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

Background: An association between inflammatory bowel disease (IBD) [which includes ulcerative colitis (UC) and Crohn's disease (CD)] and IgA nephropathy (IgAN) has been discovered in observational studies, but the causal relationship is still unknown. The aim of this study was to clarify the causal link between IBD (which includes UC and CD) and IgAN via a two-sample Mendelian randomization (MR) analysis. Methods: Eligible single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for analyses and were obtained from the publicly available genome-wide association study (GWAS) summary statistics. Inverse-variance weighting (IVW), Mendelian randomization-Egger (MR-Egger) regression, the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and the weighted median were utilized to obtain the results. The MR-PRESSO test and MR-Egger regression were also performed to detect and correct horizontal pleiotropy. The Cochran's Q test and "leave-one-out" analysis were also conducted to assess the stability and reliability of the MR results. Results: This study found that IBD, UC, and CD all had significant positive causal effects on IgAN risk (IBD: OR = 1.58, 95% CI 1.15-2.16, p = 4.53 × 10-3; UC: OR = 1.55, 95% CI 1.14-2.11, p = 4.88 × 10-3; CD: OR = 1.57, 95% CI 1.21-2.03, p = 5.97 × 10-4). No significant horizontal pleiotropic effect was found for the causal association between IBD, UC, CD, and the risk of IgAN. Cochran's Q test identified no evidence of heterogeneity for the IV estimates. The "leave-one-out" sensitivity analysis also revealed that the MR results were robust. Conclusion: The results of this two-sample MR analysis supported that IBD, UC, and CD were causally associated with the risk of IgAN, while there was no sufficient evidence for the causal effect of IgAN on IBD, UC, or CD. Our findings provide theoretical support and a new perspective for the diagnosis and treatment of these two diseases.

Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics

This study aimed to explore the causal association between inflammatory bowel disease (IBD) and the risk of type 2 diabetes (T2D) based on a two-sample Mendelian randomization (MR) study. Summary single nucleotide polymorphism (SNP)-phenotype association data were obtained from published two genome-wide association studies (GWAS) including SNPs related to IBD, UC, or CD in European participants (n = 71,997) and East Asian participants (n = 16,805). Two GWAS including SNPs associated with T2D included 655,666 Europeans and 433,540 East Asians. A series of screening processes were performed to select qualified instrumental SNPs strongly related to exposure. We applied the inverse variance weighted (IVW), the MR-Egger regression, and the weighted median to estimate the causal effects of IBD, ulcerative colitis (UC) or Crohn' disease (CD) on T2D. Cochran's Q test was conducted to evaluate the statistical heterogeneity between SNPs in the IVW method. The leave-one-out analysis was employed to assess whether the results were caused by any single SNP associated with IBD, UC, or CD. Odds ratio (OR) and 95% confidence interval (CI) were calculated. The IVW results demonstrated that IBD could increase the risk of T2D in the European population (OR = 1.0230, 95%CI: 1.0073-1.0390). UC was positively associated with the risk of T2D according to the weighted median (OR = 1.0274, 95%CI: 1.0009-1.0546) and IVW (OR = 1.0244, 95%CI: 1.0071-1.0421) results in the European population. The IVW results indicated that the CD was positively associated with the risk of T2D in the European population (OR = 1.0187, 95%CI: 1.0045-1.0330). In the East Asian population, there are no associations between the IBD, UC, or CD and the risk of T2D (all P > 0.05). MVMR results revealed that the causal effect UC on T2D was still statistically significant after including body mass index (BMI) or low-density lipoprotein (LDL). IBD, UC, or CD had causal effects on the risk of T2D in the European population, which might provide evidence for the prevention of T2D in patients with IBD, UC, or CD.

BackgroundThe risk of extracolonic cancer is increased in inflammatory bowel disease (IBD) patients, but it is not clear whether there is a causal relationship. We aimed to systematically estimate the causal relationship between IBD and extracolonic cancers.MethodsIndependent genetic variants strongly associated with IBD were extracted as instrumental variables from genome-wide association study (GWAS) conducted by the International IBD Genetics Consortium including 12,882 IBD patients, 5956 Crohn’s disease (CD) patients, and 6968 ulcerative colitis (UC) patients. Three sources of cancer GWAS were selected as outcome data. Two-sample Mendelian randomization (MR) analysis was conducted to assess the causal effects of IBD on 32 extracolonic cancers. The meta-analysis was applied to assess the combined causal effect with multiple MR results.ResultsIBD, CD, and UC have potential causal associations with oral cavity cancer (IBD: OR = 1.180, 95% CI: 1.059 to 1.316, P = 0.003; CD: OR = 1.112, 95% CI: 1.008 to 1.227, P = 0.034; UC: OR = 1.158, 95% CI: 1.041 to 1.288, P = 0.007). Meta-analysis showed a significant positive causal relationship between IBD and breast cancer (OR = 1.059; 95% CI: 1.033 to 1.086; P < 0.0001) as well as a potential causal relationship between CD and breast cancer (OR = 1.029; 95% CI: 1.002 to 1.055; P = 0.032) based on combining multiple MR results.ConclusionsThis comprehensive MR analysis suggested that genetically predicted IBD, as well as its subtypes, may be a risk factor in the development of oral cavity and breast cancer.

Background Inflammatory Bowel Disease (IBD) is increasingly recognized as a systemic disorder, given its high prevalence of extra-intestinal manifestations (EIM) affecting various organs. The frequency of these manifestations varies depending on factors such as geographical region, IBD subtype, disease location, disease duration, and the timeliness of diagnosis, yet data on this topic remain limited in Latin America. This study aimed to assess the prevalence of the primary EIMs in IBD patients in Colombia, as well as to examine differences between Crohn's disease (CD) and ulcerative colitis (UC). Methods Prospective observational descriptive multicenter study in adult and pediatric patients with IBD of the Colombian IBD Foundation, with suspicious of EIM and after confirmed with by a multidisciplinary group in Colombia. Results A total of 266 out of 482 (55.1%) patients with inflammatory bowel disease (IBD) were suspected of having extra-intestinal manifestations (EIM) by their gastroenterologists, of which 197 (74.1%) were confirmed upon evaluation by a multidisciplinary team, resulting in an EIM prevalence of 40.9%, with a predominance of female patients (67.5%). Of the cohort, 95% were adults and 5% were pediatric patients, with 134/197 (68%) diagnosed with ulcerative colitis (UC) and 63/197 (32%) with Crohn's disease (CD), 49.2% of whom required biologic therapy. In UC patients, extensive colitis (E3) was the most common disease extension, while ileo-colonic (L3) involvement predominated in CD. The most frequent types of EIM were articular (36%), followed by cutaneous (34.5%) and ocular (24.9%) manifestations. The hospitalization rate due to IBD was 72.5%, with EIM present in 37.5% of UC patients and 52.5% of CD patients (Figure 1). Hepatobiliary manifestations (odds ratio [OR] = 1.931; 95% confidence interval [CI] 0.4311-13.66, p=0.44) were more common in UC compared to CD, whereas articular (OR=2.277; 95% CI 1.228-4.22), cutaneous (OR=1.027; 95% CI 0.5474-1.925), oral (OR=2.017; 95% CI 0.8727-4.661), and ocular (OR=2.683; 95% CI 1.374-5.23) manifestations were more frequent in CD (Figure 1). In terms of the number of EIMs, 71.5% of UC patients had one, 16% had two, and 12.5% had three or more, while in CD, 50.7% had one, 27% had two, and 22.2% had three or more. A higher prevalence of EIM was observed in the central region of the country (Figure 2). Conclusion The prevalence of EIM in this Colombian cohort was high (40,9%), predominating the CD, female, extensive disease and higher requirement for biologicals.

Mendelian randomization analysis reveals causal associations between autoimmune diseases and female infertility risk.

Previous observational epidemiological studies have identified a potential association between inflammatory bowel disease (IBD) and sarcoidosis. Nonetheless, the precise biological mechanisms underlying this association remain unclear. Therefore, we adopted a Mendelian randomization (MR) approach to investigate the causal relationship between IBD with genetic susceptibility to sarcoidosis, as well as to explore the potential mediating role. The genetic associations were obtained from publicly available genome-wide association studies (GWASs) of European ancestry. The IBD dataset has 31,665 cases and 33,977 controls, consisting of 13,768 individuals with ulcerative colitis (UC) and 17,897 individuals with Crohn's disease (CD). The genetic associations of sarcoidosis with 4,854 cases and 446,523 controls. A bidirectional causality between IBD and sarcoidosis was implemented to be determined by a two-sample MR approach. The inverse variance weighted (IVW) method was utilized as the main statistical method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. A two-step MR approach was used to investigate whether the mediating pathway from IBD to sarcoidosis was mediated by PBC. The forward MR analysis indicated that genetic predisposition to IBD was significantly linked to an increased risk of sarcoidosis (OR = 1.088, 95% CI: 1.023-1.158, pIBD-sar = 7.498e-03). Similar causal associations were observed in CD (OR = 1.082, 95% CI: 1.028-1.138, pCD-sar = 2.397e-03) and UC (OR = 1.079, 95% CI: 1.006-1.158, pUC-sar = 0.034). Reverse MR analysis revealed that genetic susceptibility to sarcoidosis was correlated with an augmented risk of CD (OR = 1.306, 95% CI: 1.110-1.537, psar-CD = 1.290e-03) but not IBD or UC. The mediation analysis via two-step MR showed that the causal influence of IBD and CD on sarcoidosis effects was partly mediated by PBC, and the mediating effect was 0.018 (95% CI: 0.005-0.031, p = 7.596e-03) with a mediated proportion of 21.397% in IBD, and 0.014 (95% CI: 0.004-0.024, p = 7.800e-03) with a mediated proportion of 17.737% in CD. The MR analysis provided evidence substantiating the causal effect of IBD (CD and UC) on an increased risk of sarcoidosis, with PBC playing a mediating role in IBD and CD. However, sarcoidosis only enhances the risk of developing CD, but not IBD or UC. These findings illuminate the etiology of sarcoidosis and contribute to the management of IBD patients.

Inflammatory bowel disease (IBD) represents an immune-related inflammation of the gastrointestinal tract. Current research highlights the significant role of immune mechanisms and metabolic components on its development and progression. Nonetheless, the interplay between these factors remains inadequately explored. This study used Mendelian randomization (MR) to analyze the causality between immune cells, plasma metabolites, and IBD, and to identify potential mediation metabolites. This study used 2-sample MR analysis method to assess the associations between 731 immune cell types, 1400 plasma metabolites, and IBD, and subtypes ulcerative colitis (UC) and Crohn’s disease (CD). The inverse-variance weighted, Simple mode, Weighted median, and Weighted mode approaches confirmed the validity of the results. Horizontal pleiotropy was evaluated via MR-Egger regression, heterogeneity through Cochran’s Q test, and sensitivity using the leave-one-out method. Mediation analysis pinpointed potential mediation metabolites linking immune cells with IBD and its subtypes. MR analysis identified causal associations involving 17 immune cell phenotypes and 37 metabolites with IBD, 13 immune cell phenotypes and 15 metabolites with UC, and 11 immune cell phenotypes and 19 plasma metabolites with CD (P < .01). Mediation analysis demonstrated that the association between CD25 on IgD+ CD38br and IBD was mediated by the arachidonate (20:4n6) to oleate to vaccenate (18:1) ratio, with a mediation proportion of 7.42%. CD28+ CD45RA+ CD8dim absolute cell and HLA DR on B cells mediated the associations between 3-(4-hydroxyphenyl) lactate, carnitine C14 levels, and UC, with mediation proportions of 6.97% and 8.8%, respectively. CD27 on sw mem and CD3 on EM CD4+ mediated the associations between mannonate levels, 2-hydroxy-4-(methylthio) butanoic acid levels, and CD, with mediation proportions of 10.9% and 5.89%, respectively. The study demonstrates the causal association of immune cells and plasma metabolites with IBD, UC, and CD, providing novel insights in terms of the prevention, diagnosis, and management of these conditions.

Accumulating evidence has shown that patients with inflammatory bowel disease (IBD) have liver function abnormalities and are susceptible to liver diseases. However, the existence of a causal relationship between IBD and liver function or disease remains unclear. A two-sample Mendelian randomization (MR) analysis was performed using genetic associations from publicly available genome-wide association studies (GWAS). These associations encompass ulcerative colitis (UC), Crohn's disease (CD), liver function traits, and liver disease phenotypes. The liver function traits comprised hepatic biochemistries, percent liver fat, and liver iron content from the UK Biobank. Furthermore, the liver disease phenotypes included cholelithiasis, non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC) in cohorts of European ancestry. The primary estimation used the inverse-variance weighted method, with GWAS of C-reactive protein (CRP) in the UK Biobank serving as a positive control outcome. Genetically predicted UC is causally associated with decreased levels of albumin (ALB) and liver iron content, while genetically predicted CD is causally associated with increased levels of alkaline phosphatase (ALP). Moreover, genetically predicted UC or CD increases the risk of PSC, and CD increases the risk of PBC. Neither UC nor CD causally increases the risk of cholelithiasis and NAFLD. UC affects the levels of ALB and liver iron content, while CD affects the levels of ALP. Both UC and CD increase the risk of PSC, and CD increases the risk of PBC.

: The objective of the present study was to quantify the national pediatric inpatient inflammatory bowel disease (IBD) burden in terms of the number of IBD-related hospitalizations, the number of days spent in the hospital, and hospitalization costs. : Hospitalizations for children and adolescents 20 years and younger with a primary diagnosis of either Crohn disease (CD) or ulcerative colitis (UC) were selected from the 2006 Kids' Inpatient Database (KID). Length of the hospital stay in days (LOS) and charges for the hospitalization were found directly in the Kids' Inpatient Database, and cost was calculated using the hospital's cost-to-charge ratio. Predictor variables included patient characteristics, such as age and severity of illness, and hospital characteristics. Ordinary-least-squares regressions were developed and estimated to explain hospitalization costs. : In 2006, there were 10,777 IBD-related hospitalizations. The total and mean costs for CD were $66.3 million and $10,176 (95% confidence interval [CI] $9647-$10,705), and for UC were $48.6 million and $11,836 (95% CI $10,760-$12,912). For CD, 0- to 5-year-old patients had the highest mean LOS (8.10, 95% CI 5.53-10.67, days) and mean cost ($13,894, 95% CI $9053-$18,735), whereas, for UC, 11- to 15-year-old patients had the highest mean LOS (7.49, 95% CI 6.88-8.10, 95% CI 5.53-10.67, days) and mean cost ($13,407, 95% CI $11,704-$15,110). : For a pediatric disease with a rather low prevalence rate, the estimated annual inpatient pediatric burden of IBD is a sizeable $152.4 million (2010 US$) and 64,985 days spent in the hospital. As medications and outpatient treatments improve for the treatment of IBD, there is an opportunity for significant reduction in inpatient burden.

BackgroundObservational studies have suggested that hearing impairment (HI) was associated with the risk of falls, but it remains unclear if this association is of causal nature.MethodsA two-sample Mendelian randomization (MR) study was conducted to investigate the causal association between HI and falls in individuals of European descent. Summary data on the association of single nucleotide polymorphisms (SNPs) with HI were obtained from the hitherto largest genome-wide association study (GWAS) (n = 323,978), and statistics on the association of SNPs with falls were extracted from another recently published GWAS (n = 461,725). MR Steiger filtering method was applied to determine the causal direction between HI and falls. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal association between HI and falls, whereas weighted median, simple mode, weighted mode, and MR-Egger methods were used as complementary analyses. The MR-Egger intercept test, the MR-PRESSO test, and Cochran's Q statistic were performed to detect the potential directional pleiotropy and heterogeneity, respectively. The odds ratio (OR) with 95% confidence intervals (CIs) was used to evaluate this association.ResultsA total of 18 SNPs were identified as valid instrumental variables in our two-sample MR analysis. The positive causality between HI and risk of falls was indicated by IVW [OR 1.108 (95% CI 1.028, 1.194), p = 0.007]. The sensitivity analyses yielded comparable results. The “leave-one-out” analysis proved that lack of a single SNP did not affect the robustness of our results. The MR-Egger intercept test exhibited that genetic pleiotropy did not bias the results [intercept = −2.4E−04, SE = 0.001, p = 0.832]. Cochran's Q test revealed no heterogeneity.ConclusionOur MR study revealed a causal association between genetically predicted HI and falls. These results provide further evidence supporting the need to effectively manage HI to minimize fall risks and improve quality of life.

Recurrent pericarditis due to mesalamine hypersensitivity: a pediatric case report and review of the literature.

The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases

Background: Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), has been found to be associated with colorectal cancer (CRC) in observational studies, but there is no evidence to support a causal relationship or reverse causality between the two diseases.Methods: We employed two-sample bidirectional Mendelian randomization to estimate an unconfounded bidirectional causal relationship between IBD (including UC and Crohn’s disease (CD)) and colorectal cancer. After searching IEU GWAS database and filtering SNPs, we applied a variety of MR methods including IVW method using qualified instrumental variables, and conducted sensitivity analysis to detect the heterogeneity and pleiotropy of instrumental variables.Results: After using three groups of SNPs (CD: 106, UC: 113, IBD: 70), the IVW method MR analysis showed that the results were not significant (result for UC: odds ratio (OR) [95% Confidence Interval (CI)]: 0.9998 [0.9991–1.0005], p value: 0.58; result for CD: OR [95%CI]: 0.99962 [0.99912–1.00012], p value: 0.14; results for IBD: OR [95%CI]: 0.99959 [0.99869–1.00048], p value: 0.36). MR-Egger regression, WM method and MR-RAPS method reached the same conclusion. Sensitivity analysis did not reveal heterogeneity and pleiotropy. Bidirectional MR analysis was performed using the same procedure, and the results of IVW MR analysis were also not significant (result for CD: OR [95%CI]: 1.07985 [0.00049–2372.38304], p value 0.98; result for UC: OR [95%CI]: 0.27117 [0.00014–528.3707], p value: 0.74; result for IBD: OR [95%CI]: 0.47101 [0.0001–2242.94159], p value: 0.86). MR-Egger regression, WM method and MR-RAPS method also reached the same conclusion. Sensitivity analysis did not find any evidence of heterogeneity and pleiotropy.Conclusion: Contrary to the conclusions of previous observational studies, a two-sample MR analysis did not find a causal relationship or reverse causal relationship between IBD and CRC. Sporadic CRC (sCRC) may differ in pathogenesis from IBD-related CRC.

The extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) can be classified as the following: (a) true EIMs due to reactive IBD affecting organ systems, (b) complications secondary to IBD activity, (c) non–IBD-specific autoimmune disease which occurs in increased frequency in individuals with IBD. Overlap is frequent between EIMs and extraintestinal complications, and it is increasingly evident that multiple organ systems may be involved. This review covers EIMs through their epidemiology, etiology/genetics/pathogenesis, prognosis, complications, and treatment. Also detailed are the organ systems involved with reactive IBD, including musculoskeletal, pulmonary, dermatological, ophthalmic, and hepatobiliary manifestations. Figures show the classification, etiology, and pathogenesis of EIMs of IBD, musculoskeletal and pulmonary manifestations of IBD, metastatic Crohn disease of the intergluteal cleft, pyoderma gangrenosum, oral apthous ulcers, Sweet syndrome, leucocytoclastic vasculitis, anti-tumor necrosis factor–induced psoriasis, uveitis, episcleritis, and primary sclerosing cholangitis. Tables list the modified New York criteria for ankylosing spondylitis, pulmonary manifestations of IBD and IBD-related treatment, diagnostic techniques in lung disorders associated with IBD, dermatologic manifestations of IBD based on classifications, specific cutaneous manifestations or granulomatous cutaneous lesions with the same histological features as the underlying bowel disease, reactive cutaneous manifestation of IBD with immunological mechanisms triggered by common antigens shared by gut bacteria and skin, cutaneous disorders or dermatosis associated with IBD, secondary cutaneous manifestations due to complications of IBD and adverse effects of IBD treatment, treatment of dermatological manifestations of IBD, diagnosis of ophthalmological manifestations of IBD, and other hepatobiliary manifestations of IBD. This review contains 13 highly rendered figures, 12 tables, and 79 references.