Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study.

Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn's disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. This study supports a causal effect between AD and IBD-but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.

Meisinger C ，Freuer D 《-》

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

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. 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. 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. 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.

Li J ，Wang L ，Ma Y ，Liu Y ... -  《-》

Causal association between atopic eczema and inflammatory bowel disease: A two-sample bidirectional Mendelian randomization study of the East Asian population.

Observation studies have postulated that atopic eczema is associated with a risk of inflammatory bowel disease in the East Asian population; however, this association does not obviate the biases resulting from confounding effects and reverse causation. This study aimed to determine whether this association is causal in the East Asian population using a bidirectional two-sample Mendelian randomization design. Independent genetic variants obtained from public genome-wide association studies for atopic eczema (4296 cases, 163 807 controls) were extracted to estimate the causal effects on inflammatory bowel disease (2824 cases, 3719 controls) and its two main conditions: Crohn's disease (1690 cases, 3719 controls) and ulcerative colitis (1134 cases, 3719 controls). Atopic eczema was found to be strongly associated with inflammatory bowel disease (odds ratio [95% confidence interval]: 1.520 [1.179, 1.959]; p = 0.001), but not vice versa. Subtype analyses revealed that atopic eczema is significantly associated with Crohn's disease (1.650 [1.293, 2.106]; p = 0.000) but not with ulcerative colitis. Both Crohn's disease and ulcerative colitis were found to be causally related to atopic eczema; Crohn's disease could reduce the risk of atopic eczema (0.866 [0.807, 0.930]; p = 0.000) while ulcerative colitis could increase the risk of atopic eczema (1.112 [1.021, 1.212]; p = 0.015). In conclusion, this study revealed that statistically causal relationships are present between atopic eczema and inflammatory bowel disease in the East Asian population. These findings are significant for guiding the treatment of atopic eczema and inflammatory bowel disease in clinical practice.

Wang L ，Wang Y ，Wang XE ，Chen B ，Zhang L ，Lu X ... -  《-》

The relationship between inflammatory bowel disease and sarcopenia-related traits: a bidirectional two-sample mendelian randomization study.

Observational studies have revealed a link between inflammatory bowel disease (IBD) and sarcopenia. However, it remains unclear whether this correlation between IBD and sarcopenia is causal. The genetic instrumental variables (IVs) associated with IBD and sarcopenia-related traits were derived from publicly available genome-wide association studies. We employed a two-sample bidirectional Mendelian randomization (MR) method. we obtained genetic IVs for five phenotypes from 34,652 cases in IBD, 27,432 cases in ulcerative colitis (UC), 212356 cases in crohn's disease (CD), 9336415 cases in low hand grip strength (LHGS), and 450243 cases in appendicular lean mass (ALM), respectively. The inverse variance weighting and other MR methods were used to explore the bidirectional causal relationship. Furthermore, we performed heterogeneity test, pleiotropy test, leave-one-out sensitivity test, and multivariate MR to evaluate the robustness of the results. The forward MR results showed that the UC (OR=0.994, 95% CI: 0.9876-0.9998, P = 0.044) and CD (OR=0.993, 95% CI: 0.988-0.998, P = 0.006) was negatively correlated with ALM. In the reverse MR analysis, we also found that LHGS was negatively correlated with the IBD (OR=0.76, 95% CI: 0.61-0.94, P = 0.012) and CD (OR=0.53, 95% CI: 0.40-0.70, P <0.001). Besides, genetically predicted higher ALM reduced IBD (OR=0.87, 95% CI: 0.79-0.95, P = 0.002), UC (OR=0.84, 95% CI: 0.76-0.93, P = 0.001), and CD (OR=0.87, 95% CI: 0.77-0.99, P = 0.029). However, the results of other MR Analyses were not statistically different. We found genetically predicted UC and CD are causally associated with reduced ALM, and higher hand grip strength reduced IBD and CD risk, and higher ALM reduced IBDs risk. This MR study provides moderate evidence for a bidirectional causal relationship between IBD and sarcopenia.

Sun Z ，Liu G ，Xu J ，Zhang X ，Wei H ，Wu G ，Jiang J ... -  《Frontiers in Endocrinology》

No causal relationship between glucose and inflammatory bowel disease: a bidirectional two-sample mendelian randomization study.

Association between glucose and inflammatory bowel disease (IBD) was found in previous observational studies and in cohort studies. However, it is not clear whether these associations reflect causality. Thus, this study investigated whether there is such a causal relation between elevated glucose and IBD, Crohn's disease (CD) and ulcerative colitis (UC). We performed a two-sample Mendelian Randomization (MR) with the independent genetic instruments identified from the largest available genome-wide association study (GWAS) for IBD (5,673 cases; 213,119 controls) and its main subtypes, CD and UC. Summarized data for glucose which included 200,622 cases and glycemic traits including HbA1c and type 2 diabetes(T2DM) were obtained from different GWAS studies. Primary and secondary analyses were conducted by preferentially using the radial inverse-variance weighted (IVW) approach. A number of other meta-analysis approach and sensitivity analyses were carried out to assess the robustness of the results. We did not find a causal effect of genetically predicted glucose on IBD as a whole (OR 0.858; 95% CI 0.649-1.135; P = 0.286). In subtype analyses glucose was also suggestively not associated with Crohn's disease (OR 0.22; 95% CI 0.04-1.00; P = 0.05) and ulcerative colitis (OR 0.940; 95% CI 0.628-1.407; P = 0.762). In the other direction, IBD and its subtypes were not related to glucose and glycemic traits. This MR study is not providing any evidence for a causal relationship between genetically predicted elevated glucose and IBD as well as it's subtypes UC and CD. Regarding the other direction, no causal associations could be found. Future studies with robust genetic instruments are needed to confirm this conclusion.

Cen J ，Chen K ，Ni Z ，Dai Q ，Lu W ，Tao H ，Peng L ... -  《BMC Medical Genomics》