Inflammatory bowel disease and allergic diseases: A Mendelian randomization study.

BACKGROUND: Inflammatory bowel disease (IBD) and allergic diseases possess similar genetic backgrounds and pathogenesis. Observational studies have shown a correlation, but the exact direction of cause and effect remains unclear. The aim of this Mendelian randomization (MR) study is to assess bidirectional causality between inflammatory bowel disease and allergic diseases. METHOD: We comprehensively analyzed the causal relationship between inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC) and allergic disease (asthma, Hay fever, and eczema) as a whole, allergic conjunctivitis (AC), atopic dermatitis (AD), allergic asthma (AAS), and allergic rhinitis (AR) by performing a bidirectional Mendelian randomization study using summary-level data from genome-wide association studies. The analysis results mainly came from the random-effects model of inverse variance weighted (IVW-RE). In addition, multivariate Mendelian randomization (MVMR) analysis was conducted to adjust the effect of body mass index (BMI) on the instrumental variables. RESULTS: The IVW-RE method revealed that IBD genetically increased the risk of allergic disease as a whole (OR = 1.03, 95% CI = 1.01-1.04, fdr.p = .015), AC (OR = 1.04, 95% CI = 1.01-1.06, fdr.p = .011), and AD (OR = 1.06, 95% CI = 1.02-1.09, fdr.p = .004). Subgroup analysis further confirmed that CD increased the risk of allergic disease as a whole (OR = 1.02, 95% CI = 1.00-1.03, fdr.p = .031), AC (OR = 1.03, 95% CI = 1.01-1.05, fdr.p = .012), AD (OR = 1.06, 95% CI = 1.02-1.09, fdr.p = 2E-05), AAS (OR = 1.05, 95% CI = 1.02-1.08, fdr.p = .002) and AR (OR = 1.03, 95% CI = 1.00-1.07, fdr.p = .025), UC increased the risk of AAS (OR = 1.02, 95% CI = 0.98-1.07, fdr.p = .038). MVMR results showed that after taking BMI as secondary exposure, the causal effects of IBD on AC, IBD on AD, CD on allergic disease as a whole, CD on AC, CD on AD, CD on AAS, and CD on AR were still statistically significant. No significant association was observed in the reverse MR analysis. CONCLUSION: This Mendelian randomized study demonstrated that IBD is a risk factor for allergic diseases, which is largely attributed to its subtype CD increasing the risk of AC, AD, ASS, and AR. Further investigations are needed to explore the causal relationship between allergic diseases and IBD.

Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization.

As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.

[Phenotyping and genotyping in patients with inflammatory bowel disease in a reference center in Colombia]. / Fenotipificación y genotipificación en pacientes con enfermedad inflamatoria intestinal en un centro de referencia de Colombia.

INTRODUCTION: Attempts have been made to identify the genetic factors related to susceptibility to inflammatory bowel disease (IBD), and the current conclusions are in favor of a complex pathology model, without a clear hereditary pattern. OBJECTIVE: To perform phenotypic and genotypic characterization of patients with IBD in Colombian population and to describe its possible association with predisposition. MATERIALS AND METHODS: case series, 16 patients with IBD according to clinical and pathological criteria, onset of gastrointestinal symptoms after 18 years of age. All had pre-test genetic counseling and family trees of at least three generations were made. Also, genotyping, using a multi-gene panel that included genes related to IBD and some autoimmune disorders. Finally, a genomic analysis of variants was performed. RESULTS: 9 women and 7 men, with mean age of diagnosis of IBD of 35 years, and gastrointestinal symptoms appearance of 32 years. 11/16 (68.75%) required biological therapy. 10/16 (62.5%) were refractory to standard therapy. 3/16 (18.75%) had positive family history of IBD. 100% cases presented at least one single nucleotide polymorphism related to IBD risk in more than one gene. The genes most related to ulcerative colitis (UC) were CD48, CD6, and TYK2 for UC, and CD6 and ITGAM for Crohn's disease. The most frequent gene was CD6. It was found presence of up to 5 genes in 3/16 (18.75%), 4 in 3/16 (18.75%), and three in 5/16 (31.25%). CONCLUSION: In IBD there is the presence of genetic variants with associated predisposition, but without confirmed pathogenicity, and whose sum seems to contribute to its pathophysiology.

Exploring inflammatory bowel disease therapy targets through druggability genes: a Mendelian randomization study.

Background: Inflammatory bowel disease is an incurable group of recurrent inflammatory diseases of the intestine. Mendelian randomization has been utilized in the development of drugs for disease treatment, including the therapeutic targets for IBD that are identified through drug-targeted MR. Methods: Two-sample MR was employed to explore the cause-and-effect relationship between multiple genes and IBD and its subtypes ulcerative colitis and Crohn's disease, and replication MR was utilized to validate this causality. Summary data-based Mendelian randomization analysis was performed to enhance the robustness of the outcomes, while Bayesian co-localization provided strong evidential support. Finally, the value of potential therapeutic target applications was determined by using the estimation of druggability. Result: With our investigation, we identified target genes associated with the risk of IBD and its subtypes UC and CD. These include the genes GPBAR1, IL1RL1, PRKCB, and PNMT, which are associated with IBD risk, IL1RL1, with a protective effect against CD risk, and GPX1, GPBAR1, and PNMT, which are involved in UC risk. Conclusion: In a word, this study identified several potential therapeutic targets associated with the risk of IBD and its subtypes, offering new insights into the development of therapeutic agents for IBD.

MicroRNAs in inflammatory bowel disease: What do we know and what can we expect?

MicroRNAs (miRNAs), small non-coding RNAs composed of 18-24 nucleotides, are potent regulators of gene expression, contributing to the regulation of more than 30% of protein-coding genes. Considering that miRNAs are regulators of inflammatory pathways and the differentiation of intestinal epithelial cells, there is an interest in exploring their importance in inflammatory bowel disease (IBD). IBD is a chronic and multifactorial disease of the gastrointestinal tract; the main forms are Crohn's disease and ulcerative colitis. Several studies have investigated the dysregulated expression of miRNAs in IBD, demonstrating their important roles as regulators and potential biomarkers of this disease. This editorial presents what is known and what is expected regarding miRNAs in IBD. Although the important regulatory roles of miRNAs in IBD are clearly established, biomarkers for IBD that can be applied in clinical practice are lacking, emphasizing the importance of further studies. Discoveries regarding the influence of miRNAs on the inflammatory process and the exploration of their role in gene regulation are expected to provide a basis for the use of miRNAs not only as potent biomarkers in IBD but also as therapeutic targets for the control of inflammatory processes in personalized medicine.

Risk relationship between inflammatory bowel disease and urolithiasis: A two-sample Mendelian randomization study.

BACKGROUND: The causal genetic relationship between common parenteral manifestations of inflammatory bowel disease (IBD) and urolithiasis remains unclear because their timing is difficult to determine. This study investigated the causal genetic association between IBD and urolithiasis using Mendelian randomization (MR) based on data from large population-based genome-wide association studies (GWASs). METHODS: A two-sample MR analysis was performed to assess the potential relationship between IBD and urolithiasis. Specific single nucleotide polymorphism data were obtained from GWASs, including IBD (n = 59957) and its main subtypes, Crohn's disease (CD) (n = 40266) and ulcerative colitis (UC) (n = 45975). Summarized data on urolithiasis (n = 218792) were obtained from different GWAS studies. A random-effects model was analyzed using inverse-variance weighting, MR-Egger, and weighted medians. RESULTS: Genetic predisposition to IBD and the risk of urolithiasis were significantly associated [odds ratio (OR), 1.04 (95% confidence interval [CI], 1.00-.08), P = 0.01]. Consistently, the weighted median method yielded similar results [OR, 1.06 (95% CI, 1.00-1.12), P = 0.02]. The MR-Egger method also demonstrated comparable findings [OR, 1.02 (95% CI, 0.96-1.08), P = 0.45]. Both funnel plots and MR-Egger intercepts indicated no directional pleiotropic effects between IBD and urolithiasis. CD was strongly associated with it in its subtype analysis [OR, 1.04 (95% CI, 1.01-1.07), P = 0.01], and UC was also causally associated with urolithiasis, although the association was not significant [OR, 0.99 (95% CI, 0.95-1.03), P = 0.71]. CONCLUSION: A unidirectional positive causal correlation was identified between IBD and urolithiasis, with varying degrees of association observed among the different subtypes of IBD. Recognizing the increased incidence of urolithiasis in patients with IBD is crucial in clinical practice. Early detection and surveillance of IBD, improved patient awareness, adoption of preventive strategies, and promotion of collaborative efforts among healthcare providers regarding treatment methodologies are vital for improving patient outcomes.

Genetic Variants Associated with Biological Treatment Response in Inflammatory Bowel Disease: A Systematic Review.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD includes Crohn's disease and ulcerative colitis as the main entities. IBD is a debilitating condition that can lead to life-threatening complications, involving possible malignancy and surgery. The available therapies aim to achieve long-term remission and prevent disease progression. Biologics are bioengineered therapeutic drugs that mainly target proteins. Although they have revolutionized the treatment of IBD, their potential therapeutic benefits are limited due to large interindividual variability in clinical response in terms of efficacy and toxicity, resulting in high rates of long-term therapeutic failure. It is therefore important to find biomarkers that provide tailor-made treatment strategies that allow for patient stratification to maximize treatment benefits and minimize adverse events. Pharmacogenetics has the potential to optimize biologics selection in IBD by identifying genetic variants, specifically single nucleotide polymorphisms (SNPs), which are the underlying factors associated with an individual's drug response. This review analyzes the current knowledge of genetic variants associated with biological agent response (infliximab, adalimumab, ustekinumab, and vedolizumab) in IBD. An online literature search in various databases was conducted. After applying the inclusion and exclusion criteria, 28 reports from the 1685 results were employed for the review. The most significant SNPs potentially useful as predictive biomarkers of treatment response are linked to immunity, cytokine production, and immunorecognition.

Associations between sex hormones, receptors, binding proteins and inflammatory bowel disease: a Mendelian randomization study.

Background: Gender differences existed in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Observational studies have revealed associations between sex hormones and IBD, such as estrogen and testosterone. However, the exact relationship between these sex hormones and IBD is unclear. Method: Based on the genome-wide association studies data of eight sex hormones, two sex hormone receptors, sex hormone-binding globulin (SHBG), total IBD and its two subtypes, we performed a two-sample Mendelian randomization (MR) study to analyze their mutual relationship. For estradiol (E2), progesterone (PROG), bioavailable testosterone (BAT), total testosterone (TT) and SHBG, sex-stratified MR analyses were also performed. Inverse variance weighted method, MR-Egger regression and Weighted median method were used for causal analyses. Sensitivity analyses were conducted to test the stability of causal relationships. Besides, a reverse MR analysis was performed to estimate the reverse causation. Results: E2 (P=0.028) and TT (P=0.034) had protective effects on CD. Sex-stratified analyses revealed protective roles of E2 in males on total IBD (P=0.038) and CD (P=0.020). TT in females had protective effects on total IBD (P=0.025) and CD (P=0.029), and BAT in females decreased the risk of developing CD (P=0.047) and UC (P=0.036). Moreover, SHBG in males was also associated with a decreased risk of CD (P=0.021). The reversed MR analysis showed that CD was negatively correlated with estrogen receptor (P=0.046). UC was negatively correlated with PROG in females (P=0.015) and positively correlated with SHBG levels in males (P=0.046). Conclusion: Findings of this study revealed the mutual causal associations between sex hormones and the risk of developing IBD.

[Mechanism of traditional Chinese medicine in treating ulcerative colitis-related colorectal cancer by regulating NF-κB-related signaling pathways: a review].

Ulcerative colitis is a chronic, recurrent, and nonspecific intestinal inflammatory disease, which is difficult to cure and has the risk of deterioration into related tumors. Long-term chronic inflammatory stimulation can increase the risk of cancerization. With the signaling pathway as a key link in the regulation of tumor microenvironments, nuclear factor-kappa B(NF-κB) is an important regulator of intestinal inflammation. It can also be co-regulated as downstream factors of other signaling pathways, such as TLR4, MAPK, STAT, PI3K, and so on. At present, a large number of animal experiments have proved that traditional Chinese medicine(TCM) can reduce inflammation by interfering with NF-κB-related signaling pathways, improve intestinal inflammation, and inhibit the progression of inflammation to tumors. This article reviewed the relationship between NF-κB-related signaling pathways and the intervention mechanism of TCM, so as to provide a reference for the clinical treatment of ulcerative colitis and the optimization of related cancer prevention strategies.

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis.

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10-03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10-04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Exploring potential biomarkers and therapeutic targets in inflammatory bowel disease: insights from a mega-analysis approach.

Background: Understanding the molecular pathogenesis of inflammatory bowel disease (IBD) has led to the discovery of new therapeutic targets that are more specific and effective. Our aim was to explore the molecular pathways and genes involved in IBD pathogenesis and to identify new therapeutic targets and novel biomarkers that can aid in the diagnosis of the disease. Methods: To obtain the largest possible number of samples and analyze them comprehensively, we used a mega-analysis approach. This involved reprocessing raw data from multiple studies and analyzing them using bioinformatic and machine learning techniques. Results: We analyzed a total of 697 intestinal biopsies of Ulcerative Colitis (n = 386), Crohn's disease (n = 183) and non-IBD controls (n = 128). A machine learning analysis detected 34 genes whose collective expression effectively distinguishes inflamed biopsies of IBD patients from non-IBD control samples. Most of these genes were upregulated in IBD. Notably, among these genes, three novel lncRNAs have emerged as potential contributors to IBD development: ENSG00000285744, ENSG00000287626, and MIR4435-2HG. Furthermore, by examining the expression of 29 genes, among the 34, in blood samples from IBD patients, we detected a significant upregulation of 12 genes (p-value < 0.01), underscoring their potential utility as non-invasive diagnostic biomarkers. Finally, by utilizing the CMap library, we discovered potential compounds that should be explored in future studies for their therapeutic efficacy in IBD treatment. Conclusion: Our findings contribute to the understanding of IBD pathogenesis, suggest novel biomarkers for IBD diagnosis and offer new prospects for therapeutic intervention.

Diet-derived circulating antioxidants and risk of inflammatory bowel disease: a Mendelian randomization study and meta-analysis.

Background: Previous studies have shown conflicting results regarding the impact of circulating antioxidants on the risk of inflammatory bowel disease (IBD). In this study, our intent was to investigate the causal relationship between circulating antioxidants and IBD using Mendelian randomization (MR). Methods: Instrumental variables for absolute circulating antioxidants (ascorbate, retinol, lycopene, and ß-carotene) and circulating antioxidant metabolites (α-tocopherol, γ-tocopherol, ascorbate, and retinol) were screened from published studies. We obtained outcome data from two genome-wide association study (GWAS) databases, including the international inflammatory bowel disease genetics consortium (IIBDGC, 14,927 controls and 5,956 cases for Crohn's disease (CD), 20,464 controls and 6,968 cases for ulcerative colitis (UC), and 21,770 controls and 12,882 cases for IBD) and the FinnGen study (375,445 controls and 1,665 cases for CD, 371,530 controls and 5,034 cases for UC, and 369,652 controls and 7,625 cases for IBD). MR analysis was performed in each of the two databases and those results were pooled using meta-analysis to assess the overall effect of exposure on each phenotype. In order to confirm the strength of the findings, we additionally conducted a replication analysis using the UK Biobank. Results: In the meta-analysis of the IIBDGC and FinnGen, we found that each unit increase in absolute circulating level of retinol was associated with a 72% reduction in the risk of UC (OR: 0.28, 95% CI: 0.10 to 0.78, P=0.015). The UC GWAS data from the UK Biobank also confirmed this causal relationship (OR: 0.99, 95% CI: 0.97 to 1.00, P=0.016). In addition, there was suggestive evidence that absolute retinol level was negatively associated with IBD (OR: 0.41, 95% CI: 0.18 to 0.92, P=0.031). No other causal relationship was found. Conclusion: Our results provide strong evidence that the absolute circulating level of retinol is associated with a reduction in the risk of UC. Further MR studies with more instrumental variables on circulating antioxidants, especially absolute circulating antioxidants, are needed to confirm our results.

Association between inflammatory bowel disease and cancer risk: evidence triangulation from genetic correlation, Mendelian randomization, and colocalization analyses across East Asian and European populations.

BACKGROUND: Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), has been associated with several cancer risks in observational studies, but the observed associations have been inconsistent and may face the bias of confounding and reverse causality. The potential causal relationships between IBD and the risk of cancers remain largely unclear. METHODS: We performed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analyses using summary genome-wide association study (GWAS) data across East Asian and European populations to evaluate the causal relationships between IBD and cancers. Sensitivity analyses for the MR approach were additionally performed to explore the stability of the results. RESULTS: There were no significant genetic correlations between IBD, CD, or UC and cancers (all P values > 0.05) in East Asian or European populations. According to the main MR analysis, no significant causal relationship was observed between IBD and cancers in the East Asian population. There were significant associations between CD and ovarian cancer (odds ratio [OR] = 0.898, 95% CI = 0.844-0.955) and between UC and nonmelanoma skin cancer (OR = 1.002, 95% CI = 1.000-1.004, P = 0.019) in the European population. The multivariable MR analysis did not find any of the above significant associations. There was no shared causal variant to prove the associations of IBD, CD, or UC with cancers in East Asian or European populations using colocalization analysis. CONCLUSIONS: We did not provide robust genetic evidence of causal associations between IBD and cancer risk. Exposure to IBD might not independently contribute to the risk of cancers, and the increased risk of cancers observed in observational studies might be attributed to factors accompanying the diagnosis of IBD.

The Role of Inflammatory Biomarkers in Mediating the Effect of Inflammatory Bowel Disease on nonmalignant Digestive System Diseases: A Multivariable Mendelian Randomized Study.

Background: While observation studies have shown a positive correlation between inflammatory bowel disease (IBD) and the risk of nonmalignant digestive system diseases, a definitive causal relationship has not yet been clearly established. Methods: Mendelian randomization (MR) was employed to investigate the potential causal association between genetic susceptibility to IBD and nonmalignant gastrointestinal diseases. Genetic variants were extracted as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis, which included 12,194 cases of Crohn's disease (CD) and 28,072 control cases of European ancestry. The GWAS for ulcerative colitis (UC) included 12,366 UC and 33,609 control cases of European ancestry. All IVs reached genome-wide significance (GWAS p value <5 × 10-8). Summary-level data for acute pancreatitis (AP), irritable bowel syndrome (IBS), gastroesophageal reflux disease, cholelithiasis, and CeD (celiac disease) were obtained from the GWAS meta-analysis and the FinnGen dataset. Summary-level data on relevant inflammatory factors were provided by the International Genetic Consortium. Univariate MR analysis was conducted using inverse variance weighting as the primary method for estimating causal effects. Multivariate MR analyses were also performed to detect possible mediators. Results: Genetic susceptibility to UC was associated with an increased risk of AP (OR = 1.08; 95% CI = 1.03-1.13; p=0.002) and IBS odds ratio (OR] = 1.07; 95% confidence interval (CI] = 1.03-1.11; (p < 0.001). In terms of potential mediators, interleukin 6 (IL-6) had a driving effect on the association between UC and AP. There was no apparent evidence of increased risk with CD. Meanwhile, genetic susceptibility to CD increases the risk of CeD (OR = 1.14; 95% CI = 1.03-1.25; p=0.01). Conclusions: The evidence suggests that UC is associated with an elevated risk of AP and IBS, and IL-6 may be responsible in AP. CD is associated with an increased risk of developing CeD. Implementing a proactive monitoring program for assessing the risk of gastrointestinal diseases in UC patients, particularly those with elevated IL-6 levels, may be of interest. In addition, the presence of AP and IBS may indicate the presence of UC. Preventing CeD is an essential consideration in the therapeutic management of patients with CD.

Investigating the association between the tissue expression of miRNA-101, JAK2/STAT3 with TNF-α, IL-6, IL-1ß, and IL-10 cytokines in the ulcerative colitis patients.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by numerous factors, such as immune system dysfunction and genetic factors. MicroRNAs (miRNAs) play a crucial role in UC pathogenesis, particularly via the JAK-STAT pathway. Our aim was to investigate the association between miRNA-101 and JAK2-STAT3 signaling pathway with inflammatory cytokines in UC patients. METHODS: We enrolled 35 UC patients and 35 healthy individuals as the control group, referred to Shariati Hospital, Tehran, Iran. Patients were diagnosed based on clinical, laboratory, histological, and colonoscopy criteria. RNA and protein extracted from tissue samples. Real-time PCR was used to assess the expression levels of miRNA-101, interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and IL-10 genes, while western blot was employed to measure levels of P-STAT3, total STAT3, and JAK2 proteins. RESULTS: Expression of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 significantly increased, while the expression of IL-10 significantly decreased in the case group versus controls. Additionally, miRNA-101 expression was significantly higher in UC patients. A significant correlation between miRNA-101 and IL-6 expression was observed, indicating their relationship and possible impact on cell signaling pathways, JAK2-STAT3. No significant changes were observed in phosphorylated and total STAT3 and JAK2 protein expression. CONCLUSION: This study provides evidence of increased miRNA-101 expression in UC tissue, suggesting a potential correlation between miRNA-101 and IL-6 expression and their involvement in the JAK2-STAT3 pathway. The study confirms alterations in UC patients' pro-inflammatory cytokines and anti-inflammatory IL-10. However, further investigations are needed to understand the exact role of miRNA-101 in UC pathogenesis fully.

Type 2 diabetes and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study.

To investigate the association between T2DM and IBD by bidirectional two-sample Mendelian randomization (MR) to clarify the casual relationship. Independent genetic variants for T2DM and IBD were selected as instruments from published genome-wide association studies (GWAS), mainly in European ancestry. Instrumental variables (IVs) associated with T2DM and IBD were extracted separately from the largest GWAS meta-analysis. MR analyses included inverse variance weighting, weighted median estimator, MR Egger regression, and sensitivity analyses with Steiger filtering and MR PRESSO. In the data samples for Ulcerative colitis (UC) (6968 cases, 20,464 controls) and Crohn's disease (CD) (5956 cases, 14,927 controls), there was a negative causal relationship between T2DM and UC [IVW, OR/95%CI: 0.882/(0.826,0.942), p < 0.001]. However, the causal relationships between T2DM and CD, UC and T2DM, CD and T2DM were not significant, and the p value measured by the IVW method was ≥ 0.05. All SNPs showed no significant horizontal pleiotropy (p > 0.05). The results of the bidirectional MR Study suggest that T2DM has a negative causal effect on UC, which provides implications for clinical treatment decisions in IBD patients with T2DM. The findings do not support a causal relationship between T2DM and CD, UC and T2DM, or CD and T2DM, and the impact of IBD on T2DM needs further investigation.

The ERK-cPLA2-ACSL4 axis mediating M2 macrophages ferroptosis impedes mucosal healing in ulcerative colitis.

Ulcerative colitis (UC) is a chronic gastrointestinal disease that can be managed with 5-aminosalicylic acid (5-ASA), the standard treatment for UC. However, the effectiveness of 5-ASA is not always optimal. Our study revealed that despite 5-ASA treatment, cells continued to experience excessive ferroptosis, which may hinder mucosal healing in UC and limit the success of this treatment approach in achieving disease remission. We found that combining 5-ASA with the ferroptosis inhibitor Fer-1 led to a significant inhibition of ferroptosis in macrophages present in the colon tissue, along with an increase in the proportion of M2 macrophages, suggesting that targeting ferroptosis in M2 macrophages could be a potential therapeutic strategy for alleviating UC. Our study also demonstrated that M2 macrophages are more susceptible to ferroptosis compared to M1 macrophages, and this susceptibility is associated with the activated arachidonic acid (AA) metabolism pathway mediated by ERK-cPLA2-ACSL4. Additionally, we found that the expression of cPLA2 gene pla2g4a was increased in the colon of UC patients compared to healthy controls. Furthermore, targeted metabolomics analysis revealed that the combination treatment group, as opposed to the 5-ASA treatment group, exhibited the ability to modulate AA metabolism. Overall, our findings emphasize the importance of addressing macrophage ferroptosis in order to enhance macrophage anti-inflammation, improve mucosal healing, and achieve better therapeutic outcomes for patients with UC.

Investigating the shared genetic architecture between primary sclerosing cholangitis and inflammatory bowel diseases: a Mendelian randomization study.

BACKGROUND: Several studies have found that primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are closely associated. However, the direction and causality of their interactions remain unclear. Thus, this study employs Mendelian Randomization to explore whether there are causal associations of genetically predicted PSC with IBD. METHODS: Genetic variants associated with the genome-wide association study (GWAS) of PSC were used as instrumental variables. The statistics for IBD, including ulcerative colitis (UC), and Crohn's disease (CD) were derived from GWAS. Then, five methods were used to estimate the effects of genetically predicted PSC on IBD, including MR Egger, Weighted median (WM), Inverse variance weighted (IVW), Simple mode, and Weighted mode. Last, we also evaluated the pleiotropic effects, heterogeneity, and a leave-one-out sensitivity analysis that drives causal associations to confirm the validity of the analysis. RESULTS: Genetically predicted PSC was significantly associated with an increased risk of UC, according to the study (odds ratio [OR] IVW= 1.0014, P<0.05). However, none of the MR methods found significant causal evidence of genetically predicted PSC in CD (All P>0.05). The sensitivity analysis results showed that the causal effect estimations of genetically predicted PSC on IBD were robust, and there was no horizontal pleiotropy or statistical heterogeneity. CONCLUSIONS: Our study corroborated a causal association between genetically predicted PSC and UC but did not between genetically predicted PSC and CD. Then, we identification of shared SNPs for PSC and UC, including rs3184504, rs9858213, rs725613, rs10909839, and rs4147359. More animal experiments and clinical observational studies are required to further clarify the underlying mechanisms of PSC and IBD.

Exploring genetic associations of Crohn's disease and ulcerative colitis with extraintestinal cancers in European and East Asian populations.

Background: Previous studies have reported associations of Crohn's disease (CD) and ulcerative colitis (UC) with the risks of extraintestinal cancers, but the causality remains unclear. Methods: Using genetic variations robustly associated with CD and UC extracted from genome-wide association studies (GWAS) as instrumental variables. Nine types of extraintestinal cancers of European and Asian populations were selected as outcomes. We used the inverse variance weighted method as the primary approach for two-sample Mendelian randomization analysis. Sensitivity analyses were carried out to evaluate the reliability of our findings. Results: In the European population, we found that CD showed a potential causal relationship with pancreatic cancer (OR: 1.1042; 95% CI: 1.0087-1.2088; P=0.0318). Meanwhile, both CD (outliers excluded: OR: 1.0208; 95% CI: 1.0079-1.0339; P=0.0015) and UC (outliers excluded: OR: 1.0220; 95% CI: 1.0051-1.0393; P=0.0108) were associated with a slight increase in breast cancer risk. Additionally, UC exhibited a potential causal effect on cervical cancer (outliers excluded: OR: 1.1091; 95% CI: 1.0286-1.1960; P=0.0071). In the East Asian population, CD had significant causal effects on pancreatic cancer (OR: 1.1876; 95% CI: 1.0741-1.3132; P=0.0008) and breast cancer (outliers excluded: OR: 0.9452; 95% CI: 0.9096-0.9822; P=0.0040). For UC, it exhibited significant causal associations with gastric cancer (OR: 1.1240; 95% CI: 1.0624-1.1891; P=4.7359×10-5), bile duct cancer (OR: 1.3107; 95% CI: 1.0983-1.5641; P=0.0027), hepatocellular carcinoma (OR: 1.2365; 95% CI: 1.1235-1.3608; P=1.4007×10-5) and cervical cancer (OR: 1.3941; 95% CI: 1.1708-1.6599; P=0.0002), as well as a potential causal effect on lung cancer (outliers excluded: OR: 1.1313; 95% CI: 1.0280-1.2449; P=0.0116). Conclusions: Our study provided evidence that genetically predicted CD may be a risk factor for pancreatic and breast cancers in the European population, and for pancreatic cancer in the East Asian population. Regarding UC, it may be a risk factor for cervical and breast cancers in Europeans, and for gastric, bile duct, hepatocellular, lung, and cervical cancers in East Asians. Therefore, patients with CD and UC need to emphasize screening and prevention of site-specific extraintestinal cancers.

Meta-analysis: Risk of pancreatic cancer in patients with inflammatory bowel disease.

BACKGROUND: Studies exploring the association between inflammatory bowel disease (IBD) and pancreatic cancer have reported inconsistent results. AIMS: To provide a comprehensive overview of the risk of pancreatic cancer development in patients with IBD. METHODS: We searched Embase, PubMed, Scopus and ProQuest from inception to 31 October 2023. We included population-based cohort studies examining the risk of incident pancreatic cancer in adult patients with IBD compared to the non-IBD population. We also retrieved Mendelian randomisation (MR) studies investigating the relationship of IBD with pancreatic cancer risk. We conducted random-effects meta-analyses and provided pooled relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We included 13 studies. Among 11 cohort studies, the risk of developing pancreatic cancer increased by 79% in patients with IBD (RR = 1.79 [95% CI: 1.16-2.75]; I2 = 95.7%). Patients either with Crohn's disease (RR = 1.42 [95% CI: 1.24-1.63]) or ulcerative colitis (RR = 1.50 [95% CI: 1.17-1.92]) had increased risk (p for interaction = 0.72). The annual incidence of pancreatic cancer potentially attributable to IBD increased by 55 cases (95% CI: 17-103) per million. Two MR studies demonstrated that genetic liability to IBD was associated with an increased risk of pancreatic cancer. CONCLUSIONS: Our results suggest a moderate increase in the risk of pancreatic cancer in patients with IBD, which may be further heightened by genetic predisposition to IBD. The increased risk of pancreatic cancer is probably similar in Crohn's disease and ulcerative colitis.