Causal Association Analysis of Periodontitis and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization Study.

Periodontitis has been reported to be associated with inflammatory bowel disease (IBD), including ulcerative colitis (UC), and Crohn's disease (CD). However, the causality of these 2 diseases remains unclear. We conducted bidirectional Mendelian randomization (MR) to investigate the causal relationship between periodontitis and IBD. We obtained the genome-wide association study (GWAS) summary data of European populations from FinnGen database (for IBD) and a published article (for periodontitis), from which independent single nucleotide polymorphisms were selected as instrumental variables. Inverse variance-weighted (IVW), MR-Egger, and weighted median (WM) methods were utilized for MR analysis. Heterogeneity or pleiotropy was detected through Cochran's Q test and MR-Egger intercept, respectively. Outlier was identified with MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) and leave-one-out analysis. All statistical analyses were performed with R 4.2.1 and the packages of TwoSampleMR version 0.5.6. Genetic prediction showed that periodontitis was the risk factor of UC (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.01-1.26; P = .027), rather than of CD (OR, 0.92; 95% CI, 0.74-1.15; P = .456) and IBD (OR, 0.96; 95% CI, 0.81-1.13; P = .619). To the contrary, CD, not UC or IBD, resulted in exacerbating periodontitis in terms of the results of the IVW (OR, 1.09; 95% CI, 1.01-1.17; P = .021) and WM (OR, 1.10; 95% CI, 1.01-1.20; P = .030) methods. Heterogeneity or pleiotropy was acceptable. Our results indicated that CD was the risk factor for periodontitis; conversely, periodontitis was responsible for the exacerbation of UC, enhancing the existence of mouth-gut axis. Patients with UC should pay more attention to periodontal health, while patients with periodontitis should actively pay close heed to intestinal health.

Qing X ，Zhang C ，Zhong Z ，Zhang T ，Wang L ，Fang S ，Jiang T ，Luo X ，Yang Y ，Song G ，Wei W ... -  《-》

Exploring the causal relationship between Takayasu arteritis and inflammatory bowel disease using Mendelian randomization.

Takayasu arteritis (TA) and inflammatory bowel disease (IBD) are two distinct diseases; however, previous studies have reported many cases of IBD-TA coexistence. Additionally, the incidence of IBD in patients with TA is estimated to be significantly higher than the incidence in the general population. Therefore, the two diseases are anticipated to be linked. Mendelian randomization (MR) analysis assesses whether an exposure might causally affect an outcome by using genetic variants inherited randomly at conception, thereby reducing the impact of confounding and reverse causality. The present study aimed to investigate the potential causal relationship between TA and IBD using MR analysis. Two-sample MR analysis, in which TA and IBD were regarded as the exposure and outcome, respectively, was conducted to investigate whether the two diseases are causally related using the R TwoSampleMR package. Summary GWAS data of TA consisted of 516 Turkish cohorts and 462 controls, and 119 patients and 993 controls of European ancestry. Summary data of IBD was from a sub-study of the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) that comprised 31,665 cases and 33,977 controls of European ancestry. Additionally, separate MR analyses stratified by the two major subtypes of IBD, Crohn's disease (CD) and ulcerative colitis (UC), were performed. Various statistical tests, including the intercept of MR-Egger regression, funnel plots, Cochran's Q tests, and leave-one-out sensitivity analyses, were employed to assess the presence of heterogeneity and horizontal pleiotropy among single nucleotide polymorphisms (SNPs). In the primary analysis using the inverse-variance weighted (IVW) method, the risk of developing IBD for a patient with TA compared to a non-TA control increased 1.053 times (Odds Ratio (OR) = 1.053, P = 0.065). The MR-Egger method (OR = 1.025, P = 0.470) yielded results consistent with this null finding. However, both the weighted median method (OR = 1.038, P = 0.002) and the weighted mode method (OR = 1.051, P = 0.009) identified a significant harmful causal effect. The MR outcomes from separate subgroup analyses slightly diverged from those of IBD and TA. Specifically, for CD, three methods indicated that TA is a risk factor: IVW estimated the OR as 1.045 (P = 0.032), MR-Egger as 0.997 (P = 0.957), weighed median as 1.028 (P = 0.021), and weighted mode as 1.031 (P = 0.022), respectively. This study represents one of the initial investigations into the potential causal association between TA and IBD. With three MR methods, including the primary IVW approach, indicating a notable effect on TA on CD, our analysis findings offer some indication that TA could be a contributing risk factor for CD.

Pang X ，Yang H ，Wang C ，Tian S ... -  《-》

Effects of immune cells in mediating the relationship between inflammatory bowel disease and pyoderma gangrenosum: a two-sample, two-step mendelian randomization study.

Although the precise cause of the co-occurrence of pyoderma gangrenosum (PG) and inflammatory bowel disease (IBD) is still unknown, prior research has shown that the two conditions coexist. Moreover, it is currently unknown how immune cells function in influencing the relationship between IBD and PG. In order to choose independent single nucleotide polymorphism (SNP) as instrumental variables, we were provided with genome-wide association study (GWAS) summary data of European populations from the IEU OpenGWAS project (for IBD) and a the FinnGen database (for PG) publically available. For the MR analysis, a range of analytical techniques were employed to peer into the possible causative relationship between PG and IBD. The two-step MR analysis was used to investigate the mediating role of immune cells between IBD and PG. The chief method utilized was the inverse variance weighted (IVW) approach. Using the Cochran's Q test and the MR-Egger intercept, respectively, heterogeneity or pleiotropy was evaluated to support the findings. MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) were used to identify the outlier SNP. IBD was found to raise the incidence of PG (IVW-FE: OR = 1.604, 95%CI = 1.308-1.966, p = 5.58 × 10- 6), according to MR findings. Moreover, UC or CD were strongly correlated with a greater risk of PG (OR = 1.339, 95%CI = 1.041-1.723, p = 0.023 for UC; OR = 1.339, 95%CI = 1.107-1.621, p = 0.003 for CD). The results of the reverse MR study did not suggest a connection between PG and IBD. CD4+ regulatory T cell is the mediator that particularly stood out in the interaction between UC and PG. There was evidence of neither heterogeneity nor horizontal pleiotropy. And the validity of these conclusions was verified. In the European population, PG risk may be genetically elevated by IBD, including CD and UC, according to the current study. The effect of UC on PG may have been causally mediated by CD4+ regulatory T cells.

Zhu H ，Pan J 《-》

Causal Relationship Between Autism Spectrum Disorder and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization Study.

Patients with autism spectrum disorder (ASD) are often accompanied by inflammatory bowel disease (IBD) in observational research; however, the potential causal link between the two conditions remains unknown. In this study, we used a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal relationship between ASD and IBD and its main subtypes, Crohn's disease (CD), and ulcerative colitis (UC). Independent genetic instruments from a genome-wide association study (GWAS) for IBD (25,042 cases and 34,915 controls) were used to investigate the association of IBD with ASD data obtained from the PGC and the iPSYCH consortia (N = 46,351). The primary analysis employed the random effects inverse variance weighting (IVW) method. Horizontal pleiotropy was detected using the MR Egger regression and the MR-pleiotropy residual sum and outlier (MR-PRESSO) analysis while heterogeneity was detected using Cochran's Q. The IVW method indicated a positive causal relationship of IBD with ASD (odds ratio (OR) = 1.028, 95% confidence interval (CI) = 1.001-1.056, p = 0.042). In subtype analyses, CD was positively related to ASD (OR = 1.036; 95% CI = 1.004-1.069; p = 0.02); however, UC showed no relationship (OR = 1.021; 95% CI = 0.999-1.044; p = 0.065). In contrast, no evidence of a causal relationship between ASD and IBD or its subtypes (p > 0.05) was found. Our findings provided evidence in support of potential causal associations between IBD/CD and ASD.

Li W ，He X ，Tan C ，Zhang T ... -  《-》

Assessing inflammatory protein factors in inflammatory bowel Disease using multivariable mendelian randomization.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), decreases quality of life and causes disability. The underlying processes are not fully understood. This study uses Mendelian randomization (MR) analysis to identify cytokines that may be associated with UC and CD, aiding in early diagnosis and treatment decisions. Methods Genome-wide association study (GWAS) data for inflammatory cytokine levels were obtained from a cohort of 14,824 individuals of European descent. The outcome data were then analyzed using summary-level GWAS data for UC and CD from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). The analysis was primarily conducted using inverse-variance weighted (IVW) methods, with MR-Egger and weighted median serving as supplementary analyses. Sensitivity analyses included Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis.The inflammatory cytokines were subjected to additional scrutiny through the application of the Steiger test and reverse Mendelian randomization analysis. Subsequently, multivariable Mendelian randomization (MVMR) was employed to examine the associations of metabolites on UC and CD, in conjunction with linkage disequilibrium score regression (LDSC) and colocalization analysis. After FDR correction, we identified significant genetic associations of two inflammatory proteins (CXCL5 and CXCL9) with UC, and CXCL5 and IL-18R1 with CD. These findings were further validated by MVMR. Colocalization analyses demonstrated substantial genetic overlap between inflammatory proteins and IBD, with CXCL5 showing strong evidence of shared genetic variants with UC, and CXCL9 exhibiting genetic colocalization with CD, suggesting common genetic determinants underlying these inflammatory protein-IBD relationships. The current work presents evidence that presents evidence of significant associations between seven inflammatory protein factors and UC, as well as three inflammatory protein factors and CD. These findings provide novel insights into the biological mechanisms of IBD, and have implications for the screening, prevention, and treatment of IBD.

Su Q ，Lu Y ，He S ，Liang J ，Huang S ，He Y ，An Z ... -  《Scientific Reports》