Cholesteryl ester transfer protein (CETP) I405V polymorphism and cardiovascular disease in eastern European Caucasians – a cross-sectional study

Methods A cross-sectional study was conducted to genotype 1028 healthy blood donors and 1517 clinically well characterized elderly for CETP I405V. Results We could not find any association of this polymorphism with age for both, males or females, in any of these cohorts (P = 0.71 and P = 0.57, respectively, for males and P = 0.55 and P = 0.88, respectively, for females). In addition, no association with cardiovascular diseases could be observed in the elderly cohort (males OR = 1.12 and females OR = 0.88). In the same cohort, the CETP V405V genotype was associated with significantly enhanced HDL levels (P = 0.03), mostly owing to the female sex (P = 0.46 for males, P = 0.02 for females), whereas LDL and triglyceride levels were unchanged (P = 0.62 and P = 0.18, respectively). Conclusion Our data support the recent hypothesis that variations enhancing HDL levels without affecting LDL levels are not associated with the risk for cardiovascular diseases

TM6SF2 and MBOAT7 Gene Variants in Liver Fibrosis and Cirrhosis

Previous large-scale genetic studies identified single nucleotide polymorphisms (SNPs) of the TM6SF2 and MBOAT7 genes as risk factors for alcoholic liver cirrhosis and non-alcoholic fatty liver disease. In this study, we tried to evaluate the association between TM6SF2 variant rs58542926 and MBOAT7 variant rs641738 and the risk of hepatic fibrosis or liver cirrhosis of different etiology. In parallel, we also aimed to evaluate whether these two SNPs modify the effects of the PNPLA3 rs738409 risk variant for the development of hepatic fibrosis and liver cirrhosis. The study was conducted at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital,and included 334 patients with liver cirrhosis, 128 patients with liver fibrosis, and 550 controls. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Overall, TM6SF2 rs58542926 as well as MBOAT7 rs641738 were not linked to hepatic fibrosis, alcohol or hepatitis C virus induced liver cirrhosis in an Eastern European population. These genetic variations also didnot mediate the effect of PNPLA3 rs738409 SNP for liver developing liver fibrosis or liver cirrhosis

miR-20b and miR-451a Are Involved in Gastric Carcinogenesis through the PI3K/AKT/mTOR Signaling Pathway: Data from Gastric Cancer Patients, Cell Lines and Ins-Gas Mouse Model

Gastric cancer (GC) is one of the most common and lethal gastrointestinal malignancies worldwide. Many studies have shown that development of GC and other malignancies is mainly driven by alterations of cellular signaling pathways. MicroRNAs (miRNAs) are small noncoding molecules that function as tumor-suppressors or oncogenes, playing an essential role in a variety of fundamental biological processes. In order to understand the functional relevance of miRNA dysregulation, studies analyzing their target genes are of major importance. Here, we chose to analyze two miRNAs, miR-20b and miR-451a, shown to be deregulated in many different malignancies, including GC. Deregulated expression of miR-20b and miR-451a was determined in GC cell lines and the INS-GAS mouse model. Using Western Blot and luciferase reporter assay we determined that miR-20b directly regulates expression of PTEN and TXNIP, and miR-451a: CAV1 and TSC1. Loss-of-function experiments revealed that down-regulation of miR-20b and up-regulation of miR-451a expression exhibits an anti-tumor effect in vitro (miR-20b: reduced viability, colony formation, increased apoptosis rate, and miR-451a: reduced colony forming ability). To summarize, the present study identified that expression of miR-20b and miR-451a are deregulated in vitro and in vivo and have a tumor suppressive role in GC through regulation of the PI3K/AKT/mTOR signaling pathway

Molecular characterization and seroprevalence of hepatitis E virus in inflammatory bowel disease patients and solid organ transplant recipients

16 p.-3 fig.-5 tab.Seroprevalence rates and molecular characterization of hepatitis E virus (HEV) prevalent in the Lithuanian human population has not yet been evaluated. Immunosuppressed individuals have been recognized as a risk group for chronic hepatitis due to HEV genotype 3 (HEV-3) infections. The objectives of the present study were to determine prevalence rates of anti-HEV antibodies among inflammatory bowel disease (IBD) patients and solid organ transplant (SOT) recipients, to isolate and characterize HEV strain present in the Lithuanian human population, and to investigate its capacity to infect non-human primate (MARC-145 and Vero), swine (PK-15) and murine (Neuro-2a) cells in vitro. In the present study, the significant difference of anti-HEV IgG prevalence between healthy (3.0% (95% CI 0–6.3)) and immunosuppressed individuals (12.0% [95% CI 8.1–15.9]) was described. Moreover, our findings showed that anti-HEV IgG seropositivity can be significantly predicted by increasing age (OR = 1.032, p < 0.01), diagnosis of IBD (OR = 4.541, p < 0.01) and reception of SOT (OR = 4.042, <0.05). Locally isolated HEV strain clustered within genotype 3i subtype of genotype 3 and was capable of infecting MARC-145 cells. This study demonstrates higher HEV seroprevalence in the risk group compared to healthy control individuals without confidence interval overlap. The high level of genetic homology between human and animal strains in Lithuania and the capacity of locally isolated strains to infect cells of non-human origin suggests its potential for zoonotic transmission.This research was partly funded by the Lithuanian University of Health Sciences Science Foundation (LSMUSF), grant number 119-05 and COST Action CA15116 ASF-STOP, supported by COST (European Cooperation in Science and Technology).Peer reviewe

Association between polymorphisms of TAS2R16 and susceptibility to colorectal cancer

Background: genetics plays an important role in the susceptibility to sporadic colorectal cancer (CRC). In the last 10 years genome-wide association studies (GWAS) have identified over 40 independent low penetrance polymorphic variants. However, these loci only explain around 1‑4% of CRC heritability, highlighting the dire need of identifying novel risk loci. In this study, we focused our attention on the genetic variability of the TAS2R16 gene, encoding for one of the bitter taste receptors that selectively binds to salicin, a natural antipyretic that resembles aspirin. Given the importance of inflammation in CRC, we tested whether polymorphic variants in this gene could affect the risk of developing this neoplasia hypothesizing a role of TAS2R16 in modulating chronic inflammation within the gut. Methods: we performed an association study using 6 tagging SNPs, (rs860170, rs978739, rs1357949, rs1525489, rs6466849, rs10268496) that cover all TAS2R16 genetic variability. The study was carried out on 1902 CRC cases and 1532 control individuals from four European countries. Results: we did not find any statistically significant association between risk of developing CRC and selected SNPs. However, after stratification by histology (colon vs. rectum) we found that rs1525489 was associated with increased risk of rectal cancer with a (Ptrend of = 0.0071). Conclusions: our data suggest that polymorphisms within TAS2R16 gene do not have a strong influence on colon cancer susceptibility, but a possible role in rectal cancer should be further evaluated in larger cohorts

Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

We performed a multistage genome-wide association study (GWAS) including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT; per-allele odds ratio [OR] = 0.79; 95% confidence interval [CI] = 0.74–0.84; P = 3.0×10−12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2; OR = 1.46; 95% CI = 1.30–1.65; P = 1.1×10−10), rs9581943 at 13q12.2 (PDX1; OR = 1.15; 95% CI = 1.10–1.20; P = 2.4×10−9), and rs16986825 at 22q12.1 (ZNRF3; OR = 1.18; 95% CI = 1.12–1.25; P = 1.2×10−8). An independent signal was identified in exon 2 of TERT at the established region 5p15.33 (rs2736098; OR = 0.80; 95% CI = 0.76–0.85; P = 9.8×10−14). We also identified a locus at 8q24.21 (rs1561927; P = 1.3×10−7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study has identified multiple new susceptibility alleles for pancreatic cancer worthy of follow-up studies

Genetic variability of the ABCC2 gene and clinical outcomes in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients

Biopsy Sampling in Upper Gastrointestinal Endoscopy : A Survey from 10 Tertiary Referral Centres across Europe

Funding Information: A. Link reports grants from European Commission “Eu-ropäischer Fond für regionale Entwicklung” (EFRE), outside the submitted work. In Lithuania the work was partly supported by Lithuanian Research Council Grant no APP-2/2016. In Latvia, the methodological support was made available from the project lzp-2018/1-0135. This work was also supported by the NIHR Oxford Biomedical Research Centre (The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care). In Barcelona, we thank the CERCA Programme/Generalitat de Catalunya for the support. Publisher Copyright: © 2020 The Author(s) Published by S. Karger AG, Basel.Background: Guidelines give robust recommendations on which biopsies should be taken when there is endoscopic suggestion of gastric inflammation. Adherence to these guidelines often seems arbitrary. This study aimed to give an overview on current practice in tertiary referral centres across Europe. Methods: Data were collected at 10 tertiary referral centres. Demographic data, the indication for each procedure, endoscopic findings, and the number and sampling site of biopsies were recorded. Findings were compared between centres, and factors influencing the decision to take biopsies were explored. Results: Biopsies were taken in 56.6% of 9,425 procedures, with significant variation between centres (p < 0.001). Gastric biopsies were taken in 43.8% of all procedures. Sampling location varied with the procedure indication (p < 0.001) without consistent pattern across the centres. Fewer biopsies were taken in centres which routinely applied the updated Sydney classification for gastritis assessment (46.0%), compared to centres where this was done only upon request (75.3%, p < 0.001). This was the same for centres stratifying patients according to the OLGA system (51.8 vs. 73.0%, p < 0.001). More biopsies were taken in centres following the MAPS guidelines on stomach surveillance (68.1 vs. 37.1%, p < 0.001). Biopsy sampling was more likely in younger patients in 8 centres (p < 0.05), but this was not true for the whole cohort (p = 0.537). The percentage of procedures with biopsies correlated directly with additional costs charged in case of biopsies (r = 0.709, p = 0.022). Conclusion: Adherence to guideline recommendations for biopsy sampling at gastroscopy was inconsistent across the participating centres. Our data suggest that centre-specific policies are applied instead.publishersversionPeer reviewe

mRNA PGC-1α levels in blood samples reliably correlates with its myocardial expression: study in patients undergoing cardiac surgery

et al.[Objective]: Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcriptional coactivator that has been proposed to play a protective role in mouse models of cardiac ischemia and heart failure, suggesting that PGC-1α could be relevant as a prognostic marker. Our previous studies showed that the estimation of peripheral mRNA PGC-1α expression was feasible and that its induction correlated with the extent of myocardial necrosis and left ventricular remodeling in patients with myocardial infarction. In this study, we sought to determine if the myocardial and peripheral expressions of PGC-1α are well correlated and to analyze the variability of PGC-1α expression depending on the prevalence of some metabolic disorders. [Methods]: This was a cohort of 35 consecutive stable heart failure patients with severe aortic stenosis who underwent an elective aortic valve replacement surgery. mRNA PGC-1α expression was simultaneously determined from myocardial biopsy specimens and blood samples obtained during surgery by quantitative PCR, and a correlation between samples was made using the Kappa index. Patients were divided into two groups according to the detection of baseline expression levels of PGC-1α in blood samples, and comparisons between both groups were made by chi-square test or unpaired Student’s t-test as appropriate. [Results]: Based on myocardial biopsies, we found that mRNA PGC-1α expression in blood samples showed a statistically significant correlation with myocardial expression (Kappa index 0.66, p<0.001). The presence of higher systemic PGC-1α expression was associated with a greater expression of some target genes such as silent information regulator 2 homolog-1 (x-fold expression in blood samples: 4.43±5.22 vs. 1.09±0.14, p=0.044) and better antioxidant status in these patients (concentration of Trolox: 0.40±0.05 vs. 0.34±0.65, p=0.006). [Conclusions]: Most patients with higher peripheral expression also had increased myocardial expression, so we conclude that the non-invasive estimation of mRNA PGC-1α expression from blood samples provides a good approach of the constitutive status of the mitochondrial protection system regulated by PGC-1α and that this could be used as prognostic indicator in cardiovascular disease.Grant from Sociedad Valenciana de Cardiología, 2013 to Óscar Fabregat-Andrés.Peer Reviewe