GWAS links variants in neuronal development and actin remodeling related loci with pseudoexfoliation syndrome without glaucoma

Pseudoexfoliation syndrome (PEXS) is an age-related elastosis, strongly associated with the development of secondary glaucoma. It is clearly suggested that PEXS has a genetic component, but this has not been extensively studied. Here, a genome-wide association study (GWAS) using a DNA-pooling approach was conducted to explore the potential association of genetic variants with PEXS in a Polish population, including 103 PEXS patients without glaucoma and 106 perfectly (age- and gender-) matched controls. Individual sample TaqMan genotyping was used to validate GWAS-selected single-nucleotide polymorphism (SNP) associations. Multivariate binary logistic regression analysis was applied to develop a prediction model for PEXS. In total, 15 SNPs representing independent PEXS susceptibility loci were selected for further validation in individual samples. For 14 of these variants, significant differences in the allele and genotype frequencies between cases and controls were identified, of which 12 remained significant after Benjamini-Hochberg adjustment. The minor allele of five SNPs was associated with an increased risk of PEXS development, while for nine SNPs, it showed a protective effect. Beyond the known LOXL1 variant rs2165241, nine other SNPs were located within gene regions, including in OR11L1, CD80, TNIK, CADM2, SORBS2, RNF180, FGF14, FMN1, and RBFOX1 genes. None of these associations with PEXS has previously been reported. Selected SNPs were found to explain nearly 69% of the total risk of PEXS development. The overall risk prediction accuracy for PEXS, expressed by the area under the ROC curve (AUC) value, increased by 0.218, from 0.672 for LOXL1 rs2165241 alone to 0.89 when seven additional SNPs were included in the proposed 8-SNP prediction model. In conclusion, several new susceptibility loci for PEXS without glaucoma suggested that neuronal development and actin remodeling are potentially involved in either PEXS onset or inhibition or delay of its conversion to glaucoma

Diarrheal-associated gut dysbiosis in cancer and inflammatory bowel disease patients is exacerbated by Clostridioides difficile infection

IntroductionLow diversity gut dysbiosis can take different forms depending on the disease context. In this study, we used shotgun metagenomic sequencing and gas chromatography–mass spectrometry (GC-MS) to compared the metagenomic and metabolomic profiles of Clostridioides (Clostridium) difficile diarrheal cancer and inflammatory bowel disease (IBD) patients and defined the additive effect of C. difficile infection (CDI) on intestinal dysbiosis.ResultsThe study cohort consisted of 138 case-mix cancer patients, 43 IBD patients, and 45 healthy control individuals. Thirty-three patients were also infected with C. difficile. In the control group, three well-known enterotypes were identified, while the other groups presented with an additional Escherichia-driven enterotype. Bacterial diversity was significantly lower in all groups than in healthy controls, while the highest level of bacterial species richness was observed in cancer patients. Fifty-six bacterial species had abundance levels that differentiated diarrheal patient groups from the control group. Of these species, 52 and 4 (Bacteroides fragilis, Escherichia coli, Klebsiella pneumoniae, and Ruminococcus gnavus) were under-represented and over-represented, respectively, in all diarrheal patient groups. The relative abundances of propionate and butyrate were significantly lower in fecal samples from IBD and CDI patients than in control samples. Isobutyrate, propanate, and butyrate concentrations were lower in cancer, IBD, and CDI samples, respectively. Glycine and valine amino acids were over- represented in diarrheal patients.ConclusionOur data indicate that different external and internal factors drive comparable profiles of low diversity dysbiosis. While diarrheal-related low diversity dysbiosis may be a consequence of systemic cancer therapy, a similar phenotype is observed in cases of moderate to severe IBD, and in both cases, dysbiosis is exacerbated by incidence of CDI

Gene Expression-Based Functional Differences between the Bladder Body and Trigonal Urothelium in Adolescent Female Patients with Micturition Dysfunction

The aim of this study is to determine the molecular differences between the urothelial transcriptomes of the bladder body and trigone. The transcriptomes of the bladder body and trigonal epithelia were analyzed by massive sequencing of total epithelial RNA. The profiles of urothelial and urinal microbiomes were assessed by amplicon sequencing of bacterial 16S rRNA genes in 17 adolescent females with pain and micturition dysfunction and control female subjects. The RNA sequencing identified 10,261 differentially expressed genes (DEGs) in the urothelia of the bladder body and trigone, with the top 1000 DEGs at these locations annotated to 36 and 77 of the Reactome-related pathways in the bladder body and trigone, respectively. These pathways represented 11 categories enriched in the bladder body urothelium, including extracellular matrix organization, the neuronal system, and 15 categories enriched in the trigonal epithelium, including RHO GTPase effectors, cornified envelope formation, and neutrophil degranulation. Five bacterial taxa in urine differed significantly in patients and healthy adolescent controls. The evaluation of their transcriptomes indicated that the bladder body and trigonal urothelia were functionally different tissues. The molecular differences between the body and trigonal urothelia responsible for clinical symptoms in adolescents with bladder pain syndrome/interstitial cystitis remain unclear

GWAS Links New Variant in Long Non-Coding RNA LINC02006 with Colorectal Cancer Susceptibility

Despite great efforts, most of the genetic factors contributing to the risk of colorectal cancer (CRC) remain undetermined. Including small but homogenous populations in genome-wide association studies (GWAS) can help us discover new common risk variants specific to the studied population. In this study, including 465 CRC patients and 1548 controls, a pooled DNA samples-based GWAS was conducted in search of genetic variants associated with CRC in a Polish population. Combined with a new method of selecting single-nucleotide polymorphisms (SNPs) for verification in individual DNA samples, this approach allowed the detection of five new susceptibility loci not previously reported for CRC. The discovered loci were found to explain 10% of the overall risk of developing CRC. The strongest association was observed for rs10935945 in long non-coding RNA LINC02006 (3q25.2). Three other SNPs were also located within genes (rs17575184 in NEGR1, rs11060839 in PIWIL1, rs12935896 in BCAS3), while one was intergenic (rs9927668 at 16p13.2). An expression quantitative trait locus (eQTL) bioinformatic analysis suggested that these polymorphisms may affect transcription factor binding sites. In conclusion, four of the identified variants were located within genes likely involved in tumor invasiveness and metastasis. Therefore, they could possibly be markers of poor prognosis in CRC patients

Peripheral Blood Cells from Patients with Hodgkin’s and Diffuse Large B Cell Lymphomas May Be a Better Source of Candidate Diagnostic miRNAs Than Circulating miRNAs

Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL) represent 15% and 20%, respectively, of all lymphoma types. The aim of this study was to identify and compare circulating serum miRNA (c-miRNA) and peripheral whole blood miRNA (wb-miRNA) profiles in patients with these lymphomas. Serum samples (20 HL, 21 DLBCL, and 30 healthy controls) and whole blood samples (21 HL, 17 DLBCL patients, and 30 healthy controls) were collected at the time of diagnosis. Serum and whole blood were also collected from 18 HL/17 DLBCL and eight HL/nine DLBCL patients, respectively, after treatment. Pairwise comparisons identified 125 c-miRNAs (adjusted P value < 0.05) showing significant dysregulation between 30 healthy controls and patients; of these, 47 and 55 differentiated controls from pretherapeutic HL and DLBCL patients, respectively. In addition, 60 and 16 c-miRNAs differentiated controls from posttherapeutic HL and DLBCL, respectively. Pairwise comparisons identified 292 wb-miRNAs (adjusted P value < 0.05) showing significant dysregulation between 30 controls and patients; of these, 103 and 169 differentiated controls from pretherapeutic HL and DLBCL, respectively, and 142 and 151 wb-miRNAs differentiated controls from posttherapeutic HL and DLBCL, respectively. Thus, lymphoma-associated miRNAs may be a better source of noninvasive candidate biomarkers than miRNAs in serum. It is unclear whether miRNA alterations in lymphoma cells are similar to those observed in white blood cells