It has been proved that glucagon-like peptide-1 receptor (GLP1R) agonists have positive effects on renal outcomes in diabetic patients. However, it remains unknown whether GLP1R agonists could provide similar protection against other kidney diseases.

We performed two-sample Mendelian randomization (MR) analyses to determine the causal effects of GLP1R agonists on multiple kidney diseases. Exposure to GLP1R agonist was proxied by the available cis-eQTLs for GLP1R. Primary outcomes included the risk assessment for diabetic nephropathy, IgA nephropathy, membranous nephropathy, nephrotic syndrome, chronic kidney disease, acute glomerulonephritis, chronic glomerulonephritis and calculus of kidney/ureter. Type 2 diabetes and body mass index were used as positive control. Two-stage network MR analyses were conducted to assess the mediation effect of inflammatory proteins on the relationships between GLP1R agonists and kidney diseases.

After meta-analyses of both discovery and validation cohorts, genetically proxied GLP1R agonist was found to significantly associated with a decreased risk of diabetic nephropathy (OR = 0.72, 95%CI = 0.54-0.97, p = 0.031) and IgA nephropathy (OR = 0.58, 95%CI = 0.36-0.94, p = 0.027). Two-stage network MR revealed that there was an indirect effect of GLP1R agonist on IgA nephropathy through signaling lymphocytic activation molecule family member 1 (SLAMF1), with a mediated proportion of 34.27% (95% CI, 1.47-67.03%, p = 0.041) of the total effect.

The findings of current study presented genetic proof for the potential protective effects of GLP1R agonists in the development of diabetic nephropathy and IgA nephropathy, offering a novel sight for future mechanistic and clinical applications.

Observational epidemiological studies in Mexico have shown high mortality risks associated with type 2 diabetes (T2D). However, it is unclear whether these relationships are wholly causal. We aimed to assess the association of genetically-predicted T2D liability with risk of death in Mexico.

Between 1998 and 2004, 150,000 men and women were recruited from Mexico City and followed-up until September 2022 for cause-specific mortality. Mendelian randomisation analyses, using a genetic risk score (GRS) comprising 1055 established T2D-associated risk variants, estimated associations with risk of all-cause and cause-specific mortality at ages 35-74.

Among 121,433 included participants with a mean (standard deviation) age of 51 (11), 68% (n = 82,249) were women and 18% (n = 21,371) had T2D. The GRS explained 6.3% of T2D liability and was not associated with major potential confounders of the T2D-mortality relationship. During a median (interquartile range) of 20.2 (19.4-21.4) years' follow-up, 12,293 participants died. Genetically-predicted T2D liability was associated with a death rate ratio (RR) of 1.29 (95% confidence interval [CI] 1.23-1.36) per trebling in genetically-predicted odds of T2D. There were particularly strong associations with death from renal disease (n = 1696; RR 2.29 [95% CI 1.99-2.64]) and acute diabetic crises (n = 509; RR 2.27 [1.75-2.93]) and weaker, but still strong, associations with death from vascular disease (n = 3226; RR 1.31 [1.19-1.46]) and infection (n = 2437; RR 1.21 [1.07-1.36]). Genetically-predicted T2D liability was not clearly associated with death from cancer (n = 2016; RR 1.00 [95% CI 0.88-1.14]) or cirrhosis (n = 895; RR 0.90 [0.74-1.10]).

T2D is causally associated with death from vascular, renal and infectious diseases. Its prevention and effective management could substantially reduce premature deaths in Mexico, where T2D is common.

Wellcome Trust, the Mexican Health Ministry, the National Council for Science and Technology (CONACyT) for Mexico, Cancer Research UK, British Heart Foundation, Kidney Research UK, UK Medical Research Council, AstraZeneca, Regeneron.

Most analyses of hemoglobin A1c (HbA1c) and multiple common diseases have focused on European populations, thus there is a need for Mendelian randomization phenome-wide association study (MR-PheWAS) in East Asian populations. We used MR-PheWAS to investigate the potential causal associations between HbA1c and 159 types of diseases in the Biobank Japan dataset, employing the inverse variance weighted as the primary statistical approach, supplemented by MR-Egger and weighted median analyses. Additionally, multiple sensitivity analyses were conducted to assess heterogeneity and pleiotropy. High HbA1c levels are associated with an increased risk of type 1 diabetes (odds ratio [OR] = 4.07; 95% confidence interval [CI]: 2.34~7.07), type 2 diabetes (OR = 4.76; 95% CI: 3.01~7.55), cataract (OR = 1.33; 95% CI: 1.18~1.51), diabetic nephropathy (OR = 5.70; 95% CI: 2.24~14.46), and peripheral arterial disease (OR = 1.62; 95% CI: 1.29~2.04). Conversely, elevated HbA1c levels are associated with a reduced risk of asthma (OR = 0.76; 95% CI: 0.67~0.86), breast cancer (OR = 0.75; 95% CI: 0.65~0.87), and cerebral aneurysm (OR = 0.71; 95% CI: 0.57~0.88). The results of the causal association between HbA1c and numerous diseases in East Asian populations provides insights for the region's specialized glycemic control and disease prevention programs, as well as new preventive and treatment options.

Previous studies have indicated that patients with uterine fibroids (UF) may have an elevated risk of cardiovascular disease (CVD), although the causal relationship between UF and CVD remains unclear. In this Mendelian randomization (MR) study, we aimed to investigate the causal association between genetic susceptibility to UF and the risk of developing CVD. We extracted summary statistics for single nucleotide polymorphisms associated with UF and 5 CVDs from multiple databases for further analysis. First, we used linkage disequilibrium score regression to assess the genetic correlation across the genome. Next, we performed univariate MR (UVMR), and to ensure the robustness of our results, we conducted sensitivity analyses using several methods. Additionally, we applied multivariable MR (MVMR) to adjust for potential confounders. The linkage disequilibrium score regression results showed that there was no genetic correlation between UF and coronary heart disease, myocardial infarction (MI), atrial fibrillation, heart failure, cardioembolic stroke (CES). The UVMR revealed a significant association between UF and CES (OR = 1.113, 95% confidence interval [CI]: 1.018-1.218, P = .019, PFDR = .047) and a suggestive causal relationship between UF and MI (OR = 0.943, 95% CI: 0.899-0.989, P = .015, PFDR = .075). In the MVMR analysis, after adjusting for a range of potential confounders, the causal relationships between UF and both CES (OR = 1.104, 95% CI = 1.012-1.205, P = .027) and MI (OR = 0.935, 95% CI = 0.882-0.992, P = .025) remained significant. Our study found that UF increase the risk of CES but decrease the risk of MI, providing a theoretical basis for further research into the underlying mechanisms.

Introduction: Diverticular disease, once considered a rare geriatric gastrointestinal condition, has now become a prevalent disorder associated with increased morbidity and healthcare costs. The spectrum of complications from diverticular disease ranges from incidental findings to more serious issues such as bleeding and diverticulitis. Symptomatic diverticular disease represents a significant economic burden in the western world. Diabetes mellitus is a major global health issue. As global aging accelerates, geriatric syndromes such as diabetes mellitus (DM) and diverticular disease (DD) are becoming increasingly prevalent. Understanding their interplay is critical, particularly within the geriatric population. Both conditions are linked to lifestyle, dietary habits, and changes in gut physiology. Additionally, age-related alterations in the gut microbiome and immune system make this association more complex, contributing to morbidity and healthcare burdens in older adults. The primary aim of this review is to provide an update on the association between diabetes mellitus and diverticular disease. Methods: This narrative review explores the association between diabetes mellitus and diverticular disease. Relevant articles were identified by searching major databases. Results: Risk factors for diverticular disease include insulin resistance, diabetes mellitus, smoking, non-alcoholic fatty liver disease, lack of physical activity, a low-fibre diet, and a high-carbohydrate diet. These risk factors are also associated with the development of diabetes mellitus. Major population studies indicate that diabetes can either increase the risk of diverticular disease or have a neutral impact. A complication of diabetes mellitus includes impaired intestinal peristalsis and enteric nervous system dysfunction, which can ultimately lead to the formation of intestinal diverticula. High-calorie foods low in fibre are a staple in the diets of many type 2 diabetes mellitus patients, contributing to gut dysbiosis. A detrimental consequence of dysbiosis is a breach in the protective intestinal barrier, which promotes the development of diverticulosis. Conclusions: Diabetes mellitus may be associated with diverticular disease, and the risk factors that contribute to diabetes mellitus can also be linked to diverticular disease. Further studies are needed to explore the complex relationship between diabetes mellitus and diverticular disease.

Membranous nephropathy (MN) has not yet been fully elucidated regarding its relationship with Type I and II Diabetes. This study aims to evaluate the causal effect of multiple types of diabetes and MN by summarizing the evidence from the Mendelian randomization (MR) study.

The statistical data for MN was obtained from a GWAS study encompassing 7979 individuals. Regarding diabetes, fasting glucose, fasting insulin, and HbA1C data, we accessed the UK-Biobank, within family GWAS consortium, MAGIC, FinnGen database, MRC-IEU, and Neale Lab, which provided sample sizes ranging from 17,724 to 298,957. As a primary method in this MR analysis, we employed the Inverse Variance Weighted (IVW), Weighted Median, Weighted mode, MR-Egger, Mendelian randomization pleiotropy residual sum, and outlier (MR-PRESSO) and Leave-one-out sensitivity test. Reverse MR analysis was utilized to investigate whether MN affects Diabetes. Meta-analysis was applied to combine study-specific estimates.

It has been determined that type 2 diabetes, gestational diabetes, type 1 diabetes with or without complications, maternal diabetes, and insulin use pose a risk to MN. Based on the genetic prediction, fasting insulin, fasting blood glucose, and HbA1c levels were not associated with the risk of MN. No heterogeneity, horizontal pleiotropy, or reverse causal relationships were found. The meta-analysis results further validated the accuracy.

The MR analysis revealed the association between MN and various subtypes of diabetes. This study has provided a deeper understanding of the pathogenic mechanisms connecting MN and diabetes.

The molecular mechanisms underlying the association between type 2 diabetes (T2D) and gastrointestinal (GI) disease are unclear. To identify protein pathways, we conducted a two-stage network Mendelian randomisation (MR) study.

Genetic instruments for T2D were obtained from a large-scale summary-level genome-wide meta-analysis. Genetic associations with blood protein levels were obtained from three genome-wide association studies on plasma proteins (i.e. the deCODE study as the discovery and the UKB-PPP and Fenland studies as the replication). Summary-level data on 10 GI diseases were derived from genome-wide meta-analysis of the UK Biobank and FinnGen. MR and colocalisation analyses were performed. Pathways were constructed according to the directionality of total and indirect effects, and corresponding proportional mediation was estimated. Druggability assessments were conducted across four databases to prioritise protein mediators.

Genetic liability to T2D was associated with 69 proteins in the discovery protein dataset after multiple testing corrections. All associations were replicated at the nominal significance level. Among T2D-associated proteins, genetically predicted levels of nine proteins were associated with at least one of the GI diseases. Genetically predicted levels of SULT2A1 (odds ratio = 1.98, 95% CI 1.80-2.18), and ADH1B (odds ratio = 2.05, 95% CI 1.43-2.94) were associated with cholelithiasis and cirrhosis respectively. SULT2A1 and cholelithiasis (PH4 = 0.996) and ADH1B and cirrhosis (PH4 = 0.931) have strong colocalisation support, accounting for the mediation proportion of 72.8% (95% CI 45.7-99.9) and 42.9% (95% CI 15.5-70.4) respectively.

The study identified some proteins mediating T2D-GI disease associations, which provided biological insights into the underlying pathways.

Type II diabetes mellitus (T2DM) has been associated with increased risk of colon cancer (CC) and worse prognosis in patients with metastases. The effects of T2DM on postoperative chemoresistance rate (CRR) and long-term disease-free survival (DFS) and overall survival (OS) in patients with stage III CC who receive curative resection remain controversial.

To investigate whether T2DM or glycemic control is associated with worse postoperative survival outcomes in stage III CC.

This retrospective cohort study included 278 patients aged 40-75 years who underwent surgery for stage III CC from 2018 to 2021. Based on preoperative T2DM history, the patients were categorized into non-DM (n = 160) and DM groups (n = 118). The latter was further divided into well-controlled (n = 73) and poorly controlled (n = 45) groups depending on the status of glycemic control. DFS, OS, and CRR were compared between the groups and Cox regression analysis was used to identify risk factors.

Patients in the DM and non-DM groups demonstrated similar DFS, OS, and CRR (DFS: 72.03% vs 78.75%, P = 0.178; OS: 81.36% vs 83.12%, P = 0.638; CRR: 14.41% vs 7.5%, P = 0.063). Poorly controlled DM was associated with a significantly worse prognosis and higher CRR than well-controlled DM (DFS: 62.22% vs 78.07%, P = 0.021; OS: 71.11% vs 87.67%, P = 0.011; CRR: 24.40% vs 8.22%, P = 0.015). High preoperative fasting plasma glucose [DFS: Hazard ratio (HR) = 2.684, P < 0.001; OS: HR = 2.105, P = 0.019; CRR: HR = 2.214, P = 0.005] and glycosylated hemoglobin levels (DFS: HR = 2.344, P = 0.006; OS: HR = 2.119, P = 0.021; CRR: HR = 2.449, P = 0.009) indicated significantly poor prognosis and high CRR, while T2DM history did not (DFS: HR = 1.178, P = 0.327; OS: HR = 0.933, P = 0.739; CRR: HR = 0.997, P = 0.581).

Increased preoperative fasting plasma glucose and glycosylated hemoglobin levels, but not T2DM history, were identified as risk factors associated with poor postoperative outcomes and high CRR in patients with stage III CC.

Cholelithiasis and gastroesophageal reflux disease (GERD) contribute to significant health concerns. We aimed to investigate the potential observational, causal, and genetic relationships between cholelithiasis and GERD.

The observational correlations were assessed based on the prospective cohort study from UK Biobank. Then, by leveraging the genome-wide summary statistics of cholelithiasis (N = 334,277) and GERD (N = 332,601), the bidirectional causal associations were evaluated using Mendelian randomization (MR) analysis. Subsequently, a series of genetic analyses was used to assess the genetic correlation, shared loci, and genes between cholelithiasis and GERD.

The prospective cohort analyses revealed a significantly increased risk of GERD in individuals with cholelithiasis (hazard ratio [HR] = 1.99; 95% confidence interval [CI], 1.89-2.10) and a higher risk of cholelithiasis among patients with GERD (HR = 2.30; 95% CI, 2.18-2.44). The MR study indicated the causal effect of genetic liability to cholelithiasis on the incidence of GERD (odds ratio [OR] = 1.08; 95% CI, 1.05-1.11) and the causal effect of genetic predicted GERD on cholelithiasis (OR = 1.15; 95% CI, 1.02-1.31). In addition, cholelithiasis and GERD exhibited a strong genetic association. Cross-trait meta-analyses identified 5 novel independent loci shared between cholelithiasis and GERD. Three shared genes, including SUN2, CBY1, and JOSD1, were further identified as novel risk genes.

The elucidation of the shared genetic basis underlying the phenotypic relationship of these 2 complex phenotypes offers new insights into the intrinsic linkage between cholelithiasis and GERD, providing a novel research direction for future therapeutic strategy and risk prediction.

Sleep apnea (SA), associated with absent neural output, is characterised by recurrent episodes of hypoxemia and repeated arousals during sleep, resulting in decreased sleep quality and various health complications. Mitochondrial DNA copy number (mtDNA-CN), an easily accessible biomarker in blood, reflects mitochondrial function. However, the causal relationship between mtDNA-CN and SA remains unclear. This study aimed to investigate the causality between mtDNA-CN and SA while identifying potential mediating brain imaging phenotypes (BIPs).

Two-sample bidirectional Mendelian randomisation (MR) analysis was performed to estimate the causal relationship between mtDNA-CN and SA, with further validation using Bayesian framework-based MR analysis. A two-step approach was employed to evaluate causal relationships between BIPs, mtDNA-CN and SA, utilising the "product of coefficients" method to assess the mediating effects of BIPs. Multiple testing errors were corrected using the Benjamini-Hochberg method.

Genetically predicted mtDNA-CN had a negative causal effect on SA (OR = 0.859, 95% CI = 0.785-0.939, P = 3.20×10-4), whereas SA did not have a causal effect on mtDNA-CN (OR = 1.0056, 95% CI = 0.9954-1.0159, P = 0.2825). Among 3935 BIPs, two features related to white matter microstructure served as partial mediators: the second eigenvalue from diffusion MRI data analysed by tract-based spatial statistics in the right posterior thalamic radiation, with a mediation proportion of 11.37% (P = 0.0450), and fractional anisotropy in the right sagittal stratum, with a mediation proportion of 12.79% (P = 0.0323).

This study demonstrated a causal relationship between mtDNA-CN and SA, with specific brain white matter microstructure phenotypes potentially acting as mediators. These findings highlight the potential of mtDNA-CN as a biomarker for SA and underscore its relevance in guiding future therapeutic strategies targeting mitochondrial health and brain white matter microstructure.

The genetic relationship between daily physical activity (PA) levels and functional outcome after ischemic stroke remains unclear. This study aimed to investigate the genetic associations of PA on functional outcome after ischemic stroke using Mendelian randomization (MR).

We conducted two-sample MR analyses using genome-wide association studies (GWASs). This included data on light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) from the UK Biobank, and functional outcome after ischemic stroke from the Genetics of ischemic stroke Functional Outcome (GISCOME). The inverse-variance weighted (IVW) method served as our primary MR analysis approach, supplemented by several sensitivity analyses.

In univariable Mendelian randomization (UVMR) analysis, MVPA was significantly associated with a reduced risk of poor functional outcome (OR = 0.15, 95 % CI = 0.04-0.56, P < 0.01), whereas LPA had no genetic relationship (OR = 0.37, 95 % CI = 0.002-51.40, P = 0.69). In multivariate Mendelian randomization (MVMR) analysis adjusting for potentially confounding traits including hypertension, type 2 diabetes, and smoking, the overall patterns between MVPA and poststroke outcome remained (OR = 0.23, 95 % CI = 0.07-0.78, P = 0.02).

MVPA is a protective factor for functional outcome after ischemic stroke. This finding is important for the rehabilitation and functional outcome of stroke patients.

Type 2 diabetes mellitus (T2DM) is a pivotal chronic disease with an increasing prevalence. Recent studies have found associations between T2DM and the development of central nervous system (CNS) tumours, a special class of solid tumours with an unclear pathogenesis. In this study, we aimed to explore the relationship between T2DM and certain glycaemic factors with common CNS tumours by using genetic data to conduct Mendelian randomization (MR) and co-localisation analysis. We found a causal relationship between T2DM and glioblastoma, fasting glucose and spinal cord tumours, glycated haemoglobin and spinal cord tumours, and insulin-like growth factor-1 and spinal cord tumours, pituitary tumours, and craniopharyngiomas. These results clarify the relationship between T2DM, glucose-related factors, and common CNS tumours, and they provide valuable insight into further clinical and basic research on CNS tumours, as well as new ideas for their diagnosis and treatment.

Currently, research on the role of B cells in esophageal cancer (EC) is limited, and existing studies on their impact are controversial. Therefore, this study was conducted to elucidate the complex causal relationship between B cells and EC, expand the understanding of esophageal cancer immunology.

Bidirectional two-sample Mendelian randomization (MR) was performed to assess the causal relationships between 190 B cell phenotypes and EC. To complement the MR analysis, Bayesian Weighted Mendelian Randomization (BWMR) was employed, and sensitivity analyses were conducted to evaluate the robustness of the findings. Positive results were further validated in independent cohorts of esophageal cancer studies. In addition, RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) were utilized for validation, incorporating B cell-related gene expression analysis and functional enrichment analysis to support the MR findings.

In the primary analysis, significant causal relationships were observed between 5 B cell types and the risk of EC; the onset of EC was causally linked to 3 B cell phenotypes. Validation in other cohorts revealed that 4 outcomes aligned with the primary analysis, included were CD19 on IgD + CD38-, CD20 on IgD- CD27-, CD20 on IgD- CD38br, and CD38 on PB/PC. Further validation using RNA-seq data showed that CD38 mRNA was significantly overexpressed in EC tissues, whereas CD19 and MS4A1 mRNA levels did not differ significantly between tumor and normal tissues. Functional enrichment analysis revealed that CD19, MS4A1, and CD38 are involved in multiple tumor-related immune pathways, suggesting their pivotal role in regulating the tumor immune microenvironment.

Our study suggests a potential connection between B cell phenotypes and EC through bidirectional two-sample MR combined with BWMR analysis, providing a preliminary basis for future research.

The relationship of hypoglycemic drugs, inflammatory proteins and gallbladder diseases remain unknown.

Four hypoglycemic drugs were selected as exposure: glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and metformin. The outcome were two gallbladder diseases: cholecystitis and cholelithiasis. Mendelian Randomization (MR) was employed to determine the association between hypoglycemic drugs and gallbladder diseases.

DPP-4i and SGLT-2i had no effect on cholecystitis and cholelithiasis. However, a causal relationship was found between inhibition of ETFDH gene, a target of metformin expressed in cultured fibroblasts, and cholelithiasis (OR: 0.84, 95 %CI: (0.72,0.97), p = 0.021), as well as between GLP1R expression in the brain caudate basal ganglia and cholecystitis (OR: 1.29, 95 %CI: (1.11,1.49), p = 0.001). The effect of ETFDH inhibition on cholelithiasis through Interleukin-10 receptor subunit beta (IL-10RB) levels and Neurotrophin-3 (NT-3) levels, with a mediated proportion of 8 % and 8 %, respectively.

Metformin plays a protective role in cholelithiasis, while GLP-1RA have a harmful effect on the risk of cholecystitis. Metformin may reduce the risk of cholelithiasis by modulating the levels of Neurotrophin-3 (NT-3) and Interleukin-10 receptor subunit beta (IL-10RB). Further clinical and mechanistic studies are required to confirm these findings.

The immune system and inflammatory processes play crucial roles in the development of esophageal cancer (EC). This study aimed to investigate the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC, with a particular focus on the mediating role of circulating inflammatory proteins. Utilizing public genetic data, we applied a 2-sample Mendelian Randomization (MR) method to examine the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC. Comprehensive sensitivity analyses were conducted to assess the robustness, heterogeneity, and horizontal pleiotropy of the MR results. Additionally, a 2-step MR method was employed to quantify the impact and proportion of immune cell phenotypes mediated by circulating inflammatory proteins on EC. Eleven immune cell phenotypes and 1 inflammatory cytokine were found to have causal relationships with EC, with results stable across all sensitivity analyses. Mediation analyses revealed that only 2 cell phenotypes had causal relationships with EC through interleukin-10: CD3 on human leukocyte antigen-DR (HLA-DR)+ T cells (mediation effect = -0.009; mediation proportion = 12.01%) and monocytic myeloid-derived suppressor cell absolute count (mediation effect = 0.018; mediation proportion = 18.97%). This study enhances the understanding of the causal relationships between immune cells, circulating inflammatory proteins, and EC. The findings highlight the potential mediating role of interleukin-10, providing new insights into the mechanisms by which immune cells may influence esophageal tumorigenesis.

To examine the bidirectional association between type 2 diabetes (T2D) and irritable bowel syndrome (IBS) in a large prospective population cohort.

Participants free of IBS at baseline in the UK Biobank were included in the analysis of T2D and incident IBS (cohort 1), with 11 140 T2D patients and 413 979 non-T2D patients. Similarly, those free of T2D at baseline were included in the analysis of IBS and incident T2D (cohort 2), with 21 944 IBS patients and 413 979 non-IBS patients. Diagnoses of T2D and IBS were based on International Classification of Disease-10 codes. The Cox proportional hazards model was used to estimate adjusted hazard ratios (HRs).

In cohort 1, 8984 IBS cases were identified during a median 14.5-year follow-up. Compared with non-T2D, T2D patients had a 39.0% increased risk of incident IBS (HR = 1.39, 95% confidence interval [CI]: 1.23-1.56, P < .001), with a higher IBS risk in those with higher fasting blood glucose levels (HR = 1.43, 95% CI: 1.19-1.72, P < .001) or longer T2D duration (HR = 1.47, 95% CI: 1.23-1.74, P < .001). In cohort 2, 29 563 incident T2D cases were identified. IBS patients had an 18.0% higher risk of developing T2D versus non-IBS patients (HR = 1.18, 95% CI: 1.12-1.24, P < .001). A similar excess T2D risk was observed in IBS patients with a duration of either less than 10 years, or of 10 years or longer. Further sensitivity analysis and subgroup analysis indicated consistent findings.

T2D and IBS exhibit a bidirectional association, with an increased risk of co-morbidity. Awareness of this association may improve the prevention and management of both diseases.

Loneliness-the subjective experience of social disconnection-is now widely regarded as a health risk factor. However, whether the associations between loneliness and multiple diseases are consistent with causal effects remains largely unexplored. Here we combined behavioural, genetic and hospitalization data from the UK Biobank to examine the associations of loneliness with a wide range of non-overlapping diseases. During a median 12.2-year follow-up, loneliness was associated with greater risks in 13 of 14 disease categories and 30 of 56 individual diseases considered. Of the 30 diseases significantly associated with loneliness, 26 had genetic data available for Mendelian randomization (MR) analyses. After Benjamini‒Hochberg correction and multiple sensitivity analyses within the MR framework, non-causal associations were identified between genetic liability to loneliness and 20 out of the 26 specific diseases, including cardiovascular diseases, type 2 diabetes mellitus, obesity, chronic liver diseases, chronic kidney disease, most neurological diseases and the other common diseases. Genetic liability to loneliness was only potentially causally associated with the remaining six diseases. Socioeconomic factors, health behaviours, baseline depressive symptoms and comorbidities largely explained the associations between loneliness and diseases. Overall, our study revealed a dissociation between observational and genetic evidence regarding the associations of loneliness with multiple diseases. These findings suggest that loneliness may serve as a potential surrogate marker rather than a causal risk factor for most diseases tested here.

Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by reduced responsiveness of body cells to insulin, leading to elevated blood sugar levels. CNOT6L is involved in glucose metabolism, insulin secretion regulation, pancreatic beta-cell proliferation, and apoptosis. These functions may be closely related to the pathogenesis of T2D. However, the exact molecular mechanisms linking CNOT6L to T2D remain unclear. Therefore, this study aims to elucidate the role of CNOT6L in T2D.

The T2D datasets GSE163980 and GSE26168 profiles were downloaded from the Gene Expression Omnibusdatabase generated by GPL20115 and GPL6883.The R package limma was used to screen differentially expressed genes (DEGs). A weighted gene co-expression network analysis was performed. Construction and analysis of the protein-protein interaction (PPI) network, functional enrichment analysis, gene set enrichment analysis, and comparative toxicogenomics database (CTD) analysis were performed. Target Scan was used to screen miRNAs that regulate central DEGs. The results were verified by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), western blotting (WB), and blood glucose measurements in mice.

A total of 1951 DEGs were identified. GO and KEGG enrichment analysis revealed that differentially expressed genes were mainly enriched in the insulin signaling pathway, ECM-receptor interaction, and PPAR signaling pathway. Metascape analysis indicated enrichment primarily in the cAMP signaling pathway and enzyme-linked receptor protein signaling pathway. WGCNA analysis yielded 50 intersecting genes. PPI network construction and algorithm identification identified two core genes (CNOT6L and GRIN2B), among which CNOT6L gene was associated with multiple miRNAs. CTD analysis revealed associations of core genes with type 2 diabetes, diabetic complications, dyslipidemia, hyperglycemia, and inflammation. WB and RT-qPCR results showed that in different pathways, CNOT6L protein and mRNA levels were upregulated in type 2 diabetes.

CNOT6L is highly expressed in type 2 diabetes mellitus, and can cause diabetes complications, inflammation and other physiological processes by regulating miRNA, PPAR and other related signaling pathways, with poor prognosis. CNOT6L can be used as a potential therapeutic target for type 2 diabetes.

The objective of this study was to analyze the causal relationship between Neuroticism and aortic aneurysm using Mendelian randomization (MR). The study aimed to establish a foundation for the development of effective prevention and treatment strategies.

Genetic association data for Neuroticism were obtained from the UK Biobank, which included 393,411 individuals and 11,968,760 single nucleotide polymorphisms (SNPs). Genetic association data for aortic aneurysm were obtained from a genome-wide association study (GWAS), which included 479,194 individuals and 24,191,825 SNPs. Heterogeneity was assessed using the Cochran's Q statistic test. The study also utilized the MR Pleiotropy RESidual Sum and Outlier (Mr-PRESSO) test, as well as the MR-Egger regression method, to examine horizontal pleiotropy and determine the reliability of the findings through the leave-one-out method.

Forward MR analysis showed that the risk of aortic aneurysm was elevated in individuals with genetically predicted Neuroticism compared to those without Neuroticism (OR = 1.1315, 95 % CI: 1.0269-1.2468; P = 0.0126). The Cochran's Q test showed no heterogeneity (P > 0.05), and the MR-PRESSO test did not identify instrumental variables of horizontal pleiotropy (P > 0.05). The MR analysis remained robust after removing SNPs one by one. Inverse MR analysis did not observe an association between aortic aneurysm and having Neuroticism OR = 1.030, 95 % CI: 0.9459-1.118, P = 0.488).

Our study has established a clear causal relationship between genetically determined Neuroticism and the development of aortic aneurysms. It is therefore important to intensify screening and prevention efforts for aortic aneurysms in neurotic patients. It also opens new avenues for exploring the disease's pathogenesis.

The recent adverse reactions associated with semaglutide have led the Food and Drug Administration (FDA) to issue a "black box warning", and it is necessary to analyze all reports of adverse reactions to improve the safety of its clinical use.

Statistical analyses and signal mining were performed by obtaining the adverse event reports related to semaglutide in the FAERS database from the first quarter of 2018 to the fourth quarter of 2023. We used disproportionality and Bayesian analysis to examine clinical and demographic attributes, trends reported quarterly, and contrasts between two distinct indications (obesity and type 2 diabetes).

We found 10 unexpected adverse signals related to "pancreatic cancer", "intestinal obstruction", "cholecystitis", and "polycystic ovary" and both the two different indications had the same serious adverse reaction events occurring.

This study identified many unexpected signals of serious adverse reactions, suggesting the importance of continuous post-marketing surveillance of semaglutide to understand its potential risks.

Diabetes mellitus and inflammatory bowel disease are chronic conditions with significant overlap in their pathophysiology, primarily driven by chronic inflammation. Both diseases are characterized by an aberrant immune response and disrupted homeostasis in various tissues. However, it remains unclear which disease develops first, and which one contributes to the other. Diabetes mellitus increases the risk of inflammatory bowel disease and inflammatory bowel disease may increase the risk of developing diabetes. This review focuses on comprehensively discussing the factors commonly contributing to the pathogenesis of diabetes mellitus and inflammatory bowel disease to draw a relationship between them and the possibility of targeting common factors to attenuate the incidence of one if the other is present. A key player in the intersection of diabetes mellitus and inflammatory bowel disease is the NLRP3 inflammasome, which regulates the production of pro-inflammatory cytokines leading to prolonged inflammation and tissue damage. Additionally, toll-like receptors via sensing microbial components contribute to diabetes mellitus and inflammatory bowel disease by initiating inflammatory responses. Gut dysbiosis, a common link in both diseases, further intensifies inflammation and metabolic dysfunction. Alterations in gut microbiota composition affect intestinal permeability and immune modulation, perpetuating a vicious cycle of inflammation and disease progression by changing protein expression. The overlap in the underlying inflammatory mechanisms has led to the potential of targeting mediators of chronic inflammation using anti-inflammatory drugs and biologics that benefit both conditions or attenuate the incidence of one in the presence of the other.

Observational studies have suggested the potential benefits of several medications for Parkinson's disease (PD) and their potential for repurposing. However, the conclusions drawn from these studies are not entirely consistent. To address this inconsistency, we used the two-sample Mendelian randomization (MR) method to explore the putative causal relationships between 23 medications and the risk and progression of PD. We applied inverse-variance weighted meta-analysis (IVW) to combine MR estimates. Additionally, sensitivity analyses were conducted to evaluate the robustness of the results. Our genetic evidence suggests that thyroid preparations and calcium channel blockers reduce the risk of PD, and salicylic acid and derivatives slow the progression of PD motor symptoms. Additionally, genetic evidence also suggests that four medications were associated with PD risk or progression, but the sensitivity analysis revealed that three of the medications may have interference caused by reverse causality. Our findings suggest that there are weak causal relationships between several medications and the risk or progression of PD. Though further replication studies are needed to verify these findings, these new insights may help in understanding the etiology of the disease, generate new clues related to drug discovery, and quantify the risk of future drug intake.

Stroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke .

Cis-expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3-6 versus 0-2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome-wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes (ABCC2, ATRAID, BLK, CD93, CHST13, NR1H3, NRBP1, PI3, RIPK4, SEMG1, SLC22A4, SLC22A5, SLCO3A1, TEK, TLR4, and WNT10B) demonstrated the causal associations with ordinal modified Rankin Scale (P<1.892×10-5) or poor functional outcome (modified Rankin Scale 3-6 versus 0-2, P<1.893×10-5). Steiger filtering analysis suggested potential directional stability (P<0.05). Colocalization analysis provided further support for the associations between genetically predicted expression of ABCC2, NRBP1, PI3, and SEMG1 with functional outcome after ischemic stroke. Furthermore, phenome-wide Mendelian randomization revealed additional beneficial indications and few potential safety concerns of therapeutics targeting ABCC2, NRBP1, PI3, and SEMG1, but the robustness of these results was limited by low power.

The present study revealed 4 candidate therapeutic targets for improving functional outcome after ischemic stroke, while the underlying mechanisms need further investigation.

Gastrointestinal dysfunction are often associated with type 2 diabetes mellitus (T2DM), a complicated metabolic illness. Contributing factors have been proposed, including genetic predisposition, gene environmental, and lifestyle interactions, but the pathophysiology remains unknown.

We aim to explore the possible causes behind gastrointestinal dysfunction caused by type 2 diabetes in this study. A comprehensive analysis of the gastric sinus metabolome, transcriptome, and proteome in db/db mice with gastrointestinal dysfunction was conducted.

The model group of mice had considerably lower small intestine propulsion and gastric emptying rates, higher blood glucose levels, and were significantly obese compared to the control group. We identified 297 genes, 350 proteins, and 1,001 metabolites exhibiting significant differences between db/db and control mice (p < 0.05). Moreover, multi-omics analysis revealed that the genes, proteins, and metabolites in the T2DM-induced gastroenteropathy mice group were involved in arachidonic acid metabolism, glycerophospholipid metabolism and vitamin digestion and absorption. Specifically, Cbr3, Etnppl, and Apob were the major mRNAs associated with T2DM-induced gastrointestinal dysfunction, while Cyp2b10, Cyp2b19, Pgs1, Gpat3, Apoa4, and Tcn2 were the major proteins associated with T2DM-induced gastrointestinal injury, and 16(R)-HET, 5-HETE, LysoPC (22:0), and Pantothenic acid were the major metabolites associated with T2DM-induced gastrointestinal disorders.

The mechanism of action of diabetic gastroenteropathy may be related to vitamin digestion and absorption, glycerophospholipid metabolism, and arachidonic acid metabolism.

While circulating metabolites and immune system have been increasingly linked to hypothyroidism risk, the causality underlying these associations remains largely uninterrogated. We used Mendelian randomization to identified putative causal traits for hypothyroidism via integrating omics data. Briefly, we utilized 1180 plasma metabolites and 731 immune cells traits as exposures to identify putatively causal traits for hypothyroidism in the discovery (40,926 cases) and replication cohorts (14,871 cases). By combining MR results from two large-scale cohorts, we ultimately identified 21 putatively causal traits, including five plasma metabolites and 16 immune cell traits. CD3 on CD28+ CD4+ T cell and 1-(1-enyl-palmitoyl)-2-oleoyl-GPE (p-16:0/18:1) demonstrated the most pronounced positive and negative associations with hypothyroidism risk, respectively. The odds ratio and 95% confidence interval were 1.09 (1.07, 1.12) and 0.81 (0.75, 0.87), respectively. No evidence of horizontal pleiotropy, heterogeneity among instrumental variables or reverse causation were found for these 21 significant associations. Our study elucidates key metabolites and immune cell traits associated with hypothyroidism. These findings provide new insights into the etiology and potential therapeutic targets for hypothyroidism.

The incidence of diabetic gastrointestinal diseases is increasing year by year. This study aimed to investigate the causal relationship between antidiabetic medications and gastrointestinal disorders, with the goal of reducing the incidence of diabetes-related gastrointestinal diseases and exploring the potential repurposing of antidiabetic drugs.

We employed a two-sample Mendelian randomization (TSMR) design to investigate the causal association between antidiabetic medications and gastrointestinal disorders, including gastroesophageal reflux disease (GERD), gastric ulcer (GU), chronic gastritis, acute gastritis, Helicobacter pylori infection, gastric cancer (GC), functional dyspepsia (FD), irritable bowel syndrome (IBS), ulcerative colitis (UC), Crohn's disease (CD), diverticulosis, and colorectal cancer (CRC). To identify potential inhibitors of antidiabetic drug targets, we collected single-nucleotide polymorphisms (SNPs) associated with metformin, GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, insulin, and its analogs, thiazolidinediones, sulfonylureas, and alpha-glucosidase inhibitors from published genome-wide association study statistics. We then conducted a drug-target Mendelian randomization (MR) analysis using inverse variance weighting (IVW) as the primary analytical method to assess the impact of these inhibitors on gastrointestinal disorders. Additionally, diabetes was selected as a positive control.

Sulfonylureas were found to significantly reduce the risk of CD (IVW: OR [95% CI] = 0.986 [0.978, 0.995], p = 1.99 × 10- 3), GERD (IVW: OR [95% CI] = 0.649 [0.452, 0.932], p = 1.90 × 10- 2), and chronic gastritis (IVW: OR [95% CI] = 0.991 [0.982, 0.999], p = 4.50 × 10- 2). However, they were associated with an increased risk of GU development (IVW: OR [95%CI] = 2 0.761 [1.259, 6.057], p = 1 0.12 × 10- 2).

The results indicated that sulfonylureas had a positive effect on the prevention of CD, GERD, and chronic gastritis but a negative effect on the development of gastric ulcers. However, our research found no causal evidence for the impact of metformin, GLP-1 agonists, SGLT2 inhibitors, DPP 4 inhibitors, insulin and its analogs, thiazolidinediones, or alpha-glucosidase inhibitors on gastrointestinal diseases.

The interplay between diabetes mellitus (DM), glycemic traits, and vascular and valvular calcifications is intricate and multifactorial. Exploring potential mediators may illuminate underlying pathways and identify novel therapeutic targets.

We utilized univariable and multivariable Mendelian randomization (MR) analyses to investigate associations and mediation effects. Additionally, the multivariable MR analyses incorporated cardiometabolic risk factors, allowing us to account for potential confounders.

Type 2 diabetes mellitus (T2DM) and glycated hemoglobin (HbA1c) were positively associated with both coronary artery calcification (CAC) and calcific aortic valvular stenosis (CAVS). However, fasting glucose (FG) was only linked to CAVS and showed no association with CAC. Additionally, CAVS demonstrated a causal effect on FG. Calcium levels partially mediated the impact of T2DM on both types of calcifications. Specifically, serum calcium was positively associated with both CAC and CAVS. The mediation effects of calcium levels on the impact of T2DM on CAC and CAVS were 6.063% and 3.939%, respectively. The associations between T2DM and HbA1c with calcifications were influenced by body mass index (BMI) and smoking status. However, these associations were generally reduced after adjusting for hypertension.

Our findings suggest a genetically supported causal relationship between DM, glycemic traits, and vascular and valvular calcifications, with serum calcium playing a critical mediating role.

Epidemiological studies show dietary habits can have an impact on the risk of cholelithiasis, but the relationship is still unclear. We used a comprehensive Mendelian randomization (MR) study to explore the relationship between dietary habits and cholelithiasis.

The 18 dietary habits were divided into six categories: meat foods, cereals, vegetables, fruits, dairy products, beverages, and condiments. Cholelithiasis data came from a GWAS meta-analysis and the FinnGen consortium. The inverse variance weighted (IVW), the weighted median (WM), and MR-Egger approaches were used as the main MR analysis methods. In addition, multiple sensitivity analysis and meta-analysis were performed to verify the robustness of the results.

Dried fruit intake [odds ratio (OR) = 0.568; 95% confidence interval (CI), 0.405-0.797; p = 0.001] was discovered to reduce the risk of cholelithiasis. The sensitivity analysis and meta-analysis showed reliable results for the relationship between dried fruit intake and cholelithiasis.

Our study found that dried fruit intake is a protective factor in the development of cholelithiasis. However, the mechanisms of action need to be further explored.

In recent years, there has been increasing interest in studying gut microbiome-derived hydrolases in relation to oral drug metabolism, particularly focusing on natural product drugs. Despite the significance of natural product drugs in the field of oral medications, there is a lack of research on the regulatory interplay between gut microbiome-derived hydrolases and these drugs. This review delves into the interaction between intestinal microbiome-derived hydrolases and natural product drugs metabolism from three key perspectives. Firstly, it examines the impact of glycoside hydrolases, amide hydrolases, carboxylesterase, bile salt hydrolases, and epoxide hydrolase on the structure of natural products. Secondly, it explores how natural product drugs influence microbiome-derived hydrolases. Lastly, it analyzes the impact of interactions between hydrolases and natural products on disease development and the challenges in developing microbial-derived enzymes. The overarching goal of this review is to lay a solid theoretical foundation for the advancement of research and development in new natural product drugs and personalized treatment.

Studies suggest links between diabetes and gastrointestinal (GI) traits; however, their underlying biological mechanisms remain unclear. Here, we comprehensively assess the genetic relationship between type 2 diabetes (T2D) and GI disorders. Our study demonstrates a significant positive global genetic correlation of T2D with peptic ulcer disease (PUD), irritable bowel syndrome (IBS), gastritis-duodenitis, gastroesophageal reflux disease (GERD), and diverticular disease, but not inflammatory bowel disease (IBD). We identify several positive local genetic correlations (negative for T2D - IBD) contributing to T2D's relationship with GI disorders. Univariable and multivariable Mendelian randomisation analyses suggest causal effects of T2D on PUD and gastritis-duodenitis and bidirectionally with GERD. Gene-based analyses reveal a gene-level genetic overlap between T2D and GI disorders and identify several shared genes reaching genome-wide significance. Pathway-based study implicates leptin (T2D - IBD), thyroid, interferon, and notch signalling (T2D - IBS), abnormal circulating calcium (T2D - PUD), cardiovascular, viral, proinflammatory and (auto)immune-mediated mechanisms in T2D and GI disorders. These findings support a risk-increasing genetic overlap between T2D and GI disorders (except IBD), implicate shared biological pathways with putative causality for certain T2D - GI pairs, and identify targets for further investigation.

Colonic diverticulosis is a prevalent condition among older adults, marked by the presence of thin-walled pockets in the colon wall that can become inflamed, infected, haemorrhage or rupture. We present a case-control genetic and transcriptomic study aimed at identifying the genetic and cellular determinants underlying this condition and the relationship with other gastrointestinal disorders.

We conducted DNA and RNA sequencing on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We investigated variation in the transcriptome associated with diverticulosis and further integrated this variation with single-cell RNA-seq data from the human intestine. We also integrated our expression quantitative trait loci with genome-wide association study using Mendelian randomisation (MR). Furthermore, a Polygenic Risk Score analysis gauged associations between diverticulosis severity and other gastrointestinal disorders.

We discerned 38 genes with differential expression and 17 with varied transcript usage linked to diverticulosis, indicating tissue remodelling as a primary diverticula formation mechanism. Diverticula formation was primarily linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1 and TNFSF13, with potential causal effects on diverticulosis. Notably, ENTPD7 upregulation was confirmed in diverticulosis cases. Additionally, diverticulosis severity was positively correlated with genetic predisposition to diverticulitis.

Our results suggest that tissue remodelling is a primary mechanism for diverticula formation. Individuals with an increased genetic proclivity to diverticulitis exhibit a larger numbers of diverticula on colonoscopy.

Immunotherapy has been used in esophageal cancer (EC), but the causal relationship between EC and immune cells is not clear. Although the cellular phenotype has been reported as a biomarker for immunotherapy, the biomarker studies for immunotherapy in EC still face great challenges. Comprehensive 2-sample Mendelian randomization (MR) analysis was performed to determine the causal association between immune cell signatures and EC in this study. Based on publicly available genetic data, we explored causal associations between 731 immune cell signatures and EC risk. EC had no statistically significant effect on immunophenotypes. Nine immunophenotype types were positively associated with the risk of EC: CD20-%B cell, CD20% lymphocytes, CD25 on IgD- CD27-, CD25 on IgD+ CD24+, CD27 on IgD+ CD24+, CD28+ CD45RA- CD8br AC, CD3 on TD CD8br, IgD-CD38dim%B cells, and Mo MDSC AC. In addition, a total of 15 immunophenotypes were identified as causally associated with EC. IgD+ CD38- %B cell, IgD- CD24- %lymphocyte, CD19 on IgD- CD38dim, CD20 on IgD+ CD24+, CD62L-myeloid DC AC, CD4+ AC, Lymphocyte %leukocyte, CD3 on HLA-DR+ T cell, CD3 on CD45RA- CD4+, HVEM on naive CD4+ AC, HVEM on CD45RA- CD4+, CD4 on TD CD4+, CD4 on CD4 Treg, and CD4 on CD39+ resting Treg, and CD4 on activated & secreting Treg. Our study has demonstrated the close connection between immune cells and EC by genetic means, thus providing guidance for future clinical research.

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.

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.

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.

The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases.

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).