BackgroundWhether anti-inflammatory mechanisms mediate the protective effects of histidine against colorectal carcinogenesis remains unexplored. We aimed to assess the association between plasma histidine and colorectal cancer (CRC) and to evaluate the potential mediating role of inflammation.MethodsWe conducted a prospective cohort study using data from the UK Biobank. A total of 261,082 cancer-free participants with plasma histidine data were included. Histidine concentrations were quantified using a nuclear magnetic resonance-based metabolic profiling platform. Incident CRC cases were identified through linkage to cancer registries. Cox proportional hazards regression models were used to assess the association between plasma histidine and CRC risk. Mediation analysis was performed using a regression-based approach with closed-form parameterization and delta method inference.ResultsAfter a median follow-up of 13.3 years, 3,436 incident CRC cases were identified. An inverse association between plasma histidine and CRC risk was observed [Tertile 2 (T2) vs. T1: HR = 0.885; 95% CI = 0.816, 0.960; P = 0.003; T3 vs. T1: HR = 0.890; 95% CI = 0.820, 0.966; P = 0.005]. Mediation analysis identified neutrophils, leukocytes, and C-reactive protein (CRP) as significant mediators. CRP exhibited the largest mediation proportion (14.141%), followed by neutrophils (11.258%) and leukocytes (6.770%).ConclusionsHigher histidine levels are associated with a lower risk of CRC, and systemic inflammation mediates this association. These findings suggest that dietary interventions targeting histidine intake could offer a promising strategy for CRC prevention and burden reduction.

statistics derived from large-scale biobanks facilitate the sharing of genetic discoveries but are typically limited by fixed covariate adjustments, preventing the exploration of trait-specific adjustments. Here we present UK BioCoin (UKC), a computational device designed to enable efficient, user-specified covariate adjustment without requiring access to individual-level data. Using the UK Biobank (505 unique traits and 10 million SNPs) as a comprehensive demonstration, we demonstrate that UKC generates summary statistics that closely mirror those derived from individual-level data but with approximately 80 times greater computational efficiency. We further validate UKC's utility across diverse applications, including SNP-heritability estimation, polygenic score, and Mendelian randomization, and show that the framework is portable to other cohorts, as demonstrated by its application to the Westlake Biobank. Here, we show that UKC offers a privacy-preserving paradigm that facilitates flexible data sharing and collaborative research.

BACKGROUND:Periodontal health is increasingly recognized as an integral component of systemic homeostasis. However, whether its disruption contributes to the development of autoimmune diseases (ADs) remains unclear in prospective settings. OBJECTIVES:The aim of this study was to prospectively evaluate the association between periodontal symptoms and the risk of ADs, with particular attention to immunometabolic pathways and shared disease clusters. MATERIAL AND METHODS:A total of 465,454 participants from the UK Biobank were included. Cox proportional hazards models were employed to evaluate the association between periodontal symptoms and the incidence of 20 ADs. Sensitivity and subgroup analyses were conducted to assess the robustness of the results. Mediation analyses explored the potential mediating roles of 6 immunometabolic biomarkers. To address inter-disease correlations and reduce multicollinearity, factor analysis was applied to identify latent clusters of ADs. RESULTS:During a median follow-up of 13.3 years, 33,895 participants developed at least 1 AD. Periodontal symptoms were linked to a higher risk of several ADs, with significant associations observed for bullous disorders, lichen planus, primary biliary cholangitis (PBC), and psoriasis. Mediation analyses revealed modest but statistically significant contributions of immunometabolic markers, particularly C-reactive protein (CRP). Factor analysis identified 3 AD clusters - autoantibody-mediated, autoimmune inflammatory and autoimmune metabolic diseases - all of which were significantly associated with poor periodontal health. CONCLUSIONS:Periodontal symptoms were positively associated with multiple ADs and latent clusters, with these correlations being partly mediated by immunometabolic factors. The findings highlight the role of periodontal-systemic interactions in autoimmune pathogenesis.

Previous studies have indicated that elevated selenium levels curb systemic lupus erythematosus (SLE) risk, whereas the specific mechanisms remain to be elucidated. Thereby, our study is conducted to explore the mediating function of proteome on the association between selenium and SLE. Summary data for plasma proteins came from six large-scale genome wide association studies (GWASs). The data of selenium were derived from a GWAS meta-analysis involving 9639 individuals, and those with SLE were obtained from SLE meta-GWASs (5206 cases and 9066 controls). Two-sample Mendelian randomization (MR) was performed using inverse-variance weighting (IVW), followed by a series of sensitivity analyses to examine the causal relationship between plasma proteins and SLE. Additionally, a two-step MR (TSMR) analysis was applied to explore the mediating role of plasma proteins in the link between selenium and SLE. Moreover, multivariable MR (MVMR) was utilized to adjust and calculate the mediating effect, revealing the potential mechanisms underlying the impact of selenium on SLE. In the MR analysis, we found 24 plasma proteins associated with SLE among 4372 unique plasma proteins. Notably, three plasma proteins exhibited a causal link with selenium. Through mediation analysis, we identified sex hormone–binding globulin (SHBG) mediated the causal effect between selenium and SLE. Specifically, increased selenium levels could lower SLE risk by reducing SHBG levels, with a mediation proportion of 22

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive loss of motor neurons. Insufficiency of neurotrophic factors is suspected to underlie the disease, but direct evidence remains scarce. In this study, we discover that brain-derived neurotrophic factor (BDNF) val/met mutation, which results in a decrease in BDNF secretion, reduces survival time of ALS patients in two separate cohorts. Using a knockin mouse model of the ALS causal gene FUSR521C, we demonstrate that BDNF haploinsufficiency leads to shortened lifespan, accelerated motor dysfunctions, and exacerbated motor neuron death. Importantly, activation of the BDNF receptor TrkB by an agonistic antibody effectively rescues these ALS-associated phenotypes. In additional ALS mouse models, TrkB activation antibody also shows superior therapeutic effects compared to current ALS medication riluzole. Our data indicate that insufficient BDNF could be a crucial contributing factor for ALS progression, and activation of BDNF-TrkB pathway may represent a promising therapeutic strategy against ALS.

The global rise in ultra-processed food (UPF) consumption has been linked to several chronic diseases. However, its association with cholecystitis and cholelithiasis remains underexplored. This prospective cohort study included 154,376 UK Biobank participants. UPF consumption (assessed as percentage of total food weight, g/day) was categorized by the NOVA classification using Oxford WebQ-based 24-hour dietary assessments. Cox proportional hazards models were performed to estimate hazard ratios (HRs) and 95

Body Roundness Index (BRI) is a novel measure of visceral and total body fat. Its association with multiple cancers and predictive value relative to Body Mass Index (BMI) remain unclear. The associations between BRI and the incidence and mortality (specific, overall and all causes death) risk of 23 site-specific cancers were evaluated using Cox proportional hazards models in UK Biobank participants. Restricted cubic spline (RCS) was further employed to assess the nonlinear association between BRI and 23 cancers. Additionally, we used the C-index and NRI to compare the predictive ability of BRI and BMI for cancer incidence and mortality risk. During a median follow-up of 13.7 years, higher BRI significantly increased overall cancer risk (hazard ratio [HR] = 1.04, 95% confidence interval [CI]: 1.03-1.14), persisting after BMI or residual adjustment. Positive linear associations were observed for 10 cancers (esophagus, stomach, colorectal, gallbladder, pancreas, corpus uteri, kidney, bladder, thyroid, and Hodgkin's; HRs: 1.05-1.31). Nonlinear patterns included inverted U-shaped (breast, prostate) and U-shaped (liver) associations (Pnon-linear < 0.05). Higher BRI also predicted increased overall cancer mortality (HR = 1.04, 95% CI: 1.02-1.06) and all-cause mortality (HR = 1.07, 95% CI: 1.05-1.09), especially among breast and prostate cancer patients. However, BRI and BMI showed comparable predictive ability for both incidence and mortality (all PΔC-indices > 0.05). BRI is significantly associated with the incidence and mortality of various cancers. With predictive performance comparable to BMI, BRI serves as a valuable anthropometric indicator for assessing cancer risks.

Colorectal cancer(CRC),the third most common cancer and the second leading cause of cancer-related death globally,is responsible for more than 1.9 million new cases and 0.9 mil-lion deaths reported annually1.

Carotenoids are common natural anti-inflammatory antioxidants produced by plants and some microorganisms. However, there are limited reports on the association between carotenoids and risk of rheumatoid arthritis (RA). We analyzed data of participants from the National Health and Nutrition Examination Survey (NHANES) and UK Biobank (UKB). In the NHANES, a total of 40,410 and 13,440 participants were included to evaluate the association of dietary carotenoid intake and serum carotenoid levels with RA, respectively. Among 179,171 participants in the UKB, 2,156 individuals developed RA over a median follow-up of 7.74 years. A weighted multivariable logistic regression model and quantile G-Computation (QGC) model were established to investigate single and joint effect of carotenoid levels (alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein and zeaxanthin) on RA in NHANES by cross-sectional study design. Furthermore, Cox proportional hazards regression model was used to validate the potential association in UKB cohort, and restricted cubic spline (RCS) regression was applied to estimate the possible nonlinear association. Compared to the lowest quartile (Q1), dietary intake level of alpha-carotene in Q3 were consistently associated with a decreased risk of RA in NHANES (odds ratio [OR]: 0.771, 95

Coeliac disease (CeD) is an autoimmune enteropathy triggered by gluten exposure and is often accompanied by musculoskeletal (MSK) manifestations, but evidence on their overall comorbidity patterns remains limited. Using UK Biobank data, we conducted prospective cohort and cross-sectional analyses to systematically evaluate associations between CeD and 24 MSK conditions. Cox proportional hazards models were used to estimate associations, and logistic regression was applied to assess graded cross-sectional association between MSK burden and CeD odds. Effect modification by polygenic risk score (PRS) was also examined. To further characterize shared genetic architecture and potential directional genetic evidence, linkage disequilibrium score regression (LDSC) and generalized summary-data-based Mendelian randomization (GSMR) were performed using external GWAS summary statistics. In the cohort analyses, 6 MSK conditions—osteoporosis, osteoarthritis, rheumatoid arthritis, systemic lupus erythematosus, spondylosis, and enthesopathies/synovial disorders—were significantly associated with CeD after FDR correction. Greater overall MSK burden was also associated with CeD in both directions (CeD as exposure: HR = 1.68, 95

BACKGROUND:Jieduquyuziyin prescription (JP) was clinically effective for the treatment of systemic lupus erythematosus (SLE), with increasing evidence supporting its immunomodulatory effects. Although growth differentiation factor 15 (GDF15) has been implicated in the development of SLE, whether GDF15 mediates the therapeutic action of JP remains to be determined. PURPOSE:This research aims to identify GDF15 as a specific molecular target mediating the JP's pharmacological activity against SLE. METHODS:Serum and renal GDF15 levels were measured by ELISA and western blot, respectively, in MRL/lpr and MRL/Mpj mice at 12, 16, and 20 weeks of age. To determine whether GDF15 mediates the therapeutic effects of JP in lupus, we utilized GDF15 knockdown in RAW264.7 cells and bone marrow derived macrophages (BMDMs), and GDF15-knockout lupus mice. UPLC-MS/MS was employed to identify the main constituents of JP decoction and serum, and the major active components were subsequently validated for their effects on GDF15 expression in RAW264.7 cells and BMDMs. RESULTS:During disease progression in MRL/lpr mice, serum GDF15 levels decreased and renal GDF15 expression fluctuated, while exogenous GDF15 protein alleviated lupus manifestations, suggesting that GDF15 was closely linked to lupus pathogenesis. In addition, JP upregulated GDF15 more strongly than prednisone, leading to increased serum levels and renal expression of GDF15. Genetic ablation of GDF15 partially abolished the beneficial effects of JP on lupus. Mechanistically, JP serum strongly inhibited M1 macrophage polarization of RAW246.7 cells and BMDMs, an effect that was eliminated by GDF15 silencing or GDF15 knock-out. Furthermore, active ingredients of JP, including paeoniflorin, glycyrrhizic acid, and turanose, also inhibited M1 polarization by upregulating GDF15. CONCLUSION:These findings identify GDF15 as a key mediator and potential therapeutic target of SLE, and provided experimental evidence supporting JP as a treatment for SLE.

Evidence on dietary protein and chronic joint diseases remains limited. This study aimed to investigate the associations between protein intake and the risk of chronic joint diseases, and to evaluate the mediating roles of inflammation. Dietary protein intake was assessed using 24-hour dietary recall. The primary outcomes, including incident OA, RA, gout, and SpA, were ascertained from UK hospital inpatient records. Cox proportional hazards models estimated associations between protein intake and outcomes. Mediation analysis was conducted using the CMAverse R package. During an average follow-up of 12.19–13.18 years, a total of 23,298 incident cases of OA, 2,070 of RA, 2,934 of gout, and 728 of SpA were documented. Higher total protein intake was associated with a reduced risk of gout (Q4 vs. Q1: HR:0.87, 95

BACKGROUND:Respiratory tract infections (RTIs) remain a major global cause of morbidity, yet the causal role of circulating plasma proteins in RTI susceptibility is unclear. We aimed to systematically identify plasma proteins that causally influence the risk of upper and lower respiratory tract infections (URTIs, LRTIs) using a proteome-wide Mendelian randomization (MR) framework. METHODS:We performed two-sample MR analyses using genetic instruments for 2923 plasma proteins from 54,219 UK Biobank participants and outcome data from the FinnGen consortium (97,696 URTI and 28,542 LRTI cases). Colocalization analyses were conducted to confirm shared genetic architecture. Functional enrichment and protein-protein interaction (PPI) analyses were used to elucidate potential biological pathways. RESULTS:We identified 11 plasma proteins with significant causal associations with RTI risk. Four proteins (FKBP1B, GFRA1, UBE2L6, and CSF3) showed consistent effects for both URTI and LRTI, with moderate-to-strong colocalization evidence for UBE2L6 and GFRA1. The remaining seven proteins demonstrated infection-specific associations: YAP1 and MST1 (URTIs), and APOE, IL1RL1, and FKBPL (LRTIs). PPI and Gene Ontology (GO) enrichment analyses highlighted tumor necrosis factor (TNF) as a central hub, with cytokine-cytokine receptor interaction and leukocyte-mediated immunity as dominant pathways. CONCLUSIONS:This proteome-wide MR and colocalization study identifies novel plasma proteins and immune pathways implicated in RTI susceptibility, providing insights into potential biomarkers and therapeutic targets for infection prevention and management. Further validation in diverse populations and tissue-specific proteomic studies is warranted.

BackgroundDiabetes and thyroid disorders are modifiable risk factors for cognitive impairment. However, no studies have been conducted to comprehensively examine associations of different types of the two diseases, as well as their combinations, with dementia risks.MethodsBased on the data from UK Biobank study, patients with different types of diabetes and thyroid disorders were identified with the hospital inpatient record. Status of dementia was assessed with multi-source information. Independent and combined associations of diabetes and thyroid disorders with dementia were estimated with Cox regression models.ResultsAmong 284,081 participants, 8,236 incident cases of all-cause dementia (ACD) [3,755 Alzheimer’s disease (AD) cases, 1,893 vascular dementia (VD) cases] were identified over a mean [standard deviation (SD)] follow-up of 13.03 (2.29) years. Four types of diabetes and two types of thyroid disorders were significantly associated with increased risks of dementia. Compared with participants without diabetes and thyroid disorders, those with only thyroid disorders [hazard ratio (HR) = 1.33, 95% confidence interval (CI) = 1.21 to 1.47, P < 0.001], only diabetes (HR = 1.76, 95% CI = 1.64 to 1.89, P < 0.001), and both (HR = 2.16, 95% CI = 1.84 to 2.53, P < 0.001) had elevated risks of ACD (Ptrend < 0.001), as well as higher risks of AD and VD. Combined associations of hypothyroid and diabetes and of hyperthyroid and diabetes were also significantly positive (all P values < 0.05). Moreover, cumulative years of diabetes and thyroid were related to higher risks of dementia.ConclusionsDiabetes, thyroid disorders, and their combinations were associated with increased risks of dementia in adults aged 55 years and older.

Background:This large prospective cohort study aimed to clarify uncertain associations between sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), pure fruit/vegetable juice and breast cancer risk. Methods:In 86,247 cancer-free UK Biobank participants at baseline, Cox proportional hazard models were performed to investigate the associations of SSB, ASB, pure fruit/vegetable juice with incident breast cancer risk. Results:In total, 2,644 cases of incident breast cancer occurred during the median follow-up of 10 years. In Cox proportional hazards model, participants consuming >0 and ≤1 serving/day of pure fruit/vegetable juice had a hazard ratio (HR) of 1.13 (95% CI: 1.05-1.23; P = 0.002) compared to non-consumers (P = 0.004 for trend). However, no associations were observed for SSB and ASB with breast cancer risk. We also found that replacing 1 serving per day of pure fruit/vegetable juice with ASB was associated with 10% lower risk of incident breast cancer in substitution analyses. Conclusions:Our findings indicated that pure fruit/vegetable juice was associated with increased risk of breast cancer, highlighting the potential role of sweetened beverages in breast cancer prevention strategies and call for further research to understand the underlying mechanisms.

The relationship between long-term ambient air pollution exposure and socioeconomic status (SES) with rheumatic heart disease (RHD) has been rarely investigated. We conducted a population-based cohort study involving approximately half a million participants based on UK Biobank. Long-term exposure to five air pollutants (PM2.5, PM10, PMcoarse, NO2, and NOx) was estimated by using land-use regression models. An overall SES indicator was derived by using latent class analysis based on household income, education level, and employment status. Cox proportional hazards models, together with mediation and interaction analyses were utilized to assess the associations of air pollution and SES with incident RHD. During a median follow-up of 13.6 years among 404,317 participants, a total of 7,944 incident RHD cases were identified. Higher SES was associated with a reduced risk of incident RHD (Medium vs. Low, HR = 0.77, 95

While ambient air pollution is a recognized risk factor for various diseases, its specific link to esophagitis and esophageal ulcer remains poorly understood. Similarly, the potential role of residential water space is unclear. This study aimed to examine the individual and combined associations of ambient air pollution and residential water space with the risk of esophagitis and esophageal ulcer. We included 399,766 UK Biobank participants who were free of these conditions at baseline. Incident cases were identified via hospital records using ICD-10 codes (K20, K21.0, and K22.1). Exposures to ambient air pollutants (PM2.5, PMcoarse, PM10, NO2, and NOx) and residential water space (at 300 m and 1000 m buffers) were estimated using land-use regression models and spatial datasets. Cox proportional hazards models revealed that higher exposures to PM2.5 (HR = 1.14; 95% CI: 1.10-1.19), NO2 (HR = 1.10; 95% CI: 1.06-1.15), and NOx (HR = 1.17; 95% CI: 1.12-1.22) were associated with an increased risk of esophagitis and esophageal ulcer. Conversely, greater exposures to water space at both 300 m (HR = 0.94; 95% CI: 0.91-0.98) and 1000 m (HR = 0.91; 95% CI: 0.88-0.95) buffers were associated with a reduced risk. Mediation analyses indicated that 10.49% to 43.03% of the inverse association between water space and esophageal outcomes was statistically mediated by attenuated exposure to PM2.5 and NOx. These findings suggest that PM2.5, NO2, and NO x are associated with an elevated risk of esophagitis and esophageal ulcer, whereas residential water space is associated with a reduced risk.

Accurate identification of individuals at high risk of gastric cancer (GC) remains a major challenge for effective screening. We aimed to identify plasma proteomic signatures and develop a risk prediction model for GC risk stratification. Plasma proteomic profiling was performed using liquid chromatography–tandem mass spectrometry in a case–control discovery set (100 GC cases and 94 controls). Candidate proteins were evaluated in 52,552 UK Biobank participants with a median follow-up of 13.63 years, during which 92 incident GC cases were identified. Risk models integrating clinical, genetic, and proteomic factors were developed using LASSO-penalized Cox regression with stability selection and internally validated using bootstrap resampling. Among 2306 differentially expressed proteins in discovery, 25 were replicated in validation at nominal significance (P < 0.05) with consistent directions. Two proteins (CTSD and GGH) remained significant after false discovery rate correction. A primary proteomic model (clinical factors plus five proteins) improved discrimination versus clinical model (optimism-corrected C-index: 0.745 vs. 0.732, P = 0.046). Risk stratification revealed a clear GC risk gradient: hazard ratios were 6.08 (95

Objective. To evaluate modifiable lifestyle-genetic susceptibility interactions with the risk of developing radiographic axial spondyloarthritis (r-axSpA). Methods. This study included 382,035 individuals without r-axSpA at baseline in the UK Biobank. A combined lifestyle score consisting of 6 factors and a polygenic risk score (PRS) using r-axSpA-associated genetic loci was constructed for each participant. Participants were further classified into 3 categories (unfavorable, intermediate, or favorable lifestyle) based on their score. Cox proportional hazards regression models were applied to evaluate the associations of lifestyle and PRS with risk of developing r-axSpA. Moreover, the association between lifestyle score and r-axSpA mediated by systemic inflammation was estimated. Results. During a median follow-up period of 13.57 years, 694 patients with r-axSpA were diagnosed. With unfavorable lifestyle as the reference group, intermediate lifestyle (hazard ratio [HR] 0.67, 95% CI 0.57-0.80) and favorable lifestyle (HR 0.62, 95% CI 0.49-0.78) were associated with a decreased risk of developing r-axSpA. For the combined effect of lifestyle and PRS, participants with unfavorable lifestyle and high genetic risk had the highest risk of developing r-axSpA (HR 2.18, 95% CI 1.47-3.23) compared to those with favorable lifestyle and low genetic risk. However, no evidence of addictive and multiplicative interaction was observed. Further, mediation analyses revealed that the inverse association between healthy lifestyle score and the risk of developing r-axSpA was in part mediated by systemic inflammation, which ranged from 0.20% for neutrophil-to-high-density lipoprotein cholesterol ratio to 10.29% for C-reactive protein. Conclusion. Our study suggested that adherence to a favorable lifestyle significantly reduced the risk of developing r-axSpA by attenuating the systemic inflammatory response, which was independent of genetic susceptibility to r-axSpA.