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Hypertension and nephrology

SEPTEMBER 20, 2015

[Effect of angiotensin-converting enzyme gene insertion/deletion polymorphism on survival of hemodialyzed patients]

KISS István, SZEGEDI János, KULCSÁR Imre, AMBRUS Csaba, KERKOVITS Lóránt, TISLÉR András, KISS József Zoltán

[Introduction: There are inconsistent observations regarding the earlier studies of the connection between ACE gene I/D polymorphism and the cardiovascular mortality. In the case of hemodialyzed patients suffering from chronic kidney disease the DD polymorphism connected to the elevated ACE levels was pointed out to be connected to the mortality rate primarily in patients with diabetes. The previous observations were verified by us during the analyzation of the short-term (three year period) survival data. We hypothesized that the significance of the ACE gene I / D polymorphism in chronic kidney disease would be verified and that during long-term observations (10 year period) the previous results could be validated. Method: In our non-invasive, prospective and multicentre study clinical data was collected from 746 patients whose blood samples were genotyped for ACE gene I/D single nucleotide polymorphism. Three genotype groups (I/I, I/D és D/D) were created during the analyzation of the mortality that was done using multivariate Cox proportional hazard models. Results: The mean age of the HD patients was 54.9 years, 46,8% of all patients were female. The prevalence of diabetes was 19.3%. ACE inhibitor therapy was prescribed for 47.9% of all patients. The median duration of dialysis before the start of the study was 23.8 months (IQR 11.2-47.1). The most frequent genotype was I/D (42.6%), followed by D/D (37.7%) and I/I (19.7%) genotypes. During the ten year follow- up of patients, the median follow-up was 29.8 months (IQR 12.6-63.4). The D/D genotypes showed lower survivability (I/I vs. D/D: log-rank test: p=0.04) from the group of patients without ACE inhibitor therapy. In multivarite Cox regression models D/D genotype compared with I/I genotype only showed that it significantly determines mortality in patients with no ACE inhibitor therapy (HR 0.67, 95% CI 0.46-0.97, p=0.03). Conclusions: There was no difference in survival among unselected patients with different genotypes. Our data suggests that hemodialyzed patients with the D/D genotype might have inferior outcome, and ACE inhibitor therapy may be associated with improved survival in this subgroup.]

Clinical Neuroscience

MARCH 25, 2015

[Lack of associations between CLU and PICALM gene polymorphisms and Alzheimer’s disease in a Turkish population]

SEN Aysu, ARSLAN Mehtap, ERDAL Emin Mehmet, AY Izci Ozlem, YILMAZ Gorucu Senay, KURT Erhan, ARPACI Baki

[Background and purpose - To investigate the association between the rs11136000 single nucleotide polymorphism (SNP) of the clusterin (CLU) gene, the rs541458 and rs3851179 SNPs of the phosphatidylinositol-binding clathrin assembly protein (PICALM) gene and Alzheimer’s disease (AD) in a Turkish population, and to determine whether there are any relationships between the CLU and the PICALM genotypes and behavioral and psychological symptoms of dementia (BPSD) in the Turkish population. Methods - One-hundred and twelve AD patients and 106 controls were included in this study. BPSD were evaluated by the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD). SNPs in the CLU and the PICALM gene were genotyped by Real-Time PCR. Genotype distributions were assessed for the groups of patients and controls, for the patient groups with and without each BPSD, and “No BPSD” and “BPSD”. Results - The CLU and the PICALM genotypes were similar in the AD and control subjects, and the groups with and without each BPSD. There were also no significant differences between the “No BPSD” and the “BPSD” groups for the PICALM genotypes, but even without a statistical significance, it is notable that none of the “No BPSD” patients had genotype pattern CLU-rs11136000-TT, and the female subjects with genotype pattern CLU-rs11136000-TT had higher mean score of BEHAVE-AD. Conclusion - This study claims that investigated SNPs are not genetic risk factors for AD in a Turkish population. In addition, the rs541458 and rs3851179 of PICALM SNPs are not related to development of BPSD, but the rs11136000 of CLU SNP might be related to development of BPSD in AD female Turkish subpopulation.]

Clinical Neuroscience

MARCH 25, 2015

[Genetic polymorphisms of human beta-defensins in patients with multiple sclerosis]

SZEKERES Márta, SOMOGYVÁRI Ferenc, BENCSIK Krisztina, SZOLNOKI Zoltán, VÉCSEI László, MÁNDI Yvette

[Aims - Recent studies have started to elucidate the contribution of microbiome to the pathogenesis of multiple sclerosis (MS). It is also supposed, that neuropathological alterations might be associated with abnormal expression and regulatory function of antimicrobial peptides (AMPs), including defensins. It is in our interest to investigate the relevance of the single nucleotide polymorphisms (SNPs) of the DEFB1 gene and the copy number polymorphism of the DEFB4 genes in MS. Methods - DEFB1 polymorphisms: c.-20G > A (rs11362), DEFB1 c.-44C > G (rs1800972), DEFB1 c.-52G>A (rs1799946), and the DEFB4 gene copy number were investigated in 250 MS patients The control patients comprised 232 age- and gender-matched healthy blood donors. The occurrence of the human b-defensin 2 peptide (hBD2) in the plasma of controls and patients was determined by ELISA. Results - The DEFB1 c.-44C>G polymorphism the GG protective genotype was much less frequent among patients than among the controls. A higher frequency of a lower (<4) copy number of the DEFB4 gene was observed in the patients with MS as compared with the controls (43% vs. 28%, respectively). The median levels of the circulating hBD2 in the patients were 150.6±12.71 pg/ml vs. 262.1±23.82 pg/ml in the control group (p<0.0001). Our results suggest that b-defensins play role in the development of MS.]

Lege Artis Medicinae

DECEMBER 20, 2014

[Gene polymorphisms in drug metabolism in diffuse large BCL patients]

PÁL Ildikó, ZILAHI Erika, ILLÉS Árpád, GERGELY Lajos, RADNAY Zita, VÁRÓCZY László

[Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of all non-Hodgkin lymphoma (NHL) and 80% of agressive lymphomas. Besides the Traditional International Prognostic Index (IPI), some other factors may also influence the prognosis of DLBCL patients. Aims - Our purpose was to study how the genetic polymorphism in metabolic pathway influence the eventfree and overall survival and therapeutic response in diffuse large B-cell lymphoma. Method and patients - Fifty-one patient, 32 men and 19 women, were involved in the study. The average age was 53.1 years. DLBCL was diagnosed between 2006 and 2011 and the average follow up time was 3.78 years. These patients received 1-8 cycles (an average of 6-2 cycles) of R-CHOP immunochemotherapy. REAL Time PCR was used to determine the genetic polymorphisms of CYP2E1, GSTP1, NAT1 and NAT2 genes. Results - Our results showed that the polymorphisms of CYP2E1, GSTP1 and NAT1 genes did not influence the prognosis of DLBCL patients. In terms of the NAT2 gene, GG homozygous patients showed slightly better therapeutic response and survival results compared to those bearing an A allele, however, the differences were not statistically significant. Conclusion - Our results could not confirm that genetic polymorphism in metabolic pathways has any predictive role in diffuse large B-cell lmphoma.]

Clinical Neuroscience

SEPTEMBER 30, 2014

[Complex approaches to study complex trait genetics in multiple sclerosis]

BERNADETTE Kalman

[Multiple sclerosis (MS) is a complex trait disorder defined by several genes and their interactions with environmental factors. A comprehensive exploration of the susceptibility variants had not been feasible until recently when new developments in biotechnology and bioinformatics made possible sequencing of the whole human genome, cataloguing of nucleotide variants and alignments of these variants in haplotypes. Earlier observations from epidemiological, candidate gene and linkage studies provided ample evidence to support a complex genetic determination of MS. New biotechnology and bioinformatics resources have been recently applied to further successful explorations of the disease. These efforts were paralleled by more careful and reliable ascertainments of disease phenotypes, collaborations among specialized centers to generate sufficient sample size and involvement of clinician-scientists capable of working both on the clinical and scientific study sides. Data obtained from the whole genome association studies (GWAS) elevated our understanding of MS genetics to a new level by identifying an extensive list of genetic determinants. Pathway analyses of MS-associated variants provided evidence to support the immune etiology of the disease. Future research will likely explore how environmental factors interact with the genome, and contribute to the abnormal immune activation and inflammation. This review summarizes the outcomes of MS genetic explorations including those of recent GWAS, and highlights practical consequences of genetic and genomic studies by pointing out as to how the derived data facilitate further elucidation of MS pathogenesis. A better understanding of disease processes is necessary for future advancements in therapeutics and the development of disease prevention strategies.]

Clinical Neuroscience

JANUARY 25, 2013

[Aspirin and clopidogrel resistance: possible mechanisms and clinical relevance. Part II: Potential causes and laboratory tests]

VADÁSZ Dávid, SZTRIHA K. László, SAS Katalin, VÉCSEI László

[Recent meta-analyses have indicated that patients with vascular disease demonstrated by laboratory tests to be aspirin or clopidogrel-resistant are at an increased risk of major vascular events. The suggested mechanisms of aspirin resistance include genetic polymorphism, alternative pathways of platelet activation, aspirin-insensitive thromboxane biosynthesis, drug interactions, or a low aspirin dose. Clopidogrel resistance is likely to develop as a result of a decreased bioavailability of the active metabolite, due to genetic variation or concomitant drug treatment. Additional work is required to improve and validate laboratory tests of platelet function, so that they may become useful tools for selection of the most appropriate antiplatelet therapy for an individual patient. Improvements in antiplatelet treatment strategies in the future should lead to a reduction in premature vascular events.]

Hypertension and nephrology

DECEMBER 08, 2012

[Association between the genetic polymorphism of heat-shock protein 72 and pediatric kidney diseases]

BÁNKI Nóra Fanni, RUSAI Krisztina, KÁROLY Éva, SZEBENI Bea, VANNAY Ádám, SALLAY Péter, REUSZ György, TULASSAY Tivadar, SZABÓ J. Attila, FEKETE Andrea

[Recurring urinary tract infections (UTI) in childhood may result in chronic- and end-stage-renal-disease (ESRD), which leads to the initiation of dialysis and renal transplantation (NTx). Heat shock protein (HSP) 72 protects the kidney, whereas it refolds destroyed proteins and cells, and helps regenerating the renal tissue. The HSPA1B (1267)G allele is associated with lower HSP72 expression. This study assesses the role of HSPA1B A(1267)G polymorphism using PCR-RFLP in 103 children treated because of recurrent UTI, 26 children after NTx and 235 healthy controls. Clinical data were also evaluated. HSPA1B (1267)GG genotype and HSPA1B (1267)G allele occurred more frequently in the UTI (p=0.0001; CI: 1.378-2.68) and in the NTx (p=0.014; CI: 2.29-187.7) patient group than in the controls group, and were associated with a higher risk for scarring (p=0.012; CI: 0.33-1.00) and renal malformation (p=0.0072; CI: 1.623- 140.6). Our data indicate a relationship between the carrier status of HSPA1B (1267)G allele and the development of recurrent UTI and ESRD, raising further questions about the clinical and therapeutic relevance of these polymorphism.]

Clinical Neuroscience

MARCH 20, 2007

[ASSOCIATION OF APOLIPOPROTEIN E POLYMORPHISM WITH AGE-RELATED MACULAR DEGENERATION AND ALZHEIMER’S DISEASE IN SOUTH-WESTERN HUNGARY]

KOVÁCS Á. Katalin, PÁMER Zsuzsanna, KOVÁCS Attila, FEKETE Sándor, MISETA Attila, KOVÁCS Bálint, KOVÁCS L. Gábor

[Background - Age-related macular degeneration (AMD) and Alzheimer dementia (AD) show similarities (advanced age, formation of deposits of similar content). Recently apolipoprotein E 2 (apoE 2) has been associated with AMD, while apoE4 with AD. The question of coexistence, especially with respect to the genetic background has not been studied earlier. We investigated, therefore, the occurrence of AMD in AD patients and compared their lipid profile and apoE polymorphism. Methods - 49 AMD, 32 AD and 27 control patients were examined (risk factors, visual acuity, slit lamp biomicroscopy, fundoscopy). Following measurement of triglyceride, total and HDL cholesterol levels, apoE mutation analysis was performed. Results - AMD was found in 8% of the cooperating AD patients. The prevalence of the apoE 4 isoforms in the AMD, AD and the control patients was 2%, 47% and 22%, while that of apoE 2 was 17%, 6% and 7%, respectively. The prevalence of apoE 3 isoform was 82%, 41% and 71%, respectively. Triglyceride, total and HDL cholesterol were in the reference range; however, AD patients were characterized by a lower total cholesterol value. Conclusions - The new finding of this publication is the rare occurrence of AMD among AD patients. The higher frequency of apoE 4 among the AD population, and the higher frequency of apoE 2 among AMD patients in the South-Western region of Hungary confirms the findings of other investigators.]

Clinical Neuroscience

APRIL 20, 2002

[Genetics and hemostasis in young stroke patients]

PONGRÁCZ Endre, TORDAI Attila, CSORNAI Márta, NAGY Zoltán

[Background and purpose - The classical risk factors did not explain all the possible ethiology of cerebral stroke. Genetic polymorphisms responsible for thrombophilia were implicated recently as risk factors of stroke. In this geneticoepidemiological study the author’s aim was to analyse the tendency of genetic polymorphisms to cluster in a cohort of young and elderly stroke patients and in healthy subjects in Hungary. Methods - 253 patients with stroke were compared with 173 healthy blood donors on the basis of genetic polymorphisms of platelet GP IIb/IIIa receptor (33 LeuPro), prothrombin gene G20210A, Factor V Leiden mutation, ACE I/D, methylenetetrahydrofolate reductase (MTHFR) and β fibrinogen gene G455A. These data were acquired using PCR. Questionnaires were used to investigate the family history and to determine the risk factor profile. The subtypes of stroke were analysed in a stroke cohort grouped according to different polymorphisms. Results - An increased frequency of GP IIIa heterozygousity was found as compared to a West-European stroke cohort (31% versus 19%). The prothrombin gene variant (2.9% European and 4.8% in Hungary) was also found to increase in frequency. In young stroke patients (age <50) compared with control subjects the odds ratios were higher: in prothrombin gene (OR: 4.9), in Leiden mutation (OR: 1.67), in fibrinogen gene (OR: 1.64) and in MTHFR(+/+) (OR: 1.58). Clustering of two polymorphisms could only be detected in young patients. These clustering polymorphisms were GP IIb/IIIa with prothrombin G20210A variant (OR: 6.74, 95% CI 1.1-18.2) and prothrombin gene variant with MTHFR (OR: 5.3, CI95 1.2-8.3). Conclusion - Selected and clustered genetic polymorphisms of haemostatic factors could be responsible for the high stroke morbidity in Central Europe. The presence and clustering tendency of these factors have been described in young stroke victims.]

Clinical Neuroscience

JUNE 20, 2003

[Is there any importance of the Leiden mutation in the pathogenesis of ischaemic stroke?]

PONGRÁCZ Endre, TORDAI Attila, CSORNAI Márta, BÉLA Zsuzsanna, NAGY Zoltán

[Background - There are conflicting data about the role of Leiden mutation in the pathogenesis of cerebral arterial thrombosis. In order to obtain relevant data, authors investigated the prevalency of factor V Leiden (A506G) both in healthy subjects and in a subgroup of ischaemic stroke patients. Matherial and methods - Blood samples of 171 healthy persons and 254 ischaemic stroke patients were examined by PCR method for Leiden mutation. Ischaemic lesions in the stroke group were documented by CT or MRI. A routin questionnaire was used to study the family history of vascular events (hypertension, diabetes, POAD, stroke, myocardial infarction) of patients. Conventional vascular risk factors of patients were also documented. Results - The prevalence of Leiden mutation was 7.2% in healthy persons and 11.9% in stroke patients. The OR for 254 patient was 1,45 (0.71-2.97). In the subgroup of young patients: age <50 (n=134) the OR was 1.67 (0.75-3.70) and in the elderly patients group: age >50 (n=120) the OR was 1.21 (0.50-2.89). In the family history of stroke patients having Leiden mutation (hetero- and homozigosity) the stroke prevalence was higher (p=0.01). In the ischaemic stroke group, age<50 with polymorphism a tight correlation with hyperlipidaemia (p=0.03) was found. In the group of age<50 with heterozigosity for Leiden, a lower plasma fibrinogen concentration (p=0.02) was found. The polymorphism showed no correlation with the hypertension, hyperuricaemia, migraine, diabetes mellitus, smoking, alcohol consumption and CDS status of patients. Conclusion - When comparing stroke patients to control population there is no significant increase in the frequency of Leiden mutation. Leiden mutation together with hyperlipidaemia and stroke in the family history results in high risk for ischaemic stroke in young patients.]