 11-β-hydroxysteroid dehydrogenase 2 (11β-HSD2) gene expression patterns in human placental samples from intrauterine growth restriction (IUGR) pregnancies using normal pregnancy as control. STUDY DESIGN We compared 11-β-HSD2 gene expression in placental samples from all IUGR pregnancies treated in our clinic between January 1, 2010 and January 1, 2011 vs. 140 normal pregnancy samples from the same study period. Clinical characteristics were also assessed and compared between the IUGR and normal pregnancy groups. RESULTS Mean gestational weight gain in the IUGR group was significantly lower than in the control group. Similarly, change in body mass index (BMI) was lower. Impending intrauterine fetal asphyxia was significantly more common in the IUGR group. The 11β-HSD2 gene was underexpressed compared to controls, but this underexpression was only observed after the 33rd gestational week. Within the IUGR group, in cases of impending intrauterine fetal asphyxia the 11β-HSD2 gene was underexpressed compared to both impending asphyxia in non-IUGR cases, or IUGR without impending asphyxia. CONCLUSION Low gestational weight gain appears to predict IUGR. The 11β-HSD2 gene in IUGR is underexpressed and may result in an impaired placental barrier, decreasing protection against maternal glucocorticoids, which are thought to be prominent in fetal programming. Maternal glucocorticoid exposure resulting from an impaired placental barrier may increase the risk for cardiovascular and metobolic disorders later in adult life. In IUGR, before the 33rd gestational week, the expression of the 11β-HSD2 gene remains physiological. The underexpression of this gene after the 33rd week in impending intrauterine fetal asphyxia in IUGR points to an increased sensitivity to hypoxia when impending asphyxia is present in the late phase of IUGR pregnancies.

Gene Expression Profiling in Paget's Disease of Bone: Upregulation of Interferon Signaling Pathways in Pagetic Monocytes and Lymphocytes†‡§

We examined the gene expression profile of genes involved in bone metabolism in 23 patients with PD compared with 23 healthy controls. We found a significant overexpression of the genes of the IFN pathway along with a downregulation of tnf‐α. Our result suggest that IFN‐mediated signaling may play important roles in aberrant osteoclastogenesis of PD.

The role of transforming growth factor-beta in Marfan syndrome

The starting point, in Marfan syndrome (MFS) appears to be the mutation of fibrillin-1 gene whose deconstructed protein product cannot bind transforming growth factor beta (TGF-b), leading to an increased TGF-b tissue level. The aim of this review is to review the already known features of the cellular signal transduction downstream to TGF-b and its impact on the tissue homeostasis of microfibrils, and elastic fibers. We also investigate current data on the extracellular regulation of TGF-b level including mechanotransduction and the feedback cycles of integrin-dependent and independent activation of the latent TGF-b complex. Together these factors, by the destruction of the connective tissue fibers, may play an important role in the development of the diverse cardiac and extracardiac manifestations of MFS and many of them could be a target of conservative treatment. We present currently investigated drugs for the treatment of the syndrome, and explore possible avenues of research into pathogenesis of MFS in order to improve understanding of the disease.

Gene expression patterns of insulin-like growth factor 1, 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in human placenta from preterm deliveries: influence of additional factors

OBJECTIVE To compare patterns of human placental gene expression of IGF from pregnancies that ended with preterm delivery vs. full term pregnancies as controls. STUDY DESIGN Real-time PCR was used to assess gene expression of IGF in human placental samples from 104 preterm and 140 full term pregnancies. RESULTS In the preterm delivery group, the proportion of smokers was significantly higher than in the control group. A history of preterm delivery was more common in the preterm delivery group compared to the control group. In the preterm delivery group, placental samples showed an underexpression of the IGF-1 gene compared to controls. In cases of male fetal gender an overexpression of both the IGF-2 and the IGFBP-3 genes was observed. CONCLUSION Among environmental factors influencing preterm delivery, smoking was the most significant in our study. In the majority of cases, preterm delivery was induced by intrauterine infection leading to a decreased activity of the IGF system. This mechanism may also play a role in the development of neurological sequelae and in decreased tolerance to fetal distress. The overexpression of the IGF-2 gene observed in the placenta with male fetal gender can be explained by its physiological role in the development of the male phenotype.

Structural Polymorphisms in the Mannose-Binding Lectin Gene Are Associated with Juvenile Idiopathic Arthritis

Objective. To investigate the possible association between polymorphisms of the mannose-binding lectin gene (MBL2) and susceptibility to juvenile idiopathic arthritis (JIA). Methods. We performed a case-control association study including 118 Hungarian patients with JIA and 118 sex-matched healthy controls. MBL genotyping for the 3 mutant structural alleles at codons 54 (B), 57 (C), and 52 (D) in exon 1 and the promoter polymorphisms at position −550 (HL) and −221 (YX) were carried out by real-time PCR allelic discrimination. Serum level of MBL was determined by ELISA. Results. Variant allele frequencies of both codon 52 and 57 polymorphisms in the MBL2 gene were significantly overrepresented in JIA (p = 0.001 and p = 0.004, respectively). The frequency of low MBL genotypes (XA/XA, YA/YO, XA/YO, and YO/YO) in JIA was higher than that in healthy controls (p = 0.001). Serum MBL concentrations were found to be significantly lower in JIA patients versus control subjects (p = 0.001). The 2 promoter polymorphisms and codon 54 SNP of the MBL2 gene were not associated with JIA. Conclusion. Our findings suggest that genetically determined low MBL levels may predispose children to JIA in a Hungarian population. These data warrant further research to investigate the role of the lectin-dependent complement system in the pathogenesis of JIA.

Abnormal fetomaternal glucocorticoid metabolism in the background of premature delivery: placental expression patterns of the 11β-hydroxysteroid dehydrogenase 2 gene.

OBJECTIVE During pregnancy, 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) is involved in the development of the placental barrier, and its main function is to protect the fetus from the effects of the physiological increase of maternal glucocorticoids. We compared human placental gene expression patterns of 11β-HSD2 from pregnancies that ended with preterm delivery versus full term pregnancies as controls. STUDY DESIGN We used real-time PCR to assess the placental gene expression patterns of 11β-HSD2 in 104 preterm and 140 full term pregnancies (control group) at the time of delivery. RESULTS In the preterm delivery group, the proportion of smokers was 26.9%, significantly higher than in the control group. Preterm delivery began with premature rupture of membranes in 70.2% and spontaneous uterine activity in 29.8%. The 11β-HSD2 gene was underexpressed in the preterm delivery group compared to normal pregnancy between 28 and 36 gestational weeks, but unchanged between 24 and 28 weeks. There was no fetal gender effect on 11β-HSD2 gene expression. CONCLUSION The reduced activity of the 11β-HSD2 gene seen in the preterm delivery group may impair fetal defences against maternal glucocorticoid exposure. In cases of impending premature delivery, glucocorticoid effects, potentially including postnatal neurological abnormalities and growth restriction, may be worsened by prophylactic steroids given to accelerate fetal lung maturity. The impairment in fetal defences against maternal glucocorticoids due to reduced 11β-HSD2 enzyme activity appears to begin after gestational week 28.

Altered expression of Fcγ and complement receptors on b cells in systemic lupus erythematosus

Abstract:  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by B cell hyper‐reactivity, autoantibody production, immune complex (IC) deposition, and multiple organ damage. The contribution of IC and B cell–mediated changes in the pathogenesis of SLE is well established, however, the exact role of IC‐binding receptors expressed on B cells, Fcγ receptors, and complement receptors CR1 and CR2 in these pathological processes is unclear. Development of lupus‐like symptoms in mice defective for the inhibitory FcγRIIb and genetic association of certain FcγR genes with SLE demonstrate a significant role for these receptors but reports indicating alterations of Fcγ or complement receptor‐mediated B cell functions in human SLE are relatively few. The present review highlights a selected set of data including our own discussing the significance of animal models, genetics, and functional alterations of these IC‐binding receptors in the etiopathogenesis of SLE.

Hungarian consensus regarding the role of vitamin D in the prevention and treatment of diseases

Takács István dr.1 ■ Benkő Ilona dr.2 ■ Toldy Erzsébet dr.3 Wikonkál Norbert dr.4 ■ Szekeres László dr.5 ■ Bodolay Edit dr.6 Kiss Emese dr.7 ■ Jambrik Zoltán dr.8 ■ Szabó Boglárka dr.8 Merkely Béla dr.8 ■ Valkusz Zsuzsa dr.9 ■ Kovács Tibor dr.10 Szabó András dr.11 ■ Grigoreff Orsolya dr.1 ■ Nagy Zsolt dr.1 Demeter Judit dr.1 ■ Horváth Henrik Csaba dr.1 Bittner Nóra dr.12 ■ Várbíró Szabolcs dr.13 ■ Lakatos Péter dr.1