Suchergebnisse

ObjectivesDuring the last two decades, HIV‐1 has been spreading rapidly in former Soviet Union republics including Kyrgyzstan. The current molecular monitoring of HIV‐infection epidemic is carried out in Russia only with no or limited data from the other FSU countries. The aim of this work was to investigate the prevalence of HIV‐1 genetic variants circulating in Kyrgyzstan.MethodsBlood collection from the HIV‐infected patients was carried out by local specialists with the informed consent and the questionnaire was answered by each of the patients. The total number of samples was 100. The washed cell pellets were transferred to Moscow following with proviral DNA extraction, PCR amplification and gag, pol and env genes sequencing. The phylogenetic analysis of nucleotide sequences using neighbor‐joining method was carried out by MEGA 3 program. The preliminary data were obtained in 22 samples isolated from PBMC of HIV‐infected patients from Kyrgyzstan.ResultsAmong the samples studied 6 (27.3%) samples belonged to a subtype CRF02_AG, 16 samples ‐ to subtype A (A1). One of the samples belonging to CRF02_AG, probably, is a recombinant between CRF02_AG and A1. There was no major drug resistance mutations in the samples studied. The minor mutations were presented in small proportions: 1 in PR (L10I), 6 in RT (A62V ‐ in 3 samples, V108G, E138A, Y181F, M184I, L210M ‐ on one sample) and 1 in IN (L74M). It was impossible to associate the distribution of mutations with HIV‐1 genetic variant. The V3 loop (env gene) in 17 samples was analyzed for tropism using geno2pheno program; all samples were found to be R5‐viruses.ConclusionThe HIV‐1 subtype A seems to dominate in Kyrgyzstan like in other FSU countries. The recombinant CRF02_AG epidemiologically linked to Uzbekistan is quite widespread. The rest of Kyrgyzstan collection is under investigation and the data will be refined soon.

BACKGROUND: The severity of Obsessive-Compulsive Disorder (OCD) varies significantly among probands. No study has specifically investigated the genetic base of OCD severity. A previous study from our group found an OCD polygenic risk score to predict pre- and post-treatment severity. This study explores the genomic bases of OCD severity. METHODS: We administered the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) to 401 patients at their first visit to our clinic to measure their OCD severity. Genotyping data was collected by using the Infinium PsychArray-24 BeadChip kit (Illumina). We analyzed genetic association with OCD severity in a linear regression analysis at single-nucleotide polymorphism (SNP)- and gene-levels, this last also considering rare variants. Enrichment analyses were performed from gene-based analyses' results. RESULTS: No SNP reached significant association (p < 10-8) with the YBOCS. Six markers showed suggestive association (p < 10-5). The top SNP was an intergenic variant in chromosome 2: rs7578149 (p < 1.89 × 10-6), located in a region suggestively associated with MDD. Linkage disequilibrium was found for two clusters of SNPs located between SLC16A14 and SP110 in chromosome 2, all of them forming one peak of association. Enrichment analyses revealed OCD genes to be associated with porin activity (FDR = 0.01) and transmembrane structure (FDR = 0.04). LIMITATIONS: The size of the sample and the transversal nature of the severity measure are limitations of this study. CONCLUSION: This study contributes to better characterize OCD at an individual level, helping to know more about the prognosis of the disorder and develop more individualized treatments ; This study was supported in part by the Carlos III Health Institute (PI16/00950, PI18/00856); FEDER funds ('A way to build Europe') and by the Agency for Management of University and Research Grants of the Catalan Government (2014SGR1672). MA was supported by the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia. Grant co-funded by the European Social Fund (ESF) "ESF, Investing in your future" (2017 FI_B 00327). ER was supported by a Juan Rodés contract (JR14/00038)

15 p.-8 fig.-3 tab. ; Haemolytic Uraemic Syndrome associated with Streptococcus pneumoniae infections (SP-HUS) is a clinically well-known entity that generally affects infants, and could have a worse prognosis than HUS associated to E. coli infections. It has been assumed that complement genetic variants associated with primary atypical HUS cases (aHUS) do not contribute to SP-HUS, which is solely attributed to the action of the pneumococcal neuraminidase on the host cellular surfaces. We previously identified complement pathogenic variants and risk polymorphisms in a few Hungarian SP-HUS patients, and have now extended these studies to a cohort of 13 Spanish SP-HUS patients. Five patients presented rare complement variants of unknown significance, but the frequency of the risk haplotypes in the CFH-CFHR3-CFHR1 region was similar to the observed in aHUS. Moreover, we observed desialylation of Factor H (FH) and the FH-Related proteins in plasma samples from 2 Spanish and 4 Hungarian SP-HUS patients. To analyze the functional relevance of this finding, we compared the ability of native and "in vitro" desialylated FH in: (a) binding to C3b-coated microtiter plates; (b) proteolysis of fluid-phase and surface-bound C3b by Factor I; (c) dissociation of surface bound-C3bBb convertase; (d) haemolytic assays on sheep erythrocytes. We found that desialylated FH had reduced capacity to control complement activation on sheep erythrocytes, suggesting a role for FH sialic acids on binding to cellular surfaces. We conclude that aHUS-risk variants in the CFH-CFHR3-CFHR1 region could also contribute to disease-predisposition to SP-HUS, and that transient desialylation of complement FH by the pneumococcal neuraminidase may have a role in disease pathogenesis. ; This study was funded by the Spanish Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund from the European Union (grants PI16/00723 and PI19/00970 to PS-C). IG and EA are supported by the Spanish Autonomous Region of Madrid (Complement II-CM network; S2017/BMD-3673). IG was also supported by the Spanish Fundación Senefro (http://www.senefro.org/). The study was also supported by the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the molecular biology thematic programme of the Semmelweis University, by the National Office for Innovation and Research (KH130355 to ZP), and by the MSCA-ITN (Horizon 2020) CORVOS (Grant 860044 to ZP). DC was supported by the Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences (PPD2018-016/2018). ; Peer reviewed

<i>Background:</i> The wide use of genome wide association studies (GWAS) has led to the successful identification of multiple genetic susceptibility variants to several complex human diseases. Given the limited amount of data on genetic variation at these loci in populations of non-European origin, we investigated population variation among 11 population groups for loci showing strong and consistent association from GWAS with several complex human diseases. <i>Methods:</i> Data from the International HapMap Project Phase 3, comprising 11 population groups, were used to estimate allele frequencies at loci showing strong and consistent association from GWAS with any of 26 complex human diseases and traits. Allele frequency summary statistics and F_ST at each locus were used to estimate population differentiation. <i>Results:</i> There is wide variation in allele frequencies and F_ST across the 11 population groups for susceptibility loci to these complex human diseases and traits. Allele frequencies varied widely across populations, often by as much as 20- to 40-fold. F_ST, as a measure of population differentiation, also varied widely across the loci studied (for example, 0.019 to 0.201 for type 2 diabetes, 0.022 to 0.520 for prostate cancer loci, and 0.006 to 0.520 for serum lipid levels). <i>Conclusions:</i> The public health risk posed by any of these risk alleles is likely to show wide variation across populations simply as a function of its frequency, and this risk difference may be amplified by gene-gene and gene-environment interactions. These analyses offer compelling reasons for including multiple human populations from different parts of the world in the international effort to use genomic tools to understand disease etiology and differential distribution of diseases across ethnic groups.

INTRODUCTION: Whether detailed genetic information contributes to risk stratification of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains uncertain. Pathogenic genetic variants in some genes seem to carry a higher risk for arrhythmia and earlier disease onset than others, but comparisons between variants in the same gene have not been done. Combined Annotation Dependent Depletion (CADD) score is a bioinformatics tool that measures the pathogenicity of each genetic variant. We hypothesized that a higher CADD score is associated with arrhythmic events and earlier age at ARVC manifestations in individuals carrying pathogenic or likely pathogenic genetic variants in plakophilin-2 (PKP2). METHODS: CADD scores were calculated using the data from pooled Scandinavian and North American ARVC cohorts, and their association with cardiac events defined as ventricular tachycardia/ventricular fibrillation (VT/VF) or syncope and age at definite ARVC diagnosis were assessed. RESULTS: In total, 33 unique genetic variants were reported in 179 patients (90 males, 71 probands, 96 with definite ARVC diagnosis at a median age of 35 years). Cardiac events were reported in 76 individuals (43%), of whom 53 had sustained VT/VF (35%). The CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953-1.054, p = 0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947-1.039, p = 0.731). CONCLUSION: No correlation was found between CADD scores and clinical manifestations of ARVC, indicating that the score has no additional risk stratification value among carriers of pathogenic or likely pathogenic PKP2 genetic variants. ; Funding agencies: This work was supported by Region Östergötland (ALF) undergrant LIO-609681 and by FORSS (Medical Research Council ofSoutheast Sweden) under grant FORSS/572421 and FORSS/307961.Pyotr G. Platonov is supported by The Swedish Heart-Lung Foundation and governmental funding of clinical research (ALF). Henrik K. Jensen is supported by the Novo Nordisk Foundation (NNF18OC0031258). Wojciech Zareba is supported by NIH Grant(1R01HL116906) (Mechanisms, Genotypes and Clinical Phenotypes of Arrhythmogenic Cardiomyopathy).

30 p.-7 fig. ; Genetic analyses in atypical hemolytic uremic syndrome (aHUS) and C3-glomerulopathy (C3G) patients have provided an excellent understanding of the genetic component of the disease and informed genotype-phenotype correlations supporting an individualized approach to patient management and treatment. In this context, a correct categorization of the disease-associated gene variants is critical to avoid detrimental consequences for patients and their relatives. Here we describe a comprehensive procedure to measure levels and functional activity of complement regulator factor H (FH) encoded by CFH, the commonest genetic factor associated with aHUS and C3G, and present the results of the analysis of 28 uncharacterized, disease-associated, FH variants. Sixteen variants were not expressed in plasma and eight had significantly reduced functional activities that impact on complement regulation. In total, 24 of 28 CFH variants were unambiguously categorized as pathogenic and the nature of the pathogenicity fully documented for each. The data also reinforce the genotype-phenotype correlations that associate specific FH functional alterations with either aHUS or C3G and illustrate important drawbacks of the prediction algorithms dealing with variants located in FH functional regions. We also report that the novel aHUS-associated M823T variant is functionally impaired. This was unexpected and uncovered the important contribution of regions outside the N-terminal and C-terminal functional domains to FH regulatory activities on surfaces. Thus, our work significantly advances knowledge towards a complete functional understanding of the CFH genetic variability and highlights the importance of functional analysis of the disease-associated CFH variants. ; SRdeC is supported by the Spanish Ministerio de Economía y Competitividad/FEDER (grant number SAF2015-66287-R), the Seventh Framework Programme European Union Project EURenOmics (grantnumber 305608), and the Autonomous Region of Madrid (grantnumber S2010/BMD-2316). ; Peer reviewed

AbstractParkinson's disease (PD) is a complex disorder with a significant genetic component. Genetic variations associated with PD play a crucial role in the disease's inheritance and prognosis. Currently, 31 genes have been linked to PD in the OMIM database, and the number of genes and genetic variations identified is steadily increasing. To establish a robust correlation between phenotype and genotype, it is essential to compare research findings with existing literature. In this study, we aimed to identify genetic variants associated with PD using a targeted gene panel with next-generation sequencing (NGS) technology. Our objective was also to explore the idea of re-analyzing genetic variants of unknown significance (VUS). We screened 18 genes known to be related to PD using NGS in 43 patients who visited our outpatient clinic between 2018−2019. After 12−24 months, we re-evaluated the detected variants. We found 14 different heterozygous variants classified as pathogenic, likely pathogenic, or VUS in 14 individuals from nonconsanguineous families. We re-evaluated 15 variants and found changes in their interpretation. Targeted gene panel analysis with NGS can help identify genetic variants associated with PD with confidence. Re-analyzing certain variants at specific time intervals can be especially beneficial in selected situations. Our study aims to expand the clinical and genetic understanding of PD and emphasizes the importance of re-analysis.