Type 2 diabetes and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study
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SUBMITTER: Xu G
PROVIDER: S-EPMC10907708 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:IntroductionInflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are lifelong digestive diseases that severely impact patients' quality of life. The existence of a causal association between IBS and IBD remains unclear. This study aimed to determine the direction of causality between IBD and IBS by quantifying their genome-wide genetic associations and performing bidirectional two-sample Mendelian randomization (MR) analyses.MethodsGenome-wide association studies (GWAS) among a predominantly European patient cohort identified independent genetic variants associated with IBS and IBD. Two separate databases (a large GWAS meta-analysis and the FinnGen cohort) for both IBS and IBD were consulted to retrieve statistics on instrument-outcome associations. MR analyses included inverse-variance-weighted, weighted-median, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods, and sensitivity analyses were performed. The MR analyses were carried out for each outcome data, followed by a fixed-effect meta-analysis.ResultsGenetically predicted IBD was associated with an increased risk of IBS. Odds ratios (95% confidence intervals) for samples of 211,551 (17,302 individuals with IBD), 192,789 (7,476 Crohn's disease cases), and 201,143 (10,293 ulcerative colitis cases) individuals were 1.20 (1.00, 1.04), 1.02 (1.01, 1.03), and 1.01 (0.99, 1.03), respectively. After outlier correction using MR-PRESSO, the odds ratio for ulcerative colitis was 1.03 (1.02, 1.05) (p = 0.001). However, an association between genetically influenced IBS and IBD was not identified.DiscussionThis study confirms that IBD is causally related to IBS, which may interfere with the diagnosis and treatment of both diseases.
| S-EPMC10150057 | biostudies-literature
Project description:BackgroundAn epidemiological link between celiac disease (CeD) and inflammatory bowel disease (IBD) has been well established recently. In this study, Mendelian randomization (MR) analysis was performed employing pooled data of publicly available genome-wide association studies (GWAS) to determine the causal relationship between CeD and IBD, encompassing ulcerative colitis (UC) and Crohn's disease (CD).MethodsDataset of CeD was acquired from GWAS for 12,041 cases and 12,228 controls. A GWAS of more than 86,000 patients and controls was used to identify genetic variations underlying IBD. MR analyses were performed with an inverse-variance-weighted approach, an MR-Egger regression, a weighted-mode approach, a weighted-median method, and sensitivity analyses of MR pleiotropy residual sum and outlie (MR-PRESSO).ResultsMR demonstrated that genetic predisposition to CeD was linked to a augmented risk of IBD (OR: 1.1408; 95% CI: 1.0614-1.2261; P = 0.0003). In the analysis of the two IBD subtypes, genetic predisposition to CeD was also linked to increased risks of UC (OR: 1.1646; 95% CI: 1.0614-1.2779; P = 0.0012) and CD (OR: 1.1865; 95% CI: 1.0948-1.2859; P = 3.07E-05). Reverse MR analysis results revealed that genetic susceptibility to IBD and CD was correlated with an augmented risk of CeD. However, there was no genetic correlation between UC and CeD. All of the above results were validated with other GWAS databases.ConclusionThere is a bidirectional causal relationship of CeD with IBD and CD. However, UC only augments the risk of developing CeD.
| S-EPMC9845610 | biostudies-literature
Project description:Background: Observational research has shown a correlation between inflammatory bowel disease (IBD) [comprising ulcerative colitis (UC) and Crohn's disease (CD)] and celiac disease. However, the relationship between these two diseases remains uncertain. Methods: We utilized two-sample Mendelian randomization (MR) to estimate the bidirectional causal relationships between IBD and celiac disease. This study utilized data on single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWASs). Heterogeneity, pleiotropy, and sensitivity analyses were also performed to evaluate the MR results. Results: There was a significant causal relationship between IBD and CD and celiac disease (e.g., IBD and celiac disease, inverse variance weighting (IVW) odds ratio (OR) = 1.0828, 95% CI = 1.0258-1.1428, p = 0.0039; CD and celiac disease, IVW OR = 1.0807, 95% CI = 1.0227-1.1420, p = 0.0058). However, in the reverse direction, we found only suggestive positive causality between celiac disease and CD (e.g., IVW OR = 1.0366, 95% CI = 1.0031-1.0711, p = 0.0319). No evidence of heterogeneity between genetic variants was found (e.g., IBD vs. celiac disease, MR-Egger Q = 47.4391, p = 0.6159). Horizontal pleiotropy hardly influenced causality (e.g., IBD vs. celiac disease, MR-Egger test: p = 0.4340). Leave-one-out analysis showed that individual SNPs did not influence the general results. Conclusion: Our MR analysis revealed a positive causal link between IBD and celiac disease in the European population. In addition, several recommendations for disease prevention and clinical management have been discussed.
| S-EPMC9530974 | biostudies-literature
Project description:BackgroundPrevious observational studies have found an association between inflammatory bowel disease (IBD) and psoriasis. Using the mendelian randomization (MR) approach, we aim to determine whether there was a causal association between IBD and psoriasis.MethodsWe performed a two-sample MR with the genetic instruments identified for IBD and its main subtypes, Crohn's disease (CD) and ulcerative colitis (UC), from a genome-wide association study (GWAS) involving 25,042 cases with an IBD diagnosis and 34,915 controls. Summarized data for psoriasis were obtained from different GWAS studies which included 4510 cases and 212,242 controls without psoriasis. Causal estimates are presented as odds ratios (ORs) with 95% confidence intervals (CIs).ResultsThe overall outcome of MR analysis was to demonstrate that genetic predisposition to IBD was associated with an increased risk of psoriasis (OR: 1.1271; 95% CI: 1.0708 to 1.1864). Psoriatic arthritis (PsA) had a significant association with total IBD (OR: 1.1202; 95% CI: 1.0491 to 1.1961). Casual relationship was also identified for CD-psoriasis (OR: 1.1552; 95% CI: 1.0955 to 1.2182) and CD-PsA (OR: 1.1407; 95% CI: 1.0535 to 1.2350). The bidirectional analysis did not demonstrate that a genetic predisposition to psoriasis was associated with total IBD, although psoriasis showed association with CD (OR: 1.2224; 95% CI: 1.1710 to 1.2760) but not with UC. A genetic predisposition to PsA had a borderline association with IBD (OR: 1.0716; 95% CI: 1.0292 to 1.1157) and a suggestive association with CD (OR: 1.0667; 95% CI: 1.0194 to 1.1162).ConclusionThere appears to be a causal relationship between IBD and psoriasis, especially for PsA, but for psoriasis and IBD, only total psoriasis and PsA were associated with CD. Understanding that specific types of psoriasis and IBD constitute mutual risk factors facilitates the clinical management of two diseases.
| S-EPMC9226443 | biostudies-literature
Project description:BackgroundCathepsins, key regulators of the pathology of gastrointestinal disorders such as inflammatory bowel disease (IBD), are a target protease that has attracted much attention in recent years. IBD is a chronic and relapsing inflammatory disorder of the gut. Traditional studies have shown a correlation between cathepsin and the risk of IBD, while the causal relationship remains unclear.MethodsThis study utilized Mendelian randomization techniques to evaluate the causal relationships between eleven cathepsins and the subtypes of IBD, such as ulcerative colitis (UC) and Crohn's disease (CD). We also performed a series of sensitivity analyses to validate the primary Mendelian randomization (MR) results, including Cochran's Q test, the MR-PRESSO global test, and the MR pleiotropy test.ResultsThe forward MR analyses showed no significant association between cathepsins and IBD. Reverse Mendelian randomization analyses suggested that UC might lead to elevated cathepsin G levels [inverse-variance weighted (IVW): p = 0.038, b = 9.966], and CD might cause a decrease in cathepsin B levels [IVW: p = 0.002, b = -10.525] and cathepsin L1 levels [IVW: p = 0.045, b = -4.742].ConclusionsOur findings offer novel and comprehensive evidence on the impact of UC or CD on cathepsins, potentially providing valuable insights into the treatment and prognosis of IBD.
| S-EPMC11445167 | biostudies-literature
Project description:BackgroundMendelian randomization (MR) was used to evaluate the bidirectional causal relationship between inflammatory bowel disease (IBD) and interleukins (ILs), chemokines.MethodsGenetic instruments and summary data of five ILs and six chemokines were obtained from a genome-wide association study database, and instrumental variables related to IBD were obtained from the FinnGen Consortium. Inverse variance weighting (IVW) was used as the main MR analysis method, and several other MR methods including MR-Egger and weighted median were used to confirm the reliability of the results. Sensitivity analyses such as heterogeneity and pleiotropy were also performed.ResultsThe IVW method provided evidence to support that genetically predicted IL-16, IL-18, and CXCL10 significantly positively correlated with IBD, while IL-12p70 and CCL23 significantly negatively correlated with IBD. IL-16 and IL-18 had a suggestive association with an increased risk of ulcerative colitis (UC), and CXCL10 had a suggestive association with an increased risk of Crohn's disease (CD). However, there was no evidence to support that IBD and two main subtypes (UC and CD) are associated with changes in the levels of ILs and chemokines. The results of the sensitivity analyses were robust and no evidence of heterogeneity and horizontal pleiotropy was observed.ConclusionsThe present study showed that some ILs and chemokines affect IBD, but IBD and its main subtypes (UC and CD) have no effect on the level changes of ILs and chemokines.
| S-EPMC10203949 | biostudies-literature
Project description:Previous studies have revealed a potential link between inflammatory bowel disease (IBD) and seborrheic keratosis (SK). However, whether this association is causal or confounded remains unknown. We conducted this two-sample Mendelian randomization (TSMR) analysis to clarify bidirectional causality between IBD, including its two primary conditions Crohn's disease (CD) and ulcerative colitis (UC), and SK. The summary genetic data of IBD, CD, UC and SK were obtained from accessible genome-wide association studies (GWAS). This TSMR study was primarily performed using inverse-variance weighted (IVW) method, complemented by MR-Egger, weighted median (WM), Bayesian weighted MR (BWMR), MR-robust adjusted profile score (MR-RAPS), MR-pleiotropy residual sum and outlier (MR-PRESSO), and radial IVW MR analyses with modified second-order weights (IVW [Mod 2nd]) methods. Assessment of sensitivity and identification of potential outliers were subsequently conducted to aid interpretation of results. The forward MR results showed that IBD [odds ratio (OR) = 1.068, 95% confidence interval (CI) = 1.010-1.129, p = 0.020) and its subtype CD (OR = 1.088, 95%CI = 1.038-1.139, p < 0.001) increased the risk of SK. However, the occurrence of SK could not be affected by UC (OR = 1.090, 95%CI = 0.977-1.216, p = 0.123). In the reverse analysis, no causal relationship between SK and IBD (OR = 0.905, 95%CI = 0.813-1.008, p = 0.069), UC (OR = 0.959, 95%CI = 0.860-1.068, p = 0.443), and CD (OR = 0.933, 95%CI = 0.846-1.029, p = 0.165) was identified. These findings demonstrate that IBD and its subtype CD could increase the incidence of SK in European populations, whereas SK does not affect IBD occurrence.
| S-EPMC11289426 | biostudies-literature
Project description:Background: Growing evidence suggests a bidirectional association between bipolar disorder (BD) and inflammatory bowel disease (IBD); however, observational studies are prone to confounding, making causal inference and directional determination of these associations difficult. Methods: We performed bidirectional two-sample Mendelian randomization (MR) and selected single nucleotide polymorphisms (SNPs) associated with BD and IBD as instrumental variables (IV). SNPs and genetic associations with BD and IBD were obtained from the latest genome-wide association studies (GWAS) in Europeans (BD: cases/controls: 20352/31358; IBD: 12882/21770; Crohn’s disease (CD): 5,956/14927; ulcerative colitis (UC): 6968/20464). The inverse-variance-weighted method was the major method used in MR analyses. MR-Egger, weight mode, simple mode, and weighted median were used for quality control. Results: Genetically predicted BD (per log-odds ratio increase) was significantly positively associated with risk of IBD (OR: 1.18, 95% CI: 1.04–1.33), and UC (OR = 1.19, 95% CI: 1.05–1.35), but not CD (OR = 1.18, 95% CI: 0.95–1.48). The validation analysis found that combined OR of IBD, CD, and UC increased per log-OR of BD were 1.16(95% CI: 1.02–1.31), 1.20(95% CI: 0.98–1.48) 1.17(95% CI: 1.02–1.35), respectively. In contrast, no causal relationship was identified between genetically influenced IBD and BD. Conclusion: Our results confirm a causal relationship between BD and IBD, which may influence clinical decisions on the management of BD patients with intestinal symptoms. Although the reverse MR results did not support a causal effect of IBD on BD, the effect of the IBD active period on BD remains to be further investigated.
| S-EPMC9531165 | biostudies-literature
Project description:BackgroundAcute pancreatitis (AP) is an extraintestinal manifestation of inflammatory bowel disease (IBD). Numerous observational studies have reported an increased risk of AP in patients diagnosed with IBD. However, the causal association and directionality between IBD or its subtypes and the development of AP remains unclear due to the limitations of observational research. This study aims to explore the relationship between IBD or its subtypes and AP risk using Mendelian Randomization (MR) method.MethodsA two-sample bidirectional MR study was conducted, selecting genetic variants associated with IBD and AP as instrumental variables from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) and FinnGen databases, respectively. The inverse-variance weighted (IVW) method used as the primary approach for causal inference. The Cochran Q test was employed for heterogeneity assessment. Sensitivity analyses were performed using the MR Egger intercept test, MR-Presso, and Leave-one-out method.ResultsThe results revealed that IBD (OR = 1.049, 95% CI = 1.010-1.090, p = 0.013) and ulcerative colitis (UC) (OR = 1.057, 95% CI = 1.013-1.102, p = 0.011) were significantly associated with an increased risk of AP. However, Crohn's disease (CD) (OR = 1.023, 95% CI = 0.993-1.055, p = 0.134) did not show a causal association with the risk of AP. Interestingly, AP was suggestively associated with a decreased risk of CD (OR = 0.797, 95% CI = 0.637-0.997, p = 0.047). Furthermore, there was no causal association between AP and the risk of IBD (OR = 0.886, 95% CI = 0.753-1.042, p = 0.144) or UC (OR = 0.947, 95% CI = 0.773-1.159, p = 0.595).ConclusionIn conclusion, this study provides genetic evidence supporting the causal influence of IBD (specifically UC) on AP, while CD does not appear to have a causal impact on AP.
| S-EPMC11349681 | biostudies-literature
Project description: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.
| S-EPMC9710718 | biostudies-literature