Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

• MeSH
• autofagie * genetika   MeSH
• běloši genetika   MeSH
• duktální karcinom pankreatu * genetika   patologie   MeSH
• forkhead transkripční faktory MeSH
• genetická predispozice k nemoci * MeSH
• hepatocytární jaderný faktor 3-alfa genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• lidé MeSH
• nádorové biomarkery * genetika   MeSH
• nádorové supresorové proteiny * genetika   MeSH
• nádory slinivky břišní * genetika   patologie   MeSH
• studie případů a kontrol MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure. METHODS: Using resources from CRC consortia, including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score, including 141 variants associated with CRC risk. RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking (RERI = 0.24, 95% confidence interval [CI] = 0.13, 0.36), ever smoking (0.11 [0.05, 0.16]), high body mass index (female 0.09 [0.05, 0.13], male 0.10 [0.05, 0.14]), or high red meat intake (highest versus lowest quartile 0.18 [0.09, 0.27]) was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/nonsteroidal anti-inflammatory drugs use (-0.16 [-0.20, -0.11]) or higher intake of fruit, fiber, or calcium (highest quartile versus lowest quartile -0.12 [-0.18, -0.050]; -0.16 [-0.23, -0.09]; -0.11 [-0.18, -0.05], respectively) than those with average genetic susceptibility. CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.

• MeSH
• dieta MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• index tělesné hmotnosti MeSH
• interakce genů a prostředí * MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory * genetika   epidemiologie   MeSH
• kouření škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• pití alkoholu MeSH
• rizikové faktory MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: A new high-resolution next-generation sequencing (NGS)-based method was established to type closely related European type II Toxoplasma gondii strains. METHODS: T. gondii field isolates were collected from different parts of Europe and assessed by whole genome sequencing (WGS). In comparison to ME49 (a type II reference strain), highly polymorphic regions (HPRs) were identified, showing a considerable number of single nucleotide polymorphisms (SNPs). After confirmation by Sanger sequencing, 18 HPRs were used to design a primer panel for multiplex PCR to establish a multilocus Ion AmpliSeq typing method. Toxoplasma gondii isolates and T. gondii present in clinical samples were typed with the new method. The sensitivity of the method was tested with serially diluted reference DNA samples. RESULTS: Among type II specimens, the method could differentiate the same number of haplotypes as the reference standard, microsatellite (MS) typing. Passages of the same isolates and specimens originating from abortion outbreaks were identified as identical. In addition, seven different genotypes, two atypical and two recombinant specimens were clearly distinguished from each other by the method. Furthermore, almost all SNPs detected by the Ion AmpliSeq method corresponded to those expected based on WGS. By testing serially diluted DNA samples, the method exhibited a similar analytical sensitivity as MS typing. CONCLUSION: The new method can distinguish different T. gondii genotypes and detect intra-genotype variability among European type II T. gondii strains. Furthermore, with WGS data additional target regions can be added to the method to potentially increase typing resolution.

• MeSH
• genetická variace MeSH
• genotyp MeSH
• lidé MeSH
• multiplexová polymerázová řetězová reakce MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• protozoální DNA genetika   MeSH
• těhotenství MeSH
• Toxoplasma * genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• aktivátory chloridových kanálů terapeutické užití   MeSH
• aminofenoly * terapeutické užití   MeSH
• benzodioxoly * terapeutické užití   MeSH
• chinoliny terapeutické užití   MeSH
• chinolony * terapeutické užití   MeSH
• cystická fibróza * farmakoterapie   genetika   MeSH
• dospělí MeSH
• exokrinní pankreatická insuficience farmakoterapie   etiologie   genetika   MeSH
• fixní kombinace léků MeSH
• genotyp MeSH
• indoly * terapeutické užití   MeSH
• lidé MeSH
• protein CFTR * genetika   MeSH
• pyrazoly * terapeutické užití   MeSH
• pyridiny terapeutické užití   MeSH
• pyrrolidiny terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• kazuistiky MeSH

BACKGROUND: Among inherited cardiomyopathies involving the left ventricle, whether dilated or not, certain genotypes carry a well-established arrhythmic risk, notably manifested as sustained monomorphic ventricular tachycardia (SMVT). Nonetheless, the precise localization and electrophysiological profile of this substrate remain undisclosed across different genotypes. METHODS: Patients diagnosed with cardiomyopathy and left ventricle involvement due to high-risk genetic variants and SMVT treated by electrophysiological study were recruited from 18 European/US centers. Electrophysiological study, imaging, and outcomes data after ablation were assessed in relation to genotype. RESULTS: Seventy-one patients were included (49.6 Q1-Q3 [40-60] years, 76% men). They were divided into 4 groups according to the affected protein: desmosomal (DSP, PKP2, DSG2, and DSC2), nuclear membrane (LMNA and TMEM43), cytoskeleton (FLNC and DES), and sarcoplasmic reticulum (PLN). Desmosomal genes, TMEM43, and PLN were associated with biventricular disease, while variants in LMNA and cytoskeleton genes had predominant left ventricle involvement (P=0.001). The location of the clinical-SMVT substrate was significantly different based on genotype (P=0.005). DSP and cytoskeleton genes presented SMVTs with right bundle branch block morphology, which origin was identified in the inferolateral segments of the left ventricle. The other desmosomal genes (PKP2 and DSG2), along with TMEM43, showed SMVTs with left bundle branch block morphology and predominantly right ventricular substrate. In contrast, LMNA substrate was mainly observed in the interventricular septum. During a median of 26 Q1-Q3 (10.6-65) months, 27% of patients experienced recurrences of clinical SMVT with differences between genotypes (log-rank 0.016). Nuclear membrane genes demonstrated the highest recurrence rate compared with desmosomal genes (hazard ratio, 4.56 [95% CI, 1.5-13.8]). CONCLUSIONS: The anatomic substrate of SMVTs shows a strong correlation with the underlying genotype, electrocardiographic morphology, and recurrence rate. Particularly, patients with nuclear membrane gene variants have a significantly higher recurrence rate compared with those with desmosomal gene variants.

• MeSH
• akční potenciály MeSH
• dospělí MeSH
• elektrofyziologické techniky kardiologické MeSH
• fenotyp * MeSH
• genetická predispozice k nemoci * MeSH
• genetické asociační studie MeSH
• genotyp MeSH
• hodnocení rizik MeSH
• kardiomyopatie genetika   patofyziologie   diagnóza   MeSH
• katetrizační ablace MeSH
• komorová tachykardie * genetika   patofyziologie   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• rizikové faktory MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Geografické názvy
• Evropa MeSH

Virus hepatitidy E (HEV) je celosvětovým problémem a druhou nejčastější příčinou virové hepatitidy. Existuje osm genotypů HEV, z nichž čtyři způsobují onemocnění u lidí. Genotypy 1 a 2 se přenášejí kontaminovanou vodou, zatímco genotypy 3 a 4 jsou zoonotické a přenášejí se konzumací nedostatečně tepelně upraveného masa, zejména vepřového, zvěřiny a králičího. V České republice je endemický genotyp 3 s rezervoárem u prasat, spárkaté zvěře a králíků. Infekce HEV se projevuje podobně jako jiné typy hepatitid příznaky, jako je únava, horečka, nevolnost, žloutenka a tmavá moč. U imunokompetentních pacientů infekce obvykle odezní sama, ale u imunokompromitovaných a imusuprimovaných může přejít do chronického stavu vedoucího až k cirhóze a selhání jater. Preexistující onemocnění jater hraje v kontextu HEV významnou roli, jelikož u pacientů s chronickým onemocněním jater infikovaných HEV existuje významně vyšší riziko selhání jater, které může vést až k úmrtí. Diagnóza se provádí detekcí protilátek IgM a IgG proti HEV a HEV RNA v krvi a stolici. Doporučené diagnostické postupy se liší v závislosti na imunitním stavu pacienta a epidemiologickém prostředí. Léčba obvykle není nutná, ale v závažných případech se používá ribavirin a interferon a. Prevence zahrnuje zlepšení hygieny, dostatečnou tepelnou úpravu masa a v rozvojových zemích zvážení očkování. V Číně je dostupná vakcína Hecolin® účinná proti genotypům 1, 2 a 4, ale v Evropské unii zatím není registrována.

The hepatitis E virus (HEV) represents a significant global health concern, accounting for the second-highest incidence of viral hepatitis. Eight genotypes of HEV have been identified, four of which are associated with disease in humans. Genotypes 1 and 2 are transmitted via contaminated water, whereas genotypes 3 and 4 are zoonotic and transmitted through the consumption of undercooked meat, particularly pork, venison, and rabbit. Genotype 3 is endemic in the Czech Republic, with reservoirs in pigs, wild game, and rabbits. A hepatitis E virus (HEV) infection presents with symptoms similar to those observed in other types of hepatitis, including fatigue, fever, malaise, jaundice, and dark urine. In immunocompetent patients, the infection typically resolves spontaneously. However, in immunocompromised patients, it can progress to a chronic state, leading to cirrhosis and liver failure. The presence of preexisting liver disease is a significant factor in the context of HEV, as patients with chronic liver disease infected with HEV are at an elevated risk of liver failure, which can potentially result in death. A diagnosis is made by detecting immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to the hepatitis E virus (HEV) and HEV ribonucleic acid (RNA) in blood and stool samples. The recommended diagnostic procedures are contingent upon the patient‘s immune status and epidemiological context. In most cases, treatment is not necessary; however, ribavirin and interferon a are employed in severe instances. Prevention strategies encompass enhanced hygiene practices, thorough cooking of meat, and in developing countries, the consideration of vaccination. The vaccine Hecolin® is available in China and is efficacious against genotypes 1, 2, and 4; however, it is not yet registered in the European Union.

• MeSH
• genotyp MeSH
• hepatitida E * diagnóza   farmakoterapie   přenos   prevence a kontrola   MeSH
• lidé MeSH
• virus hepatitidy E patogenita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH
• Geografické názvy
• Česká republika MeSH

Serózní tubární intraepiteliální karcinom (STIC) je považován za prekurzor high grade serózního karcinomu pánve (HGSC), který zahrnuje karcinomy ovaria, tuby a peritonea. STIC je brzkou morfologicky rozpoznatelnou lézí v patogenezi HGSC a je nalézán převážně v distální části vejcovodu. I přes velký pokrok v objasnění patogeneze ovariálních karcinomů a zavedení nových patologických postupů při diagnostice prekurzorových lézí HGSC zůstává na tomto poli mnoho nezodpovězených otázek.

Serous tubal intraepithelial carcinoma (STIC) is considered as a precursor of high-grade serous carcinoma of the pelvis (HGSC), which includes ovarian, tubal and peritoneal carcinomas. STIC is an early morphologically recognizable lesion in the pathogenesis of HGSC and is found predominantly in the distal part of the fallopian tube. Despite a great progress in elucidating the pathogenesis of ovarian carcinomas and the introduction of new pathological procedures for the diagnosis of precursor lesions of HGSC, there remain many unanswered questions.

• MeSH
• adjuvantní chemoterapie metody   MeSH
• časná detekce nádoru metody   MeSH
• genetická predispozice k nemoci MeSH
• gynekologické chirurgické výkony metody   MeSH
• karcinom in situ diagnóza   patologie   terapie   MeSH
• lidé MeSH
• nádory cystické, mucinózní a serózní chirurgie   diagnóza   patologie   MeSH
• nádory vaječníků diagnóza   patologie   terapie   MeSH
• nádory vejcovodů * diagnóza   patologie   terapie   MeSH
• Check Tag
• lidé MeSH

OBJECTIVES: To determine whether selected single nucleotide polymorphisms (SNPs) of genes encoding proteins responsible for the activation, transport, or metabolism of dabigatran and apixaban might be associated with a risk of gastrointestinal bleeding in a cohort of adult patients treated with these drugs. No previous study has focused specifically on the association with gastrointestinal bleeding. MATERIALS AND METHODS: Ninety-one patients treated with dabigatran or apixaban were genotyped for selected polymorphisms. The following polymorphisms were studied: ABCB1 gene rs1045642, rs4148738, rs1128503 and rs2032582; CES1 gene rs2244613, rs8192935 and rs2244614; and SULT1A1 gene rs9282861 and SULT1A2 gene rs1136703. Two groups divided by particular drugs and genotypes were compared in terms of the presence (bleeding group) or absence (nonbleeding group) of gastrointestinal bleeding. The genotype distribution was expressed via dominant and recessive models. RESULTS: In patients treated either with dabigatran or with apixaban, no evidence was found to support the association of gastrointestinal bleeding with any genotype for any of the studied SNPs. CONCLUSION: In both dabigatran- and apixaban-treated patients, no associations between the selected polymorphisms and gastrointestinal bleeding risk were found, however the results should be interpreted with caution because of the small cohort size.

• MeSH
• antithrombiny škodlivé účinky   terapeutické užití   MeSH
• dabigatran * škodlivé účinky   MeSH
• dospělí MeSH
• farmakogenetika MeSH
• gastrointestinální krvácení * genetika   chemicky indukované   MeSH
• genotyp MeSH
• inhibitory faktoru Xa škodlivé účinky   terapeutické užití   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• P-glykoproteiny MeSH
• pyrazoly * škodlivé účinky   terapeutické užití   MeSH
• pyridony * škodlivé účinky   terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10-6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.

• MeSH
• butyrofiliny * genetika   metabolismus   MeSH
• COVID-19 * genetika   komplikace   imunologie   virologie   MeSH
• dítě MeSH
• genetická predispozice k nemoci MeSH
• heterozygot MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• SARS-CoV-2 * MeSH
• syndrom systémové zánětlivé reakce * genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Familial dysbetalipoproteinemia (FD) is an autosomal recessive (rarely dominant) inherited disorder that is almost exclusively associated with the apolipoprotein E gene (APOE) variability. Nonetheless, only a small proportion of APOE2/E2 subjects develop the phenotype for mixed dyslipidemia; the context of other trigger metabolic or genetic factors remains unknown. METHODS: One hundred and one patients with FD and eighty controls (all APOE2/E2 homozygotes; rs429358) were screened for 18 single-nucleotide polymorphisms (SNPs) within the genes involved in triglyceride metabolism. RESULTS: Two SNPs were significantly associated with the FD phenotype (rs439401 within APOE; P < 0.0005 and rs964184 within ZPR1/APOA5/A4/C3/A1 gene cluster; P < 0.0001). Unweighted genetic risk scores - from these two SNPs (GRS2), and, also, additional 13 SNPs with P-value below 0.9 (GRS15) - were created as an additional tool to improve the risk estimation of FD development in subjects with the APOE2/E2 genotype. Both GRS2 and GRS15 were significantly (P < 0.0001) increased in patients and both GRSs discriminated almost identically between the groups (P = 0.86). Subjects with an unweighted GRS2 of three or more had an almost four-fold higher risk of FD development than other individuals (odds ratio (OR) 3.58, 95% confidence interva (CI): 1.78-7.18, P < 0.0005). CONCLUSIONS: We identified several SNPs that are individual additive factors influencing FD development. The use of unweighted GRS2 is a simple and clinically relevant tool that further improves the prediction of FD in APOE2/E2 homozygotes with corresponding biochemical characteristics.

• MeSH
• apolipoprotein E2 * genetika   MeSH
• apolipoproteiny E genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• genetické rizikové skóre MeSH
• genotyp * MeSH
• hyperlipoproteinemie typ III genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• rizikové faktory MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH