Role of Interleukin-23 Receptor Gene Polymorphisms in Autoimmune and Immune Mediated Diseases

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GCKR gene functional variants in type 2 diabetes and metabolic syndrome: do the rare variants associate with increased carotid intima-media thickness?

BACKGROUND: Recent studies revealed that glucokinase regulatory protein (GCKR) variants (rs780094 and rs1260326) are associated with serum triglycerides and plasma glucose levels. Here we analyzed primarily the association of these two variants with the lipid profile and plasma glucose levels in Hungarian subjects with type 2 diabetes mellitus and metabolic syndrome; and also correlated the genotypes with the carotid intima-media thickness records. METHODS: A total of 321 type 2 diabetic patients, 455 metabolic syndrome patients, and 172 healthy controls were genotyped by PCR-RFLP. RESULTS: Both GCKR variants were found to associate with serum triglycerides and with fasting plasma glucose. However, significant association with the development of type 2 diabetes mellitus and metabolic syndrome could not be observed. Analyzing the records of the patients, a positive association of prevalence the GCKR homozygous functional variants and carotid intima-media thickness was found in the metabolic syndrome patients. CONCLUSIONS: Our results support that rs780094 and rs1260326 functional variants of the GCKR gene are inversely associated with serum triglycerides and fasting plasma glucose levels, as it was already reported for diabetic and metabolic syndrome patients in some other populations. Besides this positive replication, as a novel feature, our preliminary findings also suggest a cardiovascular risk role of the GCKR minor allele carriage based on the carotid intima-media thickness association

TP53inp1 Gene Is Implicated in Early Radiation Response in Human Fibroblast Cells

Tumor protein 53-induced nuclear protein-1 (TP53inp1) is expressed by activation via p53 and p73. The purpose of our study was to investigate the role of TP53inp1 in response of fibroblasts to ionizing radiation. gamma-Ray radiation dose-dependently induces the expression of TP53inp1 in human immortalized fibroblast (F11hT) cells. Stable silencing of TP53inp1 was done via lentiviral transfection of shRNA in F11hT cells. After irradiation the clonogenic survival of TP53inp1 knockdown (F11hT-shTP) cells was compared to cells transfected with non-targeting (NT) shRNA. Radiation-induced senescence was measured by SA-beta-Gal staining and autophagy was detected by Acridine Orange dye and microtubule-associated protein-1 light chain 3 (LC3B) immunostaining. The expression of TP53inp1, GDF-15, and CDKN1A and alterations in radiation induced mitochondrial DNA deletions were evaluated by qPCR. TP53inp1 was required for radiation (IR) induced maximal elevation of CDKN1A and GDF-15 expressions. Mitochondrial DNA deletions were increased and autophagy was deregulated following irradiation in the absence of TP53inp1. Finally, we showed that silencing of TP53inp1 enhances the radiation sensitivity of fibroblast cells. These data suggest functional roles for TP53inp1 in radiation-induced autophagy and survival. Taken together, we suppose that silencing of TP53inp1 leads radiation induced autophagy impairment and induces accumulation of damaged mitochondria in primary human fibroblasts

Az 5q31 IBD5-régióban található IGR és SLC22A4/SLC22A5 variánsok lehetséges szerepe a gyulladásos bélbetegség kialakulásában = Possible role of selected IGR and SLC22A4/SLC22A5 loci in development of inflammatory bowel diseases

Az idiopathiás krónikus gyulladásos bélbetegség kialakulásában környezeti tényezők, immunológiai és genetikai faktorok egyaránt szerepet játszanak. Az utóbbi években a CARD15 gén mellett egyre több adat támasztja alá más gének, többek között az 5q31-33 régióban elhelyezkedő IBD5 locus (MIM#606348) szerepét. Egyes tanulmányok ezen régióban az SLC22A4 gén C1672T szubsztitúciójának, illetve az SLC22A5 gén G-207C transzverziójának együttes szerepét hangsúlyozzák, különösen Crohn-betegség kialakulásában, míg más szerzők új minor hajlamosító tényezőket azonosítottak az IBD5 kromoszómarégióban, ezek az IGR-variánsok. Célkitűzés: Az SLC22A4 C1672T és SLC22A5 G-207C mutációk mellett az IGR2096a_1 (rs12521868) és az IGR2198a_1 (rs11739135) polimorfizmusok szerepének vizsgálata gyulladásos bélbetegség kialakulásában. Betegek és módszer: Vizsgálatunk során 440 gyulladásos bélbeteg (206 Crohn- és 234 colitis ulcerosás beteg), valamint 279 kontrollegyén perifériás vérmintájából PCR-RFLP technikával végeztünk DNS-analízist. Eredmények: Sem a C1672T, sem a G-207C allélek, sem a TC haplotípus nem bizonyult rizikófaktornak sem Crohn-betegség, sem colitis ulcerosa esetében. Ezzel ellentétben mindkét minor IGR allél frekvenciája: mind az IGR2096a_1 T (48,1%), mind az IGR2198a_1 C (46,1%) szignifikánsan magasabb volt Crohn-betegségben a kontrollokéhoz (38,5%, 38,4%) képest (p<0,05). Korra és nemre standardizált regressziós analízissel mindkét allélnél fokozott rizikót észleltünk Crohn-betegség vonatkozásában (T-allél: OR=1,694, 95%-os CI: 1,137–2,522, p=0,010, C-allél: OR=1,644, 95%-os CI=1,103–2,449, p=0,015). Colitis ulcerosa esetén nem találtunk összefüggést a két IGR-variáns és a betegség kialakulása között. Következtetés: az IGR minor alléleknek a környező kaukázusi népcsoportoktól eltérően magyarországi populációban szerepük lehet a Crohn-betegség kialakulásában. | The IBD5 locus (MIM#606348) on chromosome 5q31 has been demonstrated to confer increased risk for inflammatory bowel disease. Controversial reports have been published about the significance of individual loci located in this region. Here we investigated the possible genetic association of inflammatory bowel diseases with C1672T of SLC22A4 and G-207C SLC22A5 alleles, and with IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility variants of the IBD5 region located on chromosome 5q31. Patients and methods: Total of 440 patients, 206 with Crohn’s disease, 234 with ulcerative colitis, and 279 controls were studied by PCR-RFLP methods. Results: Neither the C1672T, and G-207C alleles, nor the TC haplotype were found to confer risk for Crohn’s disease or ulcerative colitis. By contrast, both of the minor allele frequencies of IGR2096a_1 T (48.1%) and IGR2198a_1 C (46.1%) were increased in Crohn’s disease subjects as compared with the controls (38.5% and 38.4%, respectively; p<0.05). Using regression analysis adjusted to age and gender these alleles were found to confer risk for Crohn’s disease (OR=1.694, 95% CI: 1.137–2.522; p=0.010 for T allele, OR=1.644, 95% CI=1.103–2.449; p=0.015 for C allele of IGRs). In UC no such associations were found. Conclusions: Our results revealed the susceptibility nature of the examined IGR minor alleles in Hungarians, which nation differs historically from the surrounding Caucasian populations in origin of the founders of the state

Az ittas állapotban elkövetett bűncselekményért való felelősség

INST: L_08

Autoszomális domináns öröklődésű cerebellaris ataxiák = The autosomal dominant cerebellar ataxias are hereditary neurodegenerative diseases

Az autoszomális domináns cerebellaris ataxiák örökletes neurodegeneratív betegségek. Az ataxiák még néhány évtizeddel ezelőtt is a legkevésbé megértett idegi rendellenességek közé tartoztak, de molekuláris hátterük tisztázása mára lehetőséget teremtett a pontos diagnózis megállapítására, és segítséget nyújtott számos olyan különös jelenség értelmezésében is, mint például a családon belül változatosan megjelenő fenotípus. A spinocerebellaris ataxiák patogenezisének megismerése esélyt kínálhat sikeres terápiák kifejlesztésére, a jelenlegi, pusztán tüneti kezelések helyett. A gyors egymásutánban felfedezett gének és génlocusok, valamint a kialakított ataxiaaltípusok azonban zavart is okozhatnak a betegség pontos meghatározásában. Célunk rövid betekintést nyújtani e neurodegeneratív kórképek genetikai hátterébe, és a fontosabb ataxiaaltípusok jellemzésével megkönnyíteni az egyértelmű diagnózis felállítását. Even before a few decades ataxias were among the least understood neurological disorders but the clarification of their molecular background provides possibility for the accurate establishment of the diagnosis and gives a hand in the explanation of numberous extraordinary phenomena, like variable phenotypes in the same familiy. The cognition of the pathogenesis of spinocerebellar ataxias can grant a chance to the development of successful therapies instead of the present available merely symptomatic treatments. The rapid discovery of many genes and loci together with the segregation of ataxia subtypes can, however, cause inconvenience in the precise determination of the disorder. Our aim was to provide insight to the genetic background of these neurodegenerative diseases and also to give help in the correct diagnosis by the short description of the major ataxia subtypes

Growth Differentiation Factor-15 (GDF-15) is a potential marker of radiation response and radiation sensitivity

We have investigated the importance of GDF-15 (secreted cytokine belonging to the TGF-β superfamily) in low and high dose radiation-induced cellular responses. A telomerase immortalized human fibroblast cell line (F11hT) was used in the experiments. A lentiviral system encoding small hairpin RNAs (shRNA) was used to establish GDF-15 silenced cells. Secreted GDF-15 levels were measured in culture medium by ELISA. Cell cycle analysis was performed by flow cytometry. The experiments demonstrated that in irradiated human fibroblasts GDF-15 expression increased with dose starting from 100 mGy. Elevated GDF-15 expression was not detected in bystander cells. The potential role of GDF-15 in radiation response was investigated by silencing GDF-15 in immortalized human fibroblasts with five different shRNA encoded in lentiviral vectors. Cell lines with considerably reduced GDF-15 levels presented increased radiation sensitivity, while a cell line with elevated GDF-15 was more radiation resistant than wild type cells. We have investigated how the reduced GDF-15 levels alter the response of several known radiation inducible genes. In F11hT-shGDF-15 cells the basal expression level of CDKN1A was unaltered relative to F11hT cells, while GADD45A and TGF-β1 mRNA levels were slightly higher, and TP53INP1 was considerably reduced. The radiation-induced expression of TP53INP1 was lower in the silenced than in wild type fibroblast cells. Cell cycle analysis indicated that radiation-induced early G2/M arrest was abrogated in GDF-15 silenced cells. Moreover, radiation-induced bystander effect was less pronounced in GDF-15 silenced fibroblasts. In conclusion, the results suggest that GDF-15 works as a radiation inducible radiation resistance increasing factor in normal human fibroblast cells, acts by regulating the radiation-induced transcription of several genes and might serve as a radiation-induced early biomarker in exposed cells

A mitokondriális DNS és mutációi: újabb ismeretek egy új területen = Mitochondrial DNA and its mutations: novel fields in a new era

Az utóbbi két évtizedet tartják a klinikai mitokondriális DNS-kutatás aranykorának. Folyamatosan bővül a patológiás variánsok száma, amelyek betegséggel társulnak, illetve bővül az ismeretanyag azokról az entitásokról, melyek hátterében a mitokondriális DNS kóros elváltozásai állnak. A cirkuláris mitokondriális DNS öröklődése eltér a Mendel-féle szabályoktól, anyai öröklésmenetet mutat; számos vonatkozásban eltérő sajátosságokkal rendelkezik a nukleáris DNS-hez viszonyítva. A molekuláris biológiai módszerek terjedésével egyre több kórkép ismerhető fel, noha a diagnosztika manapság is komoly kihívást jelent. Napjainkban a mitokondriális medicina számos orvosi szubspecialitáshoz kapcsolódóan jelentős előrelépéseket mutatott; így körvonalazódott a mitokondriális gasztroenterológia, endokrinológia, otológia, oftalmológia, nefrológia, hematológia, onkológia, reproduktív medicina és pszichiátria, mintegy az adott szubspecialitás mitokondriális DNS-sel kapcsolatos, többé-kevésbé részleges önállósodással megjelenő territóriuma. A jelen összefoglaló közlemény a mitokondriális medicina rövid, általános összefoglalása mellett e fejezetekre próbál rátekintést nyújtani. | The past two decades are considered as the golden age of the clinical research of mitochondrial DNA. The number of disease-associated pathologic variants is still expanding; the available knowledge about the entities caused by the abnormalities of the mitochondrial DNA is gradually increasing. The inheritance of the mitochondrial DNA exhibits maternal transmission; the properties are different from the nuclear genome in many respects. Albeit the establishment of correct diagnosis of several mitochondrial diseases still means diagnostic challenge, more and more entities can be identified due to the available molecular biology methods. Nowadays, significant progress of mitochondrial medicine can be observed in relation to several medical subspecialties; thus, mitochondrial gastroenterology, endocrinology, otology, ophthalmology, nephrology, hematology, oncology, reproductive medicine and psychiatry have been partially separated as the more or less circumscribed territory of the specific subspecialty. Besides the short overview of the general aspects of the mitochondrial medicine the present review provides an outlook to these chapters