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The cancer genome is characterized by extensive variability, in the form of Single Nucleotide Polymorphisms (SNPs) or structural variations such as Copy Number Alterations (CNAs) across wider genomic areas. At the molecular level, most SNPs and/or CNAs reside in non-coding sequences, ultimately affecting the regulation of oncogenes and/or tumor-suppressors in a cancer-specific manner. Notably, inherited non-coding variants can predispose for cancer decades prior to disease onset. Furthermore, accumulation of additional non-coding driver mutations during progression of the disease, gives rise to genomic instability, acting as the driving force of neoplastic development and malignant evolution. Therefore, detection and characterization of such mutations can improve risk assessment for healthy carriers and expand the diagnostic and therapeutic toolbox for the patient. This review focuses on functional variants that reside in transcribed or not transcribed non-coding regions of the cancer genome and presents a collection of appropriate state-of-the-art methodologies to study them.

Recently, numerous studies including various tissues have been carried out on long non-coding RNAs (lncRNAs), but still, its variability has not yet been fully understood. In this study, we characterised the inter-individual variability of lncRNAs in pigs, in the context of number, length and expression. Transcriptomes collected from muscle tissue belonging to six Polish Landrace boars (PL1–PL6), including half-brothers (PL1–PL3), were investigated using bioinformatics (lncRNA identification and functional analysis) and statistical (lncRNA variability) methods. The number of lncRNA ranged from 1289 to 3500 per animal, and the total number of common lncRNAs among all boars was 232. The number, length and expression of lncRNAs significantly varied between individuals, and no consistent pattern has been found between pairs of half-brothers. In detail, PL5 exhibits lower expression than the others, while PL4 has significantly higher expression than PL2–PL3 and PL5–PL6. Noteworthy, comparing the inter-individual variability of lncRNA and mRNA expression, they exhibited concordant patterns. The enrichment analysis for common lncRNA target genes determined a variety of biological processes that play fundamental roles in cell biology, and they were mostly related to whole-body homeostasis maintenance, energy and protein synthesis as well as dynamics of multiple nucleoprotein complexes. The high variability of lncRNA landscape in the porcine genome has been revealed in this study. The inter-individual differences have been found in the context of three aspects: the number, length and expression of lncRNAs, which contribute to a better understanding of its complex nature.

Background:Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterized by heterogeneous articular and periarticular manifestations. The achievement of remission or low disease activity is the goal of therapy. However, some patients experience primary failure and lack or loss of response to cs-, b- and ts-DMARDs. The treatment response could be affected by multiple factors, including epigenetic factors. Recently, some studies have suggested the possible involvement of lncRNAs in modulating treatment response [1]. In this context, the identification of genetic and epigenetic factors associated to treatment response could help to define new biomarkers for a more effective and personalized therapy.Objectives:The main aim of this study was to prospectively investigate lncRNAs potentially related to treatment response in a cohort of PsA patients treated with TNFi and IL17i, to identify potential predictors of drug treatment effectiveness. In addition, we analysed retrospectively a cohort of PsA patients treated with TNFi to look for possible association between lncRNAs genetic variants and the response after 6 and 12 months of TNFi.Methods:For the expression study, a cohort of 48 PsA patients starting a TNFi (n=28) or IL17i (n=20) drugs was recruited, monitoring their treatment response for 12 months in order to identify subgroup of patients Reponder e Non-Responder. For the genotyping study, we retrospectively analysed 163 PsA patients treated with TNFi. For each patient was estimated the Disease Activity in Psoriatic Arthritis (DAPsA) score at 6 and 12 months after the beginning of therapy. The expression level of lncRNA was analysed in a panel of 84 lncRNAs, after the extraction of total RNA from PBMCs. Then we validated the differentially expressed lncRNAs, resulted from the array experiments, by qRT-PCR using specific primer assay. Web-based data analysis tool (NPInter v4.0 and DIANALncBase v3) were used to confirm miRNA target genes of the validated lncRNAs. For the genotyping study, we extracted genomic DNA from PBMCs and we performed allelic discrimination assay by TaqMan assays. We evaluated a possible association between the selected SNPs and the response to therapy at 6 and 12 months from the beginning of the TNFi treatment, using the clinical parameter of DAPsA value.Results:We observed a significant difference in the expression level between Responder and non-Responder patients, of 4 lncRNAs in the group of PsA patients treated with TNFi and of 3 lncRNAs in the group of patients treated with IL17i. Then, we confirmed a significant decrease of MEG3 expression in non-Responder patients compared to Responder patients, both considering the whole cohort (P= 0.01) and stratifying patients by drugs (P= 0.05 and P= 0.03, respectively for TNFi and IL17i) (Figure 1). In addition, we observed an association between the variant allele of rs7158663 and a lower expression of MEG3 compared to the wild-type allele, although without statistical significance. We also observed that the variant allele of rs941576 (MEG3) was associated with a better response at T6 and T12, with a linear decrease of mean DAPsA value among wildtype, heterozygous and homozygous variant patients. Interestingly, we noticed that the variant allele of rs941576 SNV resulted associated with a better response regarding joints involvement. Indeed, the number of TJ and SJ decreases more in patients carrying the variant allele, both at T6 and T12 (P= 0.0006 and P= 0.032, respectively) (Table 1).Conclusion:Our study suggests a possible role, both in terms of genetic variability and expression, of the lncRNA MEG3 in the treatment response to TNFi and IL17i in PsA patients.REFERENCES:[1] De Benedittis G, Latini A, Ciccacci C, et al. Impact of TRAF3IP2, IL10 and HCP5 Genetic Polymorphisms in the Response to TNF-i Treatment in Patients with Psoriatic Arthritis. J Pers Med. 2022;12(7):1094.Acknowledgements:NIL.Disclosure of Interests:None declared.

Epidemiological studies have showed that polycyclic aromatic hydrocarbons (PAHs) were associated with heart rate variability (HRV), but the role of long non-coding RNAs (lncRNAs) in the association is unknown. We aimed to identify PAHs-related lncRNAs and assess their associations with HRV among coke oven workers. Differential lncRNAs expression between 12 exposed workers and 12 controls was tested by Human 8X60k LncRNA Arrays in discovery stage, then selected NR_024564 was validated in 353 workers using droplet digital RT-PCR. Microarray results showed that 1234 lncRNAs were downregulated with 805 lncRNAs upregulated in exposed group (≥ 2-fold change). In validation stage, no significant association was observed between NR_024564 and PAH exposure or HRV in total subjects, while urinary 2-hydroxyfluorene (2-OHFlu) was inversely related to root mean square successive difference (RMSSD). However, in current smokers, NR_024564 was inversely related to urinary 2-OHFlu, 2-hydroxyphenanthrene, 1-hydroxypyrene (1-OHP), and total PAHs metabolites (ΣOH-PAHs), of which 1-OHP accounted for the strongest estimation for interaction with smoking status ( P interaction = 0.011). Also, the positive associations of NR_024564 with RMSSD and high frequency power showed an interaction with smoking status ( P interaction = 0.034 and 0.023, respectively). Also, urinary 2-OHFlu and ΣOH-PAHs were inversely associated with RMSSD in current smokers. In addition, elevated NR_024564 was dose-responsive related to increased RMSSD in above high-PAHs groups among smokers (all P trend < 0.05). Our results revealed that NR_024564 and its interactions with smoking status might act as novel mechanisms regulating the adverse effects of PAHs on HRV.

BackgroundBetween the 1990s and 2000s, relative inequalities in all-cause mortality increased, whereas absolute inequalities decreased in many European countries. Whether similar trends can be observed for inequalities in other health outcomes is unknown. This paper aims to provide a comprehensive overview of trends in socioeconomic inequalities in self-assessed health (SAH) in Europe between 1990 and 2010.MethodsData were obtained from nationally representative surveys from 17 European countries for the various years between 1990 and 2010. The age-standardised prevalence of less-than-good SAH was analysed by education and occupation among men and women aged 30–79 years. Socioeconomic inequalities were measured by means of absolute rate differences and relative rate ratios. Meta-analysis with random-effects models was used to examine the trends of inequalities.ResultsWe observed declining trends in the prevalence of less-than-good SAH in many countries, particularly in Southern and Eastern Europe and the Baltic states. In all countries, less-than-good SAH was more prevalent in lower educational and manual groups. For all countries together, absolute inequalities in SAH were mostly constant, whereas relative inequalities increased. Almost no country consistently experienced a significant decline in either absolute or relative inequalities.ConclusionsTrends in inequalities in SAH in Europe were generally less favourable than those found for inequalities in mortality, and there was generally no correspondence between the two when we compared the trends within countries. In order to develop policies or interventions that effectively reduce inequalities in SAH, a better understanding of the causes of these inequalities is needed.

Sjögren’s Syndrome (SS) is a chronic autoimmune inflammatory disease. It is considered a multifactorial pathology, in which underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to development. The epigenetic regulations represent a link between genetic predisposition and environmental factors. Recent studies suggested a regulatory role for non-coding RNAs in critical biological and disease processes. Among non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play a critical role in the post-transcriptional mRNA expression, forming a complex network of gene expression regulation. This review aims to give an overview of the latest studies that have investigated the role of miRNAs and lncRNAs in the SS. We included papers that investigated the expression of non-coding RNAs on different tissues, in particular on peripheral blood mononuclear cells and salivary glands. However, regarding the involvement of non-coding RNAs genetic variability in SS susceptibility very few data are available. Further research could help to elucidate underlying pathogenic processes of SS and provide new opportunities for the development of targeted therapies.

Colonies of the bumblebee Bombus terrestris are characterized by wide phenotypic variability among genetically similar full-sister workers, suggesting a major role for epigenetic processes. Here, we report a high level of ADAR-mediated RNA editing in the bumblebee, despite the lack of an ADAR1-homolog. We identify 1.15 million unique genomic sites, and 164 recoding sites residing in 100 protein coding genes, including ion channels, transporters, and receptors predicted to affect brain function and behavior. Some edited sites are similarly edited in other insects, cephalopods and even mammals. The global editing level of protein coding and non-coding transcripts weakly correlates with task performance (brood care vs. foraging), but not affected by dominance rank or juvenile hormone known to influence physiology and behavior. Taken together, our findings show that brain editing levels are high in naturally behaving bees, and may be regulated by relatively short-term effects associated with brood care or foraging activities. Bumblebee workers are genetically highly similar but they show different behaviors such as brood care and foraging. Here the authors report a high level of ADAR-mediated RNA editing in the bumblebee Bombus terrestris and its weak correlation to task performance.

Small extracellular vesicles (sEV) are nano-sized (40-150 nm), membrane-encapsulated vesicles that are released by essentially all cells into the extracellular space and function as intercellular signaling vectors through the horizontal transfer of biologic molecules, including microRNA (miRNA) and other small non-coding RNA (ncRNA), that can alter the phenotype of recipient cells. sEV are present in essentially all extracellular biofluids, including serum, urine and saliva, and offer a new avenue for discovery and development of novel biomarkers of various disease states and exposures. The objective of this study was to systematically interrogate similarities and differences between sEV ncRNA derived from saliva, serum and urine, as well as cell-free small ncRNA (cf-ncRNA) from serum. Saliva, urine and serum were concomitantly collected from 4 healthy donors to mitigate potential bias that can stem from interpersonal and temporal variability. sEV were isolated from each respective biofluid, along with cf-RNA from serum. sEV were isolated from the respective biofluids via differential ultracentrifugation with a 30% sucrose cushion to minimize protein contamination. Small RNA-sequencing was performed on each sample, and cluster analysis was performed based on ncRNA profiles. While some similarities existed in terms of sEV ncRNA cargo across biofluids, there are also notable differences in ncRNA class and ncRNA secretion, with sEV in each biofluid bearing a unique ncRNA profile, including major differences in composition by ncRNA class. We conclude that sEV ncRNA cargo varies according to biofluid, so thus should be carefully selected and interpreted when designing or contrasting translational or epidemiological studies.

Expression of eukaryotic genes is largely regulated by non-coding RNAs (ncRNA). Sequence variations in the regulatory RNAs may have critical biological consequences including transcriptional and post-transcriptional gene regulation. ncRNA-derived markers thus can be proved useful in molecular breeding, QTL mapping and association studies for trait dissection. In present study, we identified a total of 661 SSRs dwelling in pre-miRNA (15), small nuclear RNA (25) and lncRNA (621). Of these, 46 were validated and 100% amplification success was observed in selected wheat genotypes. A set of 36 ncRNA-SSRs markers was utilized for genetic variability assessment in forty-eight Indian wheat genotypes (which includes bread wheat, durum wheat and relatives). Number of alleles ranged from 1 to 4 with an average of two alleles per SSR locus. Mean PIC, observed heterozygosity and Shannon information index were found to be 0.258, 0.37 and 0.476 which suggests ncRNA-SSRs show higher polymorphism compared to genic SSRs but lower polymorphism compared to genomic SSRs. Thirty-six ncRNA-SSRs showed transferability ranging from 42.1% to 100%. Average genetic dissimilarity among wheat genotypes was found to be 0.29 based on Jaccard’s dissimilarity. This is the first report of ncRNA-SSRs in wheat which will be useful for molecular breeding and genetic improvement of wheat.

Autism spectrum disorder is a complex neurodevelopmental disorder that appears during the first three years of infancy and lasts throughout a person's life. Recently a large category of genomic structural variants, denoted as copy number variants (CNVs), were established to be a major contributor of the pathophysiology of autism. To date almost all studies have focussed only on the genes present in the CNV loci, but the impact of non-coding regulatory microRNAs (miRNAs) present in these regions remain largely unexplored. Hence we attempted to elucidate the biological and functional significance of miRNAs present in autism-associated CNV loci and their target genes by using a series of computational tools. We demonstrate that nearly 11% of the CNV loci harbor miRNAs and a few of these miRNAs were previously reported to be associated with autism. A systematic analysis of the CNV-miRNAs based on their interactions with the target genes enabled the identification of top 10 miRNAs namely hsa-miR-590-3p, hsa-miR-944, hsa-miR-570, hsa-miR-34a, hsa-miR-124, hsa-miR-548f, hsa-miR-429, hsa-miR-200b, hsa-miR-195 and hsa-miR-497 as hub molecules. Further, the CNV-miRNAs formed a regulatory loop with transcription factors and their downstream target genes, and annotation of these target genes indicated their functional involvement in neurodevelopment and synapse. Moreover, miRNAs present in deleted and duplicated CNV loci may explain the difference in dosage of the crucial genes controlled by them. These CNV-miRNAs can also impair the global processing and biogenesis of all miRNAs by targeting key molecules in the miRNA pathway. To our knowledge, this is the first report to highlight the significance of CNV-microRNAs and their target genes to contribute towards the genetic heterogeneity and phenotypic variability of autism.