Koldo Garcia-Etxebarria

Aims/hypothesis: Genome-wide association studies increasingly highlight the role of non-coding regions in complex diseases such as type 1 diabetes, pointing, in particular, to long non-coding RNAs (lncRNAs) as potentially active molecular players. Emerging evidence suggests that lncRNAs may encode (small) peptides with the potential to modulate cellular processes, including immune responses. In this study, we have investigated whether these (micro)peptides translated from lncRNAs can act as neoantigens capable of activating autoreactive CD4 ^⁺ T cells in individuals with type 1 diabetes. Methods: We have integrated transcriptomic, proteomic and in silico data to identify a subset of lncRNAs with genuine peptide-coding potential in basal or inflamed-condition beta cells. We further assessed the suitability of those candidates to encode (micro)peptides by sequence analysis and in vitro experimentation techniques. Finally, we have predicted HLA-II epitopes within the micropeptide candidates and evaluated their immunogenicity by analyzing T cell activation responses in peripheral blood mononuclear cells from HLA matching individuals with type 1 diabetes. Results: By merging ribosome-bound RNA sequencing with nascent peptide mass spectrometry, we identified a total of 30 lncRNAs with potential coding capacity. We verified the peptide-coding ORF translation for three lncRNA candidates: UXT-AS1 , RAPGEF4-AS1 and ENSG00000227066 . After predicting potential type 1 diabetes risk-associated HLA-DRB1*03:01 and HLA-DRB1*04:01 -binding epitopes within translated lncRNA (micro)peptides, we identified several peptides that elicited CD4 ⁺ T cell activation. Furthermore, several epitopes elicited T cell activation in multiple donors with type 1 diabetes. T cell lines were isolated and studied to confirm responses restricted by type 1 diabetes risk HLA alleles. Conclusions: These results reveal a novel class of immunogenic (micro)peptides derived from lncRNAs, supporting their potential role in the autoimmune response that underlies type 1 diabetes. Our findings open new perspectives on the contribution of non-coding genomic elements to autoimmunity and highlight the need to further investigate lncRNA-encoded (micro)peptides as possible targets for future immunotherapies. RESEARCH IN CONTEXT: What is already known about this subject?: Short proteins can sometimes be translated from lncRNAs. Type 1 diabetes neoepitopes arising from non-native forms of proteins and their post translational modifications have been described. What is the key question?: Can lncRNA-encoded peptides be recognized by the human immune system and contribute to type 1 diabetes development? What are the new findings?: We have identified three candidate lncRNAs with peptide coding capacity. Epitopes derived from these peptides drive T cell activation in PBMCs of individuals with type 1 diabetes. Presentation of some of these peptides are restricted to type 1 diabetes risk-associated HLA-DRB1*03:01 and *04:01 molecules. How might this impact on clinical practice in the foreseeable future?: Discovery of lncRNA-derived peptide reactive T cells might serve as a diagnostic or stratification indicator in the early stages of disease development, aiding the development of more personalized treatments and unlocking a new array of therapeutic targets.

It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue–specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue–specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.

Background: Infliximab seems to be the most efficacious of the three available anti-TNF agents for ulcerative colitis (UC) but little is known when it is used as the second anti-TNF. Objectives: To compare the clinical and treatment outcomes of a second subcutaneous or intravenous anti-TNF in UC patients. Design: Retrospective observational study. Methods: Patients from the ENEIDA registry treated consecutively with infliximab and a subcutaneous anti-TNF (or vice versa), naïve to other biological agents, were identified and grouped according to the administration route of the first anti-TNF into IVi (intravenous initially) or SCi (subcutaneous initially). Results: Overall, 473 UC patients were included (330 IVi and 143 SCi). Clinical response at week 14 was 42.7% and 48.3% in the IVi and SCi groups (non-statistically significant), respectively. Clinical remission rates at week 52 were 32.8% and 31.4% in the IVi and SCi groups (nonsignificant differences), respectively. A propensity-matched score analysis showed a higher clinical response rate at week 14 in the SCi group and higher treatment persistence in the IVi group. Regarding long-term outcomes, dose escalation and discontinuation due to the primary failure of the first anti-TNF and more severe disease activity at the beginning of the second anti-TNF were inversely associated with clinical remission. Conclusion: The use of a second anti-TNF for UC seems to be reasonable in terms of efficacy, although it is particularly reduced in the case of the primary failure of the first anti-TNF. Whether the second anti-TNF is infliximab or subcutaneous does not seem to affect efficacy.

Background: Irritable bowel syndrome is a heterogeneous syndrome and it is difficult to find an effective treatment. Previously, a starch- and sucrose-reduced diet (SSRD) demonstrated promising short-term outcomes. It was proposed that genetic variants in the sucrose-isomaltase gene might influence this success. Our aim in this work was to extend the follow-up study to 1 year and to analyse the effect of the genetic variants of genes involved in starch and sucrose metabolism.Methods: IBS-SSS questionnaire, IBS-QoL questionnaire and questionnaires about adherence, difficulty and food assessment were sent to 34 patients after 6 months and 1 year after the end of the dietary intervention. In addition, 11 genes involved in sucrose and starch metabolism were sequenced.Results: Twenty-three participants responded to the 6 months follow-up and 16 to the 1 year follow-up. IBS-SSS total value increased 59.71% in the 6 months follow-up compared with the end of the intervention (p = 0.0018), and 55.39% in the 1 year follow-up (p = 0.0166); while IBS-QoL score decreased 24.09% (p = 0.0002) and 18.07% (p = 0.0022), respectively. The adherence decreased by 29.11% (p = 4.8 × 10⁻⁵) and 27.21% (p = 0.0054), respectively. In addition, carriers of pathogenic variants on the SI gene showed a slightly better performance than non-carriers. Finally, the participants showed less satisfaction over time with 18 allowed foods in the diet.Conclusion: Over time the SSRD is difficult to follow and the genotype might affect the performance of the diet. Since this diet could be a promising therapeutic option, a larger cohort needs to be analysed to validate the results and to compare it with other diets.

Background: Some genetic polymorphisms (SNPs) have been proposed as predictors for different colorectal cancer (CRC) outcomes. This work aims to assess their performance in our cohort and find new SNPs associated with them. Methods: A total of 833 CRC cases were analyzed for seven outcomes, including the use of chemotherapy, and stratified by tumor location and stage. The performance of 63 SNPs was assessed using a generalized linear model and area under the receiver operating characteristic curve, and local SNPs were detected using logistic regressions. Results: In total 26 of the SNPs showed an AUC > 0.6 and a significant association (p < 0.05) with one or more outcomes. However, clinical variables outperformed some of them, and the combination of genetic and clinical data showed better performance. In addition, 49 suggestive (p < 5 × 10⁻⁶) SNPs associated with one or more CRC outcomes were detected, and those SNPs were located at or near genes involved in biological mechanisms associated with CRC. Conclusions: Some SNPs with clinical data can be used in our population as predictors of some CRC outcomes, and the local SNPs detected in our study could be feasible markers that need further validation as predictors.

Colorectal cancer is a major health concern since it is a highly diagnosed cancer and the second cause of death among cancers. Thus, the most suitable biomarkers for its diagnosis, prognosis, and treatment have been studied to improve and personalize the prevention and clinical management of colorectal cancer. The emergence of omic techniques has provided a great opportunity to better study CRC and make personalized medicine feasible. In this review, we will try to summarize how the analysis of the omic layers can be useful for personalized medicine and the existing difficulties. We will discuss how single and multiple omic layer analyses have been used to improve the prediction of the risk of CRC and its outcomes and how to overcome the challenges in the use of omic layers in personalized medicine.

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To cite Zamfir-Taranu A, Löscher B-S, Husein DM, et al. Gut Epub ahead of print: [please include Day Month Year].

Background: Irritable bowel syndrome (IBS) is a common gastrointestinal condition which entails a high burden in the quality of life (QoL) of patients. Nutritional interventions have been proposed to alleviate symptoms, since still no effective treatments exist for IBS. Objectives: Our aim is to analyse the feasibility of the use of starch- and sucrose-reduced diet (SSRD). Design: In this study, we used a SSRD accompanied by nutritional and culinary recommendations to measure the effects in IBS patients with diarrhoea. Methods: In all, 34 participants completed a 4-week nutritional intervention based on SSRD. Symptoms, QoL and dietary habits were assessed by several questionnaires that were completed at the beginning, daily, after 2 weeks, at the end, and after 2 months. Results: 85.29% of the participants reached the primary endpoint [reduction of 50 points or more in IBS-symptom severity scale (SSS)], and 58.82% the secondary endpoint (reduction of 50% or more in IBS-SSS). The relief of symptoms and improvement of the QoL were significant after 2 weeks of intervention, at the end and after 2 months. Dietary habits were consistent with the diet and high adherence was achieved. Conclusions: SSRD and individualized nutritional and culinary guidance improved symptoms and QoL of IBS patients with diarrhoea, with a high adherence.

Summary: Type 1 diabetes-associated single nucleotide polymorphisms are mainly located in non-coding regions of the human genome. Single nucleotide polymorphisms located in long non-coding RNAs may result in the disruption of their secondary structure, affecting their function. Here, we functionally characterized the virus-induced type 1 diabetes-associated lncRNA ARGI (Antiviral Response Gene Inducer). ARGI upregulation in pancreatic β cells leads to the transcriptional activation of antiviral and pro-inflammatory genes. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic β cells and binds to CTCF to interact with the regulatory regions of IFNβ and interferon-stimulated genes, promoting their transcriptional activation in an allele-specific manner. The presence of the risk allele for type 1 diabetes in ARGI induces an hyperactivation of type I IFN response in β cells, an expression signature that is present in the pancreas of diabetic patients. These data shed light on the molecular mechanisms by which type 1 diabetes-related single nucleotide polymorphisms in long non-coding RNAs influence pathogenesis at the pancreatic β cell level.