Higher Adherence to Cardioprotective Diet is Associated with Reduced Risk of Enterotomy and All-Cause Mortality among 5549 Individuals with Inflammatory Bowel Disease in a Prospective Cohort Study.

BACKGROUND: The cardioprotective diet has been previously reported to be inversely associated with the development of inflammatory bowel disease (IBD), but whether it is beneficial to improve adverse outcomes in IBD remains unknown. OBJECTIVES: We aimed to investigate whether the cardioprotective diet is associated with enterotomy and all-cause mortality among individuals with IBD. METHODS: We conducted a prospective cohort study of 5549 participants with IBD from the UK Biobank. Cardioprotective diet scores (range 0-7) were calculated based on the consumption of 7 common food groups collected by a validated food frequency questionnaire. Outcomes of interest were enterotomy and all-cause mortality, ascertained via inpatient data and death registry, respectively. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During an average follow-up duration of 12.0 y, we documented 506 enterotomy and 566 death events. Compared with participants with the lowest adherence to the cardioprotective diet (score of 0-2), participants with the highest adherence to the cardioprotective diet (score of 5-7) were observed to have a lower risk of enterotomy (HR: 0.60; 95% CI: 0.47, 0.76; P < 0.001; P-trend < 0.001) and all-cause mortality (HR: 0.77; 95% CI: 0.61, 0.98; P = 0.031; P-trend = 0.025). CONCLUSIONS: A greater adherence to the cardioprotective diet is associated with a lower risk of enterotomy and all-cause mortality among individuals with IBD.

Can visceral adipose tissue and skeletal muscle predict recurrence of newly diagnosed Crohn's disease in different treatments.

BACKGROUND AND AIMS: It is crucial to manage the recurrence of Crohn's disease (CD). This study is aimed to explore whether visceral adipose tissue (VAT) and skeletal muscle (SM) are associated with the recurrence of CD upon different treatments. METHODS: All patients with a definite diagnosis of CD were retrospectively divided into three groups according to distinct treatment regimens: 5-amino salicylic acid group (Group A), steroids + azathioprine (Group B) and biologics (Group C). The pretreatment computerized tomography (CT) images and clinical data were collected. The VAT area, mesenteric fat index (MFI), the ratio of VAT area to fat mass (VAT area/FM) were assessed. The primary end point was the recurrence of CD within 1 year of follow-up. RESULTS: A total of 171 CD patients were enrolled, including 57 (33.33%) patients in Group A, 70 (40.94%) patients in Group B and 44 (25.73%) patients in Group C. Patients with 1-year recurrence had higher MFI (P = 0.011) and VAT area/FM (P = 0.000). ROC curve demonstrated that patients with the ratio of VAT area/FM and MFI higher than 0.578 and 1.394 tended to have recurrence with the AUC of 0.707 and 0.709. Similar results could be observed in Group A & B but not in Group C. CONCLUSIONS: High VAT area/FM and MFI are related to recurrence within 1 year for newly diagnosed CD patients treated by 5-amino salicylic or azathioprine + steroids rather than biologics. We could not observe any radiological data associated with the recurrence of CD patients under biological treatment.

Necroptosis in inflammatory bowel disease: A potential effective target. / ç‚Žç—‡æ€§è‚ ç— ä¸­çš„åæ­»æ€§å‡‹äº¡ï¼šä¸€ä¸ªæ½œåœ¨çš„æ²»ç–—é¶ç‚¹ï¼ˆè‹±æ–‡ï¼‰.

The morbidity of inflammatory bowel diseases (IBD) is rising rapidly but no curative therapies to prevent its recurrence. Cell death is crucial to maintaining homeostasis. Necroptosis is a newly identified programmed cell death and its roles played in IBD need to be explored. Necroptosis is mediated by receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), which resulted in cell swelling, plasma membrane rupture, intracellular content leaking, and eventually cell death as well as the promotion of inflammation. Studies have found that inhibiting necroptosis alleviated IBD in animal models and IBD patients with an increased level of necroptosis in inflammatory tissues, indicating that necroptosis is related to the pathogenesis of IBD. However, due to the complexity in regulation of necroptosis and the involvement of multiple functions of relevant signaling molecules, the specific mechanism remains elusive. Necroptosis may play a vital regulatory role in the pathogenesis of IBD, which provides a new idea and method for further exploring the therapeutic target of IBD.

Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel disease.

BACKGROUND: Mitochondrial dysfunction has been linked to the development of inflammatory bowel disease (IBD), but the genetic pathophysiology was not fully elucidated. We employed Mendelian randomization and colocalization analyses to investigate the associations between mitochondrial-related genes and IBD via integrating multi-omics. METHODS: Summary-level data of mitochondrial gene methylation, expression and protein abundance levels were obtained from corresponding methylation, expression and protein quantitative trait loci studies, respectively. We obtained genetic associations with IBD and its two subtypes from the Inflammatory Bowel Disease Genetics Consortium (discovery), the UK Biobank (replication), and the FinnGen study (replication). We performed summary-data-based Mendelian randomization analysis to assess the associations of mitochondrial gene-related molecular features with IBD. Colocalization analysis was further conducted to assess whether the identified signal pairs shared a causal genetic variant. FINDINGS: After integrating the multi-omics data between mQTL-eQTL and eQTL-pQTL, we identified two mitochondrial genes, i.e., PARK7 and ACADM, with tier 1 evidence for their associations with IBD and ulcerative colitis (UC). PDK1 and FISI genes were associated with UC risk with tier 2 and tier 3 evidence, respectively. The methylation of cg05467918 in ACADM was associated with lower expression of ACADM, which fits with the positive effect of cg05467918 methylation on UC risk. Consistently, the inverse associations between gene methylation and gene expression were also observed in PARK7 (cg10385390) and PDK1 (cg17679246), which were corroborated with the protective role in UC. At circulating protein level, genetically predicted higher levels of PARK7 (OR 0.36, 95% CI 0.25-0.52) and HINT1 (OR 0.47, 95% CI 0.30-0.74) were inversely associated with IBD risk; genetically predicted higher level of HINT1 was associated with a decreased risk of Crohn's disease (CD) (OR 0.26, 95% CI 0.14-0.49) and a higher level of ACADM (OR 0.67, 95% CI 0.55-0.83), PDK1 (OR 0.63, 95% CI 0.49-0.81), FIS1 (OR 0.63, 95% CI 0.47-0.83) was associated with a decreased risk of UC. INTERPRETATION: We found that the mitochondrial PARK7 gene was putatively associated with IBD risk, and mitochondrial FIS1, PDK1, and ACADM genes were associated with UC risk with evidence from multi-omics levels. This study identified mitochondrial genes in relation to IBD, which may enhance the understanding of the pathogenic mechanisms of IBD development. FUNDING: XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and Healthy Zhejiang One Million People Cohort (K-20230085).

Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities.

BACKGROUND: Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown. OBJECTIVES: We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities. METHODS: A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy. RESULTS: The network Mendelian randomization analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Low-density lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%-49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. Five proteins (interleukin-6 receptor subunit alpha, LRP12, prothrombin, angiopoietin-1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities. CONCLUSION: This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.

Risk of subsequent gastrointestinal disease assessed by skeletal muscle strength and mass in a prospective cohort study.

Skeletal muscle may mutually interact with gastrointestinal disease through metabolic homeostasis and nutritional status and therefore may be a marker for early risk detection. We conducted a prospective cohort analysis including 393,606 participants (mean age 56.0 years, 53.9% female) from the UK Biobank. The exposures were grip strength and skeletal muscle mass (SMM). The primary outcomes were 24 incident gastrointestinal diseases. During a mean follow-up of 12.1 years, we found that one sex-specific SD increase in grip strength and SMM were associated with reduced risk of 16 and 19 gastrointestinal diseases, respectively. For grip strength, the HRs ranged from 0.94 (for ulcerative colitis) to 0.80 (for liver cancers). For SMM, the HRs ranged from 0.92 (for colorectal cancer) to 0.51 (for non-alcoholic fatty liver disease). Our finding suggested that grip strength and SMM might be significant indicators for gastrointestinal diseases risk screen.

Adherence to the Mediterranean diet is associated with reduced chronic pancreatitis risk: a longitudinal cohort study.

Background: The role of diet on the risk of chronic pancreatitis (CP) is understudied. The health benefits of the Mediterranean diet (MedDiet) pattern have long been recognized, but its association with CP risk is unclear. We aimed to investigate the association between adherence to MedDiet and the incidence of CP in a large-scale cohort. Methods: 190 790 participants from the UK Biobank were involved, all free of CP and with typical diet recall data at recruitment. The diagnosis of CP was ascertained by the combination of hospital inpatient data, primary care data, and death registry data. Multivariable Cox regression models were used to evaluate the associations between MedDiet adherence, measured by the Mediterranean Diet Adherence Screener (MEDAS) continuous score, and the incidence of CP. The mediating role of inflammation (assessed by C-reactive protein) and metabolic status between MedDiet adherence and CP risk was also investigated. Results: During a mean of 10.8 years of follow-up, 214 participants developed CP. Individuals with the highest adherence to MedDiet, defined by continuous MEDAS scores, exhibited significantly lower risk of developing CP (hazard ratio [HR] = 0.57, 95% confidence interval [CI]: 0.40-0.82; p = 0.002) compared to those in the lowest tertiles. Metabolic status mediated 4.74% of the association between MedDiet adherence and CP risk, while the mediating role of C-reactive protein was not significant. Conclusion: Greater Mediterranean diet adherence is associated with reduced chronic pancreatitis risk.

Greater adherence to the Mediterranean Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet is associated with lower risk of inflammatory bowel disease: a prospective cohort study.

Background: The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet is emerging as a promising candidate for preventive measures against inflammatory bowel disease (IBD), though there is currently no direct evidence from population-based studies. This study aims to bridge the gap in understanding of the association of the MIND diet with IBD risk. Methods: We utilized data from 187 490 participants in the UK Biobank who provided dietary information and were free of IBD at baseline. Dietary information was obtained using a validated web-based 24-hour dietary recall questionnaire. A MIND diet score was evaluated based on the intake of ten beneficial and five unhealthy food groups and the scores were further grouped into tertiles. The outcome of interest was incident IBD, Crohn's disease (CD), and ulcerative colitis (UC). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models adjusted for demographic characteristics, lifestyle factors, cancer history, and other dietary factors. Mediation analyses were performed to evaluate the role of systemic inflammation and metabolic disorders represented by the integrated biomarkers in the MIND diet-IBD association. Results: After a mean follow-up of 10.7 years, we documented 825 incident IBD cases (250 CD and 575 UC). The average age of the participants was 56.2 years, of which 55.0% were females. We found that greater adherence to the MIND diet, represented by a higher diet score, was associated with a lower risk of IBD (HRcomparing extreme tertiles 0.74, 95% CI 0.62-0.90, p = 0.002; p for trend = 0.005), CD (HR 0.66, 95% CI 0.47-0.94, p = 0.022; p for trend = 0.023), and UC (HR 0.78, 95% CI 0.62-0.98, p = 0.031; p for trend = 0.022). The associations were partially mediated by metabolic and inflammation status (mediation proportion: 5.5-15.9%). Conclusion: We found higher adherence to the MIND diet was associated with a lower risk of IBD, and that inflammatory and metabolic conditions may play an important role in the underlying mechanistic pathways.

Sedentary lifestyle, physical activity, and gastrointestinal diseases: evidence from mendelian randomization analysis.

BACKGROUND: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. METHODS: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 × 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. FINDINGS: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. INTERPRETATION: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases. FUNDING: Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), Natural Science Foundation of Hunan Province (2021JJ30999), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), Swedish Cancer Society (Cancerfonden), the Wellcome Trust (225790/7/22/Z), United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and National Institute for Health Research Cambridge Biomedical Research Centre (NHIR203312).

Plasma phospholipid arachidonic acid in relation to non-alcoholic fatty liver disease: Mendelian randomization study.

OBJECTIVES: The role of plasma phospholipid arachidonic acid (AA) in the development of non-alcoholic fatty liver disease (NALFD), cirrhosis, and liver cancer remains unclear. This study aimed to determine the causality of the associations of plasma phospholipid AA with NALFD, cirrhosis, and liver cancer using Mendelian randomization analysis. METHODS: Nine independent single-nucleotide polymorphisms associated with plasma phospholipid AA at the genome-wide significance were used as instrumental variables. Summary-level data for three outcomes were obtained from 1) a genome-wide association study for NAFLD, 2) the UK Biobank study, and 3) the FinnGen study. The sensitivity analysis excluding the pleiotropic variant rs174547 in the FADS1 gene was performed. Estimates from different sources were combined using the fixed-effects meta-analysis method. RESULTS: Per standard deviation increase in AA levels, the combined odds ratio was 1.06 (95% confidence interval, 1.02-1.11; P = 0.008) for NAFLD, 1.05 (95% confidence interval, 1.01-1.09; P = 0.009) for cirrhosis, and 0.99 (95% confidence interval, 0.94-1.05; P = 0.765) for liver cancer. The associations remained stable in the sensitivity analysis excluding rs174547. CONCLUSIONS: This study suggests potential causal associations of high levels of plasma phospholipid AA with the risk of NAFLD and cirrhosis.

Therapeutic role of interleukin-1 receptor antagonist in pancreatic diseases: mendelian randomization study.

Background: The interleukin-1 pathway has been linked to pancreatic diseases. We applied the Mendelian randomization approach to explore whether higher interleukin-1 receptor antagonist (IL-1RA) levels reduce the risk of acute and chronic pancreatitis and pancreatic cancer. Methods: Genetic variants associated with blood IL-1RA levels at the genome-wide significance level and located 5MB downstream or upstream of the IL1RN gene were extracted from a genome-wide meta-analysis of 21,758 participants. After pruning, genetic variants without linkage disequilibrium were used as genetic instrument for IL-1RA. Summary-level data on acute and chronic pancreatitis and pancreatic cancer were obtained from the UK Biobank and FinnGen studies. The associations were meta-analyzed for one outcome from two sources. Results: Genetically predicted higher levels of IL-1RA were associated with a lower risk of acute and chronic pancreatitis and pancreatic cancer. In the meta-analysis of UK Biobank and FinnGen, the combined odds ratio was 0.87 (95% confidence interval [CI] 0.77-0.97, P=0.003) for acute pancreatitis, 0.73 (95% CI 0.65-0.82, P=2.93×10-8) for chronic pancreatitis, and 0.86 (95% CI 0.77-0.96, P=0.009) for pancreatic cancer per one standard deviation increment in genetically predicted levels of IL-1RA. Conclusion: This study suggests a protective role of IL-1RA in three major pancreatic diseases, which hints the therapeutic potentials of IL-1RA in pancreatic diseases.

Associations of sugar-sweetened beverages, artificially sweetened beverages, and natural juices with cardiovascular disease and all-cause mortality in individuals with inflammatory bowel disease in a prospective cohort study.

Background: Beverage consumption was found to be associated with cardiovascular disease and mortality in the general population. However, it is unclear whether this association still exists in individuals with inflammatory bowel disease (IBD). Objectives: To investigate the associations of sugar-sweetened beverages, artificially sweetened beverages, and natural juices with cardiovascular disease and all-cause mortality among individuals with IBD. Design: Prospective cohort study. Methods: We included 1981 participants with IBD in the UK Biobank. Consumption of beverages was measured using a validated 24-h diet recall. Outcomes of interest were overall cardiovascular disease and all-cause mortality. Cox proportional hazard models were used to estimate the hazard ratios and 95% confidence intervals (CIs). Results: During a mean (SD) follow-up of 10.1 (1.7) years, we documented 205 cardiovascular events and 133 deaths. Compared to non-consumers, those consuming sugar-sweetened beverages more than 1 unit/day (reported in glasses/cans/250 ml/cartons) were associated with 64% (95% CI: 5-155, p = 0.030) and 97% (95% CI: 16-233, p = 0.012) increased risk of cardiovascular disease and all-cause mortality, respectively. We also observed a 78% (95% CI: 3-205, p = 0.038) increased risk of cardiovascular disease in participants who consumed artificially sweetened beverages more than 1 unit/day when compared with non-consumers. We did not observe significant associations between natural juice consumption and the two outcomes in IBD. Conclusion: Higher sugar- and artificially sweetened beverage consumption were associated with adverse cardiovascular and mortality outcomes in IBD. These exploratory results were consistent with the evidence in the general population and highlighted the importance of diet management in individuals with IBD.

Smoking, alcohol consumption, and 24 gastrointestinal diseases: Mendelian randomization analysis.

Background: Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases. Methods: Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption. Results: Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis, and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn's disease, and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, and acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 20 associations persisted after adjusting for genetically predicted alcohol consumption. Genetically predicted higher alcohol consumption was associated with increased risk of duodenal ulcer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain statistically significant after adjustment for genetic predisposition to smoking initiation. Conclusions: This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases. Funding: The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.

People who smoke cigarettes or drink large amounts of alcohol are more likely to develop disorders with their digestive system. But it is difficult to prove that heavy drinking or smoking is the primary cause of these gastrointestinal diseases. For example, it is possible that having a digestive disorder makes people more likely to take up these habits to reduce pain or discomfort caused by the illness (an effect known as reverse causation). The association may also be the result of confounding factors, such as age or diet, which contribute to digestive problems as well as the health outcomes of smoking and drinking. Additionally, many people who smoke also drink alcohol and vice versa, making it challenging to determine if one or both behaviors contribute to the disease. One solution is to employ Mendelian randomization which uses genetics to determine if two variables are linked. Using this statistical approach, Yuan, Chen, Ruan et al. investigated if people who display genetic variants that predispose someone to becoming a smoker or drinker are at greater risk of developing certain digestive disorders. This reduces the possibility of confounding and reverse causation, as any association between genetic variants will have been present since birth, and will have not been impacted by external factors. Yuan, Chen, Ruan et al. used data from two studies that had collected the genetic and health information of thousands of people living in the United Kingdom or Finland. The analyses revealed that genetic variants associated with cigarette smoking increase the risk of 20 of the 24 gastrointestinal diseases investigated. This risk persisted for most of the disorders, even after adjusting for genes linked with alcohol consumption. Further analysis showed that genetic variants linked to heavy drinking increase the risk of duodenal ulcer, alcoholic liver disease, cirrhosis, and chronic pancreatitis. However, accounting for smoking-linked genes eliminated the relationship with duodenal ulcer. These findings suggest that smoking has detrimental effects on gastrointestinal health. Reducing the number of people who start smoking or encouraging smokers to quit may help prevent digestive diseases. Even though there were fewer associations between heavy alcohol consumption and gastrointestinal illness, further studies are needed to investigate this relationship in more depth.

Gastrointestinal Consequences of Type 2 Diabetes Mellitus and Impaired Glycemic Homeostasis: A Mendelian Randomization Study.

OBJECTIVE: We conducted a Mendelian randomization (MR) study to examine the associations of type 2 diabetes and glycemic traits with gastrointestinal diseases (GDs). RESEARCH DESIGN AND METHODS: Uncorrelated genetic variants associated with type 2 diabetes (n = 231), fasting insulin (n = 38), fasting glucose (n = 71), and hemoglobin A1c (n = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with 23 common GDs were obtained from the FinnGen and UK Biobank studies and other large consortia. RESULTS: Genetic liability to type 2 diabetes was associated with the risk of 12 GDs. Per 1-unit increase in the log-transformed odds ratio (OR) of type 2 diabetes, the OR was 1.06 (95% CI, 1.03-1.09) for gastroesophageal reflux disease, 1.12 (95% CI, 1.07-1.17) for gastric ulcer, 1.11 (95% CI, 1.03-1.20) for acute gastritis, 1.07 (95% CI, 1.01-1.13) for chronic gastritis, 1.08 (95% CI, 1.03-1.12) for irritable bowel syndrome, 1.04 (95% CI, 1.01-1.07) for diverticular disease, 1.08 (95% CI, 1.02-1.14) for acute pancreatitis, 1.09 (95% CI, 1.05-1.12) for cholelithiasis, 1.09 (95% CI, 1.05-1.13) for cholelithiasis with cholecystitis, 1.29 (95% CI, 1.17-1.43) for nonalcoholic fatty liver disease, 1.12 (95% CI, 1.03-1.21) for liver cirrhosis, and 0.93 (95% CI, 0.89-0.97) for ulcerative colitis. Genetically predicted higher levels of fasting insulin and glucose were associated with six and one GDs, respectively. CONCLUSIONS: Associations were found between genetic liability to type 2 diabetes and an increased risk of a broad range of GDs, highlighting the importance of GD prevention in patients with type 2 diabetes.

Birth weight, childhood obesity, adulthood obesity and body composition, and gastrointestinal diseases: a Mendelian randomization study.

OBJECTIVE: This Mendelian randomization study aimed to investigate the associations of birth weight, childhood BMI, and adulthood BMI, waist-hip ratio, and body composition with the risk of 24 gastrointestinal diseases. METHODS: Independent genetic instruments associated with the exposures at the genome-wide significance level (p < 5 × 10-8 ) were selected from corresponding large-scale genome-wide association studies. Summary-level data for gastrointestinal diseases were obtained from the UK Biobank, the FinnGen study, and large consortia of European ancestry. RESULTS: Genetically predicted higher levels of birth weight were associated with a lower risk of gastroesophageal reflux. Genetically predicted higher childhood BMI was associated with an increased risk of duodenal ulcer, nonalcoholic fatty liver disease, and cholelithiasis. However, the associations did not persist after adjusting for genetically predicted adulthood BMI. Genetically predicted higher adulthood BMI and waist-hip ratio were associated with 19 and 17 gastrointestinal diseases, respectively. Genetically predicted greater visceral adiposity was associated with an increased risk of 17 gastrointestinal diseases. There were no strong associations among genetically predicted whole-body fat and fat-free mass indices with gastrointestinal diseases. CONCLUSIONS: This study suggests that greater adulthood adiposity, measured as either BMI, waist-hip ratio, or visceral adipose tissue, is causally associated with an increased risk of a broad range of gastrointestinal diseases in the European population.

Depression and 24 gastrointestinal diseases: a Mendelian randomization study.

The causality of the association between depression and gastrointestinal diseases is undetermined. We conducted Mendelian randomization (MR) analyses to systematically explore the associations of depression with 24 gastrointestinal diseases. Independent genetic variants associated with depression at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analysis was conducted to explore the mediation effects of body mass index, cigarette smoking, and type 2 diabetes. After multiple-testing corrections, genetic liability to depression was associated with an increased risk of irritable bowel syndrome, non-alcohol fatty liver disease, alcoholic liver disease, gastroesophageal reflux, chronic pancreatitis, duodenal ulcer, chronic gastritis, gastric ulcer, diverticular disease, cholelithiasis, acute pancreatitis, and ulcerative colitis. For the causal effect of genetic liability to depression on non-alcoholic fatty liver disease, a substantial proportion was mediated by body mass index. Genetic predisposition to smoking initiation mediated half of effect of depression on acute pancreatitis. This MR study suggests that depression may play a causal role in many gastrointestinal diseases.

Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses.

BACKGROUND: Identifying new drug targets for inflammatory bowel disease (IBD) is urgently needed. The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) and colocalization analyses to identify possible targets for IBD. METHODS: Summary-level data of 4907 circulating protein levels were extracted from a large-scale protein quantitative trait loci study including 35,559 individuals. Genetic associations with IBD and its subtypes were obtained from the Inflammatory Bowel Disease Genetics Consortium (25,024 cases and 34,915 controls), the FinnGen study (7206 cases and 253,199 controls), and the UK Biobank study (7045 cases and 449,282 controls). MR analysis was conducted to estimate the associations between protein and IBD risk. The colocalization analysis was used to examine whether the identified proteins and IBD shared casual variants. FINDINGS: Genetically predicted levels of 3, and 5 circulating proteins were associated with IBD and ulcerative colitis (UC), respectively. With high supporting evidence of colocalization, genetically predicted MST1 (macrophage stimulating 1) and HGFAC (hepatocyte growth factor activator) levels were inversely associated with IBD risks. The associations of STAT3 (signal transducer and activator of transcription 3), MST1, CXCL5 (C-X-C motif chemokine ligand 5), and ITPKA (inositol-trisphosphate 3-kinase A) with the risk of UC were supported by colocalization analysis. INTERPRETATION: The proteome-wide MR investigation identified many proteins associated with the risk of IBD. MST1, HGFAC, STAT3, ITPKA, and CXCL5 deserve further investigation as potential therapeutic targets for IBD. FUNDING: SCL is supported by research grants from the Swedish Research Council for Health, Working Life and Welfare (Forte; grant no. 2018-00123) and the Swedish Research Council (Vetenskapsrådet; grant no. 2019-00977). XYW is supported by research grants from the National Natural Science Foundation of China (81970494) and Key Project of Research and Development Plan of Hunan Province (2019SK2041). XL is supported by research grants from the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001).

Antioxidants, minerals and vitamins in relation to Crohn's disease and ulcerative colitis: A Mendelian randomization study.

BACKGROUND: Evidence for antioxidants, minerals and vitamins in relation to the risk of Crohn's disease (CD) and ulcerative colitis (UC) is limited and inconsistent. This mendelian randomization (MR) study aimed to examine the causal associations of circulating levels of antioxidants, minerals and vitamins with CD and UC. METHODS: Single-nucleotide polymorphisms associated with antioxidants (beta-carotene, lycopene and uric acid), minerals (copper, calcium, iron, magnesium, phosphorus, zinc and selenium), and vitamins (folate, vitamins A, B6, B12, C, D, E and K1) were employed as instrumental variables. Genetic associations with CD and UC were extracted from the UK Biobank, the FinnGen study and the International Inflammatory Bowel Disease Genetics Consortium. The inverse variance weighted method and sensitivity analyses were performed. RESULTS: Genetically predicted higher lycopene (OR = 0.94, 95% CI: 0.91-0.97), vitamins D (OR = 0.65, 95% CI: 0.54-0.79) and K1 (OR = 0.93, 95% CI: 0.90-0.97) levels were inversely associated with CD risk, whereas genetically predicted higher magnesium (OR = 1.53, 95% CI: 1.23-1.90) levels were positively associated with CD risk. Higher levels of genetically predicted lycopene (OR = 0.91, 95% CI: 0.88-0.95), phosphorus (OR = 0.69, 95% CI: 0.58-0.82), selenium (OR = 0.91, 95% CI: 0.85-0.97), zinc (OR = 0.91, 95% CI: 0.89-0.94), folate (OR = 0.71, 95% CI: 0.56-0.92) and vitamin E (OR = 0.78, 95% CI: 0.69-0.88) were associated with reduced UC risk, whereas genetically predicted high levels of calcium (OR = 1.46, 95% CI: 1.22-1.76) and magnesium (OR = 1.24, 95% CI: 1.03-1.49) were associated with increased risk of UC. CONCLUSIONS: Our study provided evidence that circulating levels of antioxidants, minerals and vitamins might be causally linked to the development of IBD.

Rheumatoid arthritis and risk of site-specific cancers: Mendelian randomization study in European and East Asian populations.

BACKGROUND: The associations of rheumatoid arthritis (RA) with risk of site-specific cancers beyond lymphohematopoietic cancer have been scarcely explored. We conducted a Mendelian randomization investigation of the associations of RA with site-specific cancers in European and East Asian populations. METHODS: Independent genetic variants strongly associated with RA in European and East Asian populations were selected as instrumental variables from genome-wide association studies of 58,284 European individuals (14,361 cases and 43,923 controls) and 22,515 East Asian individuals (4873 cases and 17,642 controls), respectively. The associations of genetic variants with overall and 22 site-specific cancers were extracted from the UK Biobank study (n = 367,561), the FinnGen study (n = 260,405), Biobank Japan (n = 212,453), and international consortia. The associations for one outcome from different data sources were combined by meta-analysis. RESULTS: In the European population, the combined odds ratios per 1-unit increase in log odds of genetic liability to RA were 1.06 (95% confidence interval [CI] 1.03-1.10) for head and neck cancer, 1.06 (95% CI 1.02-1.10) for cervical cancer, 0.92 (95% CI 0.87-0.96) for testicular cancer, and 0.94 (95% CI 0.90-0.98) for multiple myeloma. In the East Asian population, the corresponding odds ratios were 1.17 (95% CI 1.06-1.29) for pancreatic cancer, 0.91 (95% CI 0.88-0.94) for breast cancer, and 0.90 (95% CI 0.84-0.96) for ovarian cancer. There were suggestive associations for breast and ovarian cancer and overall cancer in the European population. No other associations were observed. CONCLUSION: This study suggests that RA may play a role in the development of several site-specific cancers.

Endoscopists' Acceptance on the Implementation of Artificial Intelligence in Gastrointestinal Endoscopy: Development and Case Analysis of a Scale.

Background: The purpose of this paper is to develop and validate a standardized endoscopist acceptance scale for the implementation of artificial intelligence (AI) in gastrointestinal endoscopy. Methods: After investigating endoscopists who have previously used AI and consulting with AI experts, we developed a provisional scale to measure the acceptance of AI as used in gastrointestinal endoscopy that was then distributed to a sample of endoscopists who have used AI. After analyzing the feedback data collected on the provisional scale, we developed a new formal scale with four factors. Cronbach's alpha, confirmatory factor analysis (CFA), content validity, and related validity were conducted to test the reliability and validity of the formal scale. We also constructed a receiver operating characteristic (ROC) curve in order to determine the scale's ability to distinguish higher acceptance and satisfaction. Results: A total of 210 valid formal scale data points were collected. The overall Cronbach's alpha was 0.904. All the factor loadings were >0.50, of which the highest factor loading was 0.86 and the lowest was 0.54 (AVE = 0.580, CR = 0.953). The correlation coefficient between the total score of the scale and the satisfaction score was 0.876, and the area under the ROC curve was 0.949 ± 0.031. Endoscopists with a score higher than 50 tend to be accepting and satisfied with AI. Conclusion: This study yielded a viable questionnaire to measure the acceptance among endoscopists of the implementation of AI in gastroenterology.