Multivariate Analysis of Dopaminergic Gene Variants asRisk Factors of Heroin Dependence

Background: Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants. Objective: To study the potential association between allelic variants of dopamine D2 receptor (DRD2), ANKK1 (ankyrin repeat and kinase domain containing 1), dopamine D4 receptor (DRD4), catechol-O-methyl transferase (COMT) and dopamine transporter (SLC6A3) genes and heroin dependence in Hungarian patients. Methods: 303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs) rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs) were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA). Findings and conclusions: In single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence. Moreover, –521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A) allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462) of the DRD4 gene and this effect is mediated through the –521 C/T (rs1800955) polymorphism in the promoter

Az éhség és a gastrointestinális hormontermelés változásának vizsgálata totális gastrectomizált, valamint kóros kövérségben szenvedő betegekben = Evaluation of satiation, satiety and GI hormone production in patients after total gastrectomy and in morbidly obese

1.Két total gastrectomia utáni rekonstrukciós típust hasonlítottunk össze, melyek a pótgyomor helyében (oralis vagy aborális) különböztek egymástól. A vizsgált paraméterekben nem találtunk szignifikáns különbséget. 2.Gastrointestinalis panaszokat és egyéb életminőségi paramétereket hasonlítottunk össze két rekonstrukciós típusban, ahol a duodenumbekötés jelenlétében volt csak különbség. Megtartott duodenalis passzázs mellett a korai dumpinges panaszok szignifikánsan ritkábban jelentkeztek. 3.Vizsgáltuk a plazma cholecystokinin, ghrelin és leptin szintet éhomra és tesztétel fogyasztása után és egészséges egyedekhez hasonlítottuk. Az éhomi CCK és ghrelin szint szignifikánsan magasabb volt a duodenum visszakötésnél és magasabb maradt tesztétel elfogyasztása után is. A leptin szintekben nem találtunk különbséget. 4.Állatkísérletekben a ghrelin szint alacsonyabb, a leptin szint, a táplálékfelvétel, a súlygyarapodás magasabb volt a duodenum bekötésnél. 5.Anti CCK adásával mindkét csoportban szignifikáns táplálékfelvételt igazoltunk. Az anti CCK fokozza az éhségérzetet. 6. Funkcionális MRI-vel vizsgáltuk az aktivitásváltozást a kórosan kövér és normális testsúlyú betegeknél tesztétel elfogyasztás után. Számos agyi régióban észleltünk jelentős aktivitás különbséget a két csoport között kellemes és kellemetlen íz hatására. Az eredmények segíthetnek megtalálni a központi idegrendszer szerepét a kóros kövérség kialakulásában, új módszerek kifejlesztésében a súlycsökkentés elérésére. | 1.We compared two types of reconstructions after total gastrectomy, an aboral and an oral pouch with preserved duodenal passage, differing only in the site of the pouch. The site of the reservoir does not influence the outcome.2.We investigated different alimentary symptoms and QOL parameters in correlation with the reconstruction type. Preservation of the duodenal passage reduces the prevalence of early dumping syndrome.3.Fasting and postalimentary plasma CCK, ghrelin and leptin levels were measured in the two different reconstruction types and compared to healthy contols. Fasting leves of CCK and ghrelin were significantly higher after preservation of the duodenal passage and remained higher postprandially as well. There were no significant differences in leptin levels between the groups.4.In a rat model the level of ghrelin was lower, the level of leptin, the food intake and body weight gain was higher after duodenal preservation.5.Administration of anti-CCK significantly increases food intake in both groups in animal model. Anti-CCK increases apetite.6.We studied the brain functional MRI (fMRI) activity changes of normal and obese persons, triggered by gustatory stimulation. Our current fMRI investigations revealed different activations of numerous brain regions of normal and obese individuals, triggered by pleasant and unpleasant gustation. This method can help to recognize the role of the central nervous system in obesity, and to develop new therapies for weight loss

Association of GDNF and CNTNAP2 gene variants with gambling

Some form of gambling can be observed in nearly every society, as the gratification felt upon winning in uncertain conditions is universal. A culturally distinct form of gambling, associated with a traditional sporting event of archery known as "teer," is innate to the province of Meghalaya, India. The objective of this study was to find genetic variants underlying this unique form of behavioral addiction. To better understand game-based gambling, we studied genetic variants related to dopaminergic pathways and other genes previously linked to various psychological disorders.This study was carried out on a sample of 196 Indo-Aryan adults from Shillong, Meghalaya. Genotyping of glial cell line-derived neurotrophic factor (GDNF) polymorphisms was carried out using real-time PCR. We further investigated 32 single nucleotide polymorphisms located in the 3' UTR of additional genes of interest using an OpenArray® real-time PCR platform.Case-control analysis revealed a significant association between GDNF variant rs2973033 (p = .00864, χ2 = 13.132, df = 2) and contactin-associated protein-like 2 (CNTNAP2) variant rs2530311 (p = .0448, χ2 = 13.132, df = 2) with gambling.Association of the GDNF gene with gambling could be attributed to its involvement in the development and survival of dopaminergic neurons. Our result is in good agreement with previous data indicating the role of GDNF in certain substance addictions. Several rare variants in the CNTNAP2 gene were also implicated in alcohol addiction in a previous study. This pilot study provides further support for the role of GDNF and CNTNAP2 in addiction behaviors

A végrehajtó funkciók összefüggése a testtömegindexszel és a DRD4-VNTR 7-es alléllal

Absztrakt: Bevezetés és célkitűzés: Szakirodalmi eredmények alapján a kórosan sovány és az elhízott személyek gyengébben teljesítenek végrehajtó funkciókat mérő feladatokban, mint a normál súlyúak. Ismert továbbá, hogy a jutalmazó rendszerben kulcsfontosságú dopaminerg rendszer működésének fontos szerepe lehet a testsúlyszabályozásban és a táplálékfelvételben. A jelen vizsgálat célja az volt, hogy az egészséges spektrumon belül megvizsgáljuk a testtömegindex, egy kandidáns dopaminerg génvariáns és a végrehajtó funkciókat mérő Stroop-feladatban elért teljesítmény összefüggéseit, és mindezek alapján pszichogenetikai következtetéseket vonjunk le. Módszer: Kutatásunkban 152, cukorbetegségben vagy pszichiátriai zavarban nem szenvedő személy vett részt. DNS-izolálás céljából nem invazív mintavételt alkalmaztunk, a résztvevőktől demográfiai, testsúly- és testmagasságadatokat gyűjtöttünk, valamint megoldottak egy számítógépes Stroop-feladatot. 11 fő az alultáplált (átlag-testtömegindex: 17,9 kg/m2), 98 fő a normál súlyú (átlag-testtömegindex: 21,8 kg/m2), 43 fő a túlsúlyos (átlag-testtömegindex: 28,9 kg/m2) testtömegindex-kategóriába került. A testtömegindex és a genotípusok alapján csoportosított személyek átlagos teljesítményét összehasonlítva kerestünk pszichogenetikai összefüggéseket. Eredmények: A testtömegindex és a Stroop-feladat próbáinak típusa szignifikáns interakciót mutatott a hibaszámra (p = 0,045): az inkongruens próbákban a normál-testtömegindexet mutató személyek szignifikánsan kevesebbet hibáztak, mint az alultápláltak vagy a túlsúlyosak. A 7-es allélt hordozók tendenciaszinten többet hibáztak, mint a 7-es allélt nem hordozók. Míg a normál-BMI-kategóriába tartozó személyek genotípusuktól függetlenül hasonlóan alacsony szinten hibáztak, a szélsőséges súlycsoportokba tartozó személyek közül a 7-es alléllal rendelkezők többet hibáztak, mint azok, akik nem hordozták ezt a variánst. Következtetés: A válaszgátlást igénylő feladatok nehezebbek azok számára, akik az átlagostól eltérő testtömegindexet mutatnak. Ez összefüggésben lehet azzal, ahogyan a táplálkozással kapcsolatos jelzőingerekre reagálnak. Orv Hetil. 2019; 160(39): 1554–1562. | Abstract: Introduction and aim: Earlier results in the literature suggest that overweight subjects show weaker performance in executive function tasks as compared to normal weight people. Dopaminergic system is strongly linked to executive functions, body mass regulation and ingestion. The aim of the present study was to examine the possible relationship between DRD4 VNTR 7-repeat allele, body mass index and Stroop performance in a healthy adult population, and to draw psychogenetic conclusions. Method: 152 subjects without diabetic or psychiatric history participated in the study. Along with non-invasive DNA sampling, demographic, weight and height data were collected. The participants also solved the computerized Stroop task. 11 subjects belonged to the underweight (mean body mass index = 17.9 kg/m2), 98 subjects to the normal (mean body mass index = 21.8 kg/m2), and 43 subjects to the overweight (mean body mass index = 28.9 kg/m2) category. After grouping participants according to their body mass index and DRD4 VNTR genotype, we compared their mean performance to investigate the possible psychogenetic associations. Results: Body mass index and stimuli type showed significant interaction on error number (p = 0.045): subjects with normal body mass index made significantly less error as compared to under- and overweight subjects in incongruent trials. The 7-repeat allele carriers made tendentiously more errors than non-carriers. Normal weight people made less error – independently from their genotype –, while subjects with either low or high BMI carrying the 7-repeat allele made more errors compared to non-carriers. Conclusion: Under- and overweight subjects perform weaker where inhibition is necessary in the task. This may reflect their reactions to food-related situations. Orv Hetil. 2019; 160(39): 1554–1562

Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms

The activation of the ATP-gated P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) produces microglial activation, a process which has been demonstrated in depression, bipolar disorder, and schizophrenia. Emerging data over the last years highlighted the importance of P2X7 cation channel as a potential drug target for these central nervous system disorders. The Gln460Arg (rs2230912) polymorphism of the P2RX7 gene has been widely studied in mood disorders, however the results are still controversial. Therefore, we aimed to investigate the C-terminal region of this gene in major depressive and bipolar disorders (MDD and BD) by studying possibly functional, non-synonymous polymorphisms within a 7 kb long region around the Gln460Arg, including Ala348Thr (rs1718119), Thr357Ser (rs2230911), and Glu496Ala (rs3751143) variants. Since Gln460Arg is located at the 3' end of the P2RX7 gene, we included additional, potentially functional single nucleotide polymorphisms (SNPs) from the 3' untranslated region (UTR), which can be in linkage with Gln460Arg. Based on in silico search, we chose two SNPs in putative microRNA target sites which are located in consecutive positions: rs1653625 and rs1718106.P2RX7 SNPs from the C-terminal region were selected based on previous functional assays, 3' UTR variants were chosen using PolymiRTS and Patrocles databases. The genotyping of the non-synonymous SNPs was carried out by pre-designed TaqMan® kits, while the 3' UTR variants were analyzed by PCR-RFLP method. Case-control analyses were carried out between 315 inpatients with acute major depressive episode (195 MDD, 120 BD) and 406 healthy control subjects. The two subscales of the Hospital Anxiety and Depression Scale (HADS) self-report questionnaire were used for quantitative analyses, including an additional, "at-risk" population of 218 patients with diabetes mellitus. The in vitro reporter gene assays were carried out on HEK and SK-N-FI cells transiently transfected with pMIR vector constructs containing the P2RX7 3' UTR downstream of the luciferase gene.Haplotype analysis indicated a relatively high linkage between the analyzed P2RX7 SNPs. Our case-control study did not yield any association between P2RX7 gene variants and depression. However, dimensional analyses showed significant associations of the HADS depression severity scores with Gln460Arg (rs2230912) and Ala348Thr (rs1718119) in the depressed and diabetic patient groups. In the in vitro experiments, the P2RX7 3' UTR constructs with the lowest predicted binding efficiency to their miRNAs showed the highest expression of the gene. The combination of the depression-associated P2RX7 C-terminal and 3' UTR SNPs contributed to the highest depression severity score in the haplotype analysis. Based on our findings, we propose that a P2RX7 haplotype combination of the Gln460Arg and neighboring SNPs contribute to the observed genetic association with depressive symptoms

The characteristics and prognostic role of acute abdominal on-admission pain in acute pancreatitis: A prospective cohort analysis of 1432 cases

Introduction Pain is the most common symptom in acute pancreatitis (AP) and is among the diagnostic criteria. Therefore, we aimed to characterize acute abdominal pain in AP. Methods The Hungarian Pancreatic Study Group prospectively collected multicentre clinical data on 1435 adult AP patients between 2012 and 2017. Pain was characterized by its intensity (mild or intense), duration prior to admission (hours), localization (nine regions of the abdomen) and type (sharp, dull or cramping). Results 97.3% of patients (n = 1394) had pain on admission. Of the initial population with acute abdominal pain, 727 patients answered questions about pain intensity, 1148 about pain type, 1134 about pain localization and 1202 about pain duration. Pain was mostly intense (70%, n = 511/727), characterized by cramping (61%, n = 705/1148), mostly starting less than 24 h prior to admission (56.7%, n = 682/1202). Interestingly, 50.9% of the patients (n = 577/1134) had atypical pain, which means pain other than epigastric or belt-like upper abdominal pain. We observed a higher proportion of peripancreatic fluid collection (19.5% vs. 11.0%; p = 0.009) and oedematous pancreas (8.4% vs. 3.1%; p = 0.016) with intense pain. Sharp pain was associated with AP severity (OR = 2.481 95% CI: 1.550-3.969) and increased mortality (OR = 2.263, 95% CI: 1.199-4.059) compared to other types. Longstanding pain (>72 h) on admission was not associated with outcomes. Pain characteristics showed little association with the patient's baseline characteristics. Conclusion A comprehensive patient interview should include questions about pain characteristics, including pain type. Patients with sharp and intense pain might need special monitoring and tailored pain management. Significance Acute abdominal pain is the leading presenting symptom in acute pancreatitis; however, we currently lack specific guidelines for pain assessment and management. In our cohort analysis, intense and sharp pain on admission was associated with higher odds for severe AP and several systemic and local complications. Therefore, a comprehensive patient interview should include questions about pain characteristics and patients with intense and sharp pain might need closer monitoring

Metabolic stress-induced microRNA and mRNA expression profiles of human fibroblasts

Metabolic and oxidative stresses induce physiological adaptation processes, disrupting a finely tuned, coordinated network of gene expression. To better understand the interplay between the mRNA and miRNA transcriptomes, we examined how two distinct metabolic stressors alter the expression profile of human dermal fibroblasts.Primary fibroblast cultures were obtained from skin biopsies of 17 healthy subjects. Metabolic stress was evoked by growing subcultured cells in glucose deprived, galactose enriched (GAL) or lipid reduced, cholesterol deficient (RL) media, and compared to parallel-cultured fibroblasts grown in standard (STD) medium. This was followed by mRNA expression profiling and assessment of >1000 miRNAs levels across all three conditions. The miRNA expression levels were subsequently correlated to the mRNA expression profile.Metabolic stress by RL and GAL both produced significant, strongly correlated mRNA/miRNA changes. At the single gene level four miRNAs (miR-129-3p, miR-146b-5p, miR-543 and miR-550a) showed significant and comparable expression changes in both experimental conditions. These miRNAs appeared to have a significant physiological effect on the transcriptome, as nearly 10% of the predicted targets reported changes at mRNA level. The two distinct metabolic stressors induced comparable changes in the miRNome profile, suggesting a common defensive response of the fibroblasts to altered homeostasis. The differentially expressed miR-129-3p, miR-146b-5p, miR-543 and miR-550a regulated multiple genes (e.g. NGEF, NOVA1, PDE5A) with region- and age-specific transcription in the human brain, suggesting that deregulation of these miRNAs might have significant consequences on CNS function. The overall findings suggest that analysis of stress-induced responses of peripheral fibroblasts, obtained from patients with psychiatric disorders is a promising avenue for future research endeavors. © 2013 Elsevier Inc