The immune system is a major driver in pancreatic cancer development. Several prospective cohort studies have found associations for single immune system-derived proteins such as IL6 or CRP, but results are inconclusive, and Omics-based research is scarce. Hence, we aimed to investigate associations of a comprehensive protein panel with the risk of pancreatic cancer. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, 92 immune proteins were measured in baseline blood samples of 406 incident pancreatic cancer cases and 406 sex- and age-matched controls, using the Olink Immuno-Oncology panel. Multivariable adjusted conditional logistic regression was used to estimate odds ratios (OR, 95% CI) for protein levels in association with pancreatic cancer risk. Eight biomarkers were associated with pancreatic cancer risk (MMP12, LAMP3, CD28, IL-6, IL-12, FASLG, PD-L2, and PDCD1) but only MMP12 was significantly associated after multivariable adjustments for confounders and the seven proteins, with OR = 1.56 (95% CI: 1.20-2.03) for a doubling in protein concentration. After correction for multiple testing, none of the proteins were associated with risk. Restricting analyses to cases diagnosed within the first 4 years and 4-8 years after recruitment resulted in OR of 1.89 (95% CI: 1.28-2.80) and 1.37 (95% CI: 1.01-1.86) for MMP12, respectively. Higher levels of MMP12 were associated with pancreatic cancer risk specifically in those diagnosed shortly after recruitment, while other immune-related factors were not associated with risk. Further cohort studies are needed to confirm our initial findings.

New obesity medications have demonstrated efficacy in trials, but their real-world deployment is partly limited by the absence of approaches that identify individuals for treatment based on risks for obesity-related complications. Here we present a risk prediction model to guide prioritization of high-risk individuals. In a population-based sample of ~200,000 individuals with a body mass index (BMI) exceeding 27 kg m-2, our machine learning framework identified the 20 most informative features, from among thousands tested, that predict future onset of 18 complications of obesity, providing information beyond BMI. An integrated model (OBSCORE) successfully stratified individuals into risk groups based on incidence over 10 years: for example, 5.7%, 1.8%, 0.9%, 0.4% and 0.1% for cardiovascular mortality. We demonstrate generalizability of the model in independent populations of European and non-European ancestry and, in SURMOUNT-1 trial participants, show that weight loss was similar across baseline OBSCORE risk groups and that predicted risks decreased following treatment with tirzepatide. In summary, OBSCORE provides a framework for prioritizing high-risk individuals with overweight or obesity based on their risk of obesity-related complications, complementing BMI-based frameworks.

Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes mellitus. Although sleep duration may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. In the present study, we conducted genome-wide gene by sleep duration meta-analyses, separately assessing interactions of short and long sleep, for fasting glucose, fasting insulin, and hemoglobin A1c in up to 489,309 individuals without diabetes from seven different population groups. In total, 16 loci were identified to interact with sleep duration - six with short sleep and ten with long sleep. Of these, four loci were identified through cross-population meta-analysis. Mapped genes exhibit pathway connections to pericyte apoptosis, NMDA receptor activity, the GLUT1 receptor, neurological health, and sleep architecture. Eleven loci (VRK2, PCDH7, TFAP2A, CAP2, PAPPA, ZCCHC2, MYH9, SGIP1, JAKMIP3, RRAS2, MAPT) have not been reported in previous glycemic trait genome-wide association studies. Interaction loci identify divergent biological mechanisms for short and long sleep duration influencing glycemic control, suggesting specific pathways of intervention for precision medicine approaches to diabetes prevention and management.

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a major therapeutic target in type 2 diabetes and obesity. Missense variation in GIPR could confer phenotypic effects through alterations to constitutive activity or functional responses to GIP or pharmacological agonists. In this study, we aimed to provide a deep understanding of the molecular mechanisms that underpin the cellular and physiological impacts of GIPR coding variation by studying 30 GIPR coding variants in cellular models and pancreatic islets. Many variants showed impaired GIP-induced cyclic adenosine monophosphate responses, and population-based association analysis highlighted that these loss-of-function variants decrease body mass index but increase glycemia. In many cases, reduced function was partly driven by reduced expression at the cell surface due to impaired stability and redirection toward proteasomal degradation. Molecular dynamics simulations suggest distinct variant-induced perturbations in inter- and intrahelical interactions, which interfere with receptor stability. This study highlights the mechanisms and consequences of GIPR coding variation, which may have implications for the therapeutic targeting of this receptor.

To investigate socio-economic disparities in the association between dietary diversity and type 2 diabetes (T2D). Prospective secondary analysis study of 10,363 incident cases of T2D over 12 years and a random sub-cohort of 13,937 individuals in the EPIC-InterAct case-cohort study. We used baseline self-reported diet data (1991–1998) to construct scores for diversity between food groups (range: 0–5) and diversity within subtypes of vegetables (0–4), and plant protein sources (0–5). Prentice-weighted Cox regressions estimated multivariable-adjusted hazard ratios (HR) and 95

CONTEXT:Testosterone supplementation is increasingly widespread and has well-established beneficial effects on sexual function and metabolic health. However, there remains uncertainty regarding associated cardiovascular risks. OBJECTIVE:Human genetics studies demonstrated that Mendelian randomization approaches recapitulate the beneficial effects of testosterone therapy; here we apply this to cardiovascular disease. DESIGN:We performed a Mendelian randomization study to assess the causal effect of higher circulating testosterone on coronary artery disease (CAD). We also tested the phenotypic association between measured circulating testosterone and CAD in the cohort of men aged 40 to 69. PATIENTS OR OTHER PARTICIPANTS:Testosterone genetic instrument data were derived from 425 097 European ancestry adults from the UK Biobank study and CAD from single nucleotide polymorphism-level summary statistics from 1 165 690 individuals in CARDIoGRAMplusC4D. MAIN OUTCOME MEASURE(S):CAD as defined in CARDIoGRAMplusC4D was the main outcome. In longitudinal analyses, CAD was defined according to medical records and self-report. RESULTS:We found that higher genetically predicted circulating testosterone conferred a higher risk of CAD in men [odds ratio (OR): 1.17, 95% confidence interval (CI) 1.07-1.27, P = 3.32 × 10-4]. There was no evidence of an effect in women (OR: 1.01, 95% CI 0.94-1.10, P = .73). The genetic association in men appeared to be mediated by higher blood pressure. In longitudinal observational analyses, a directionally opposite association was observed in men, likely arising due to confounding by type 2 diabetes and body mass index. CONCLUSION:These data suggest that increased testosterone may increase the risk of cardiovascular disease and that this safety concern should be a focus in future clinical trials for testosterone supplementation.

Despite the introduction of genome sequencing (GS) for rare disease diagnostics, a genetic cause is not identified in most patients. Here, we explored the potential of proteomics to improve the diagnostic yield in 424 patients with rare diseases from the 100,000 Genomes Project (100kGP) without a genetic diagnosis. Serum proteomic profiling was performed using the Olink Explore 1536 assay ( N = 1463 proteins). For 13 patients without genetic diagnoses, detection of lower serum protein “outliers” ( z -score < −2) led to confirmed genetic diagnoses by resolving variants of uncertain significance or prioritizing genes for targeted GS reanalysis. For 23 additional patients without genetic diagnoses (64% of findings), we identified candidate gene-disease links and variants through convergent evidence from lower protein outliers and variants ranked through the variant prioritization tool Exomiser. For example, we identified a candidate heterozygous missense variant [Genome Aggregation Database (gnomAD) minor allele frequency = 0.006%] in tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains 1 ( TIE1 ) that was only present in a patient with lower TIE1 serum abundance ( z -score = −5.12) and their father, both of whom were affected by the same monogenic cardiac disorder, but in no other individuals from the 100kGP. Missense (52.5%) and splice region (27.5%) variants accounted for most diagnostic or candidate variants prioritized. This proof-of-principle study demonstrated that serum proteomics can support rare disease diagnosis and identify disease-causing genes in patients undiagnosed after GS, although successful implementation will likely depend on tissue specificity of protein expression, detectability in blood, proteomic platform coverage, and sensitivity.

Dicarbonyls are reactive precursors of advanced glycation end-products. They are formed during food processing, and endogenously in humans during glycolysis and lipid peroxidation. Higher plasma dicarbonyls, particularly methylglyoxal (MGO), promote insulin resistance and type 2 diabetes, but the association between dietary dicarbonyls intake and type 2 diabetes is unknown. This study examined the associations between dietary dicarbonyls and type 2 diabetes incidence. 11,995 incident type 2 diabetes cases and a sub-cohort of 15,797 controls from the prospective multi-center European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct cohort were included. Intakes of three major dicarbonyls MGO, glyoxal [GO], and 3-deoxyglucosone [3-DG] were estimated at baseline using dietary questionnaires. Type 2 diabetes risk according to dietary dicarbonyl intake was estimated by multivariable-adjusted hazard ratios from Prentice-weighted Cox-regression analyses. Higher intakes of MGO (sample-specific mean intake 3.4 ± 1.3 mg/d) and 3-DG (13.8 ± 10.5) were associated with lower incidence of type 2 diabetes (HR 0.92 [95

Previous estimations of the associations between fruits and vegetables (F/V) intake with diabetes markers showed mixed results, possibly partly because of the subjective assessment of dietary intake. We aimed to examine the relationship between plasma carotenoids and α-tocopherol (as objective markers of F/V intake) and fasting glucose. This was a population-based cross-sectional study in 592 adults in Cameroon. Self-reported F/V intake was assessed using the WHO STEPS questionnaire, and the biomarkers were analysed by HPLC. The mean age of participants was 38·5 (sd 8·6) years (63·7 % women). The median (IQR) number of times participants self-reported consuming fruits in a typical week was 2(1-5) and vegetables was 4(2-7) times/week. Plasma total carotenoids was positively correlated with self-reported intake of fruits (r = 0·13) and vegetables (r = 0·29), both P-values < 0·01. In unadjusted analysis, the difference in fasting glucose comparing the highest against the lowest tertile of the biomarkers concentrations was -0·28 (95 % CI -0·56, -0·001) mmol/l for total carotenoids and -0·31 (-0·59, -0·03) mmol/l for plasma α-carotene. The associations became stronger after adjusting for sociodemographics, lifesyle factors and cholesterol (-0·36 (-0·73, -0·002) mmol/l for total carotenoids and -0·41 (-0·79, -0·03) mmol/l for α-carotene). There was no evidence of an association between α-tocopherol and fasting glucose. We showed an inverse association of total carotenoids and α-carotene, objective indicators of F/V intake, with fasting glucose; suggesting that higher F/V intake may be beneficial for diabetes prevention in African populations where F/V intake is low.

Background:The longitudinal relationship between planetary heath diets and adiposity remains understudied in Europeans. We investigated the association between changes in adherence to the EAT-Lancet planetary health diet (PHD) and changes in adiposity and body fat distribution. Methods:We evaluated 6845 adults (mean age 49.4 years, 51% women), with repeat assessments in the Fenland Study at baseline (2005-2015) and follow-up (2014-2020). Diet was assessed with food frequency questionnaires and scaled to the PHD Index (PHDI) as a measure of adherence to the PHD (range: 0-140 points). Anthropometry, total fat, visceral, subcutaneous fat and lean mass, and liver fat score was measured at both visits. Multivariable-adjusted linear regression, adjusted for sociodemographic, lifestyle and clinical variables, assessed the association between changes in the PHDI and concurrent changes in adiposity. Findings:The mean (standard deviation) change in PHDI was 2.1 (±9.1) points. An increase in the PHDI (per 10 points, equivalent to ∼1 standard deviation), was associated negatively with changes in adiposity indices: total body weight (adjusted beta-coefficient: -0.47 kg; 95% confidence interval: -0.63, -0.31), waist circumference (-0.55 cm; -0.73, -0.37), fat mass (-0.43 kg; -0.56, -0.30), subcutaneous fat (-24.5 g; -34.0, 15.0), visceral fat (-40.0 g; -51.5, -28.5), liver fat score (-0.12; -0.15, -0.09), and lean mass (-0.08 kg; -0.13, -0.02). After further adjustment for changes in total body weight, inverse associations persisted for waist circumference, visceral fat, and liver fat. We found stronger associations among those with a BMI ≥30 kg/m2 for body weight, fat mass, lean mass, subcutaneous fat, visceral fat, and liver fat score (p for interaction<0.05). Interpretation:Increasing adherence to the PHD in midlife may reduce or slow gaining adiposity and improve body fat distribution, with greater magnitude in those already obese. These findings suggest a beneficial impact of adherence to the PHD on adiposity in Europeans. Funding:Funded by the UK Medical Research Council, NIHR Cambridge Biomedical Research Centre and the Independent Research Fund Denmark (1057-00016B) and Danish Diabetes Association.

Smoking increases the risk of type 2 diabetes, but its role in autoimmune diabetes remains unclear. We investigated whether smoking is associated with being GAD65 autoantibody (GAD65Ab) positive or the risk of progressing to diabetes. We also assessed its interaction with genetic susceptibility to type 1 diabetes. We used data from the EPIC-InterAct case–cohort study including 11,161 incident cases of adult-onset diabetes and 14,922 subcohort participants. Logistic regression was used to estimate odds ratios (ORs) for being GAD65Ab positive at baseline by smoking status. Hazard ratios (HRs) of diabetes by baseline smoking and GAD65Ab status were estimated using Prentice-weighted Cox regression. Two- and three-way interactions between smoking, GAD65Ab status and a type 1 diabetes genetic risk score (T1D-GRS) were assessed by attributable proportion due to interaction (AP). There was no evidence that smoking was associated with being GAD65Ab positive (OR 1.00, 95

BACKGROUND:Evidence regarding thyroid function changes with ageing remains inconsistent and the implications of potential changes are unclear. We aimed to investigate ageing-related thyroid function changes and their associations with mortality. METHODS:In this individual participant data (IPD) analysis, prospective population-based cohorts were eligible for inclusion when data on thyroid function measurements and mortality were available in individuals aged 18 years and older. Eligible datasets were identified through a systematic search of PubMed. We excluded cohorts of participants with only thyroid disease or thyroid-altering medications, or pregnant individuals. We requested data from all eligible cohorts that agreed to participate in the study. Linear mixed models were used to investigate associations between age and thyroid function, stratified for sex and regional iodine status. Annual changes in thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were estimated per individual and categorised into quintiles, with the highest and lowest quintiles defined as increasing and decreasing, respectively, and the rest as stable. Patterns of thyroid function change were identified based on combined TSH and FT4 evolution. We used cohort-stratified Cox models to assess associations between changing patterns and all-cause mortality. This study is registered with PROSPERO, CRD42023408086. FINDINGS:In this IPD analysis, we analysed data collected between Jan 1, 2011, and Oct 13, 2022, from 31 cohorts across Europe (n=19), the USA (n=5), Asia (n=3), Brazil (n=2), and Australia (n=2; 137 488 participants; 68 322 [49·7%] were female and 69 166 [50·3%] were male; median age 60 years [range 18-106]). Cross-sectionally, older age was associated with higher TSH in iodine-sufficient regions and with lower TSH in iodine-insufficient regions. Longitudinal analyses showed that TSH increased with increasing age regardless of iodine status. The overall increase in TSH from age 18 years to 100 years was 0·61 mIU/L (0·52 SD) for female participants and 0·99 mIU/L (0·76) for male participants from iodine-sufficient regions. Greater variability in population distribution and longitudinal TSH changes was observed in adults aged 65 years or older. Higher FT4 with older age was suggested cross-sectionally, but longitudinally FT4 increased in iodine-sufficient regions and decreased in iodine-insufficient regions. Compared with stable thyroid function, all changing patterns were associated with increased all-cause mortality: hazard ratios of 1·80 (95% CI 1·57-2·06) for increasing TSH with stable or decreasing FT4; 2·45 (2·01-2·97) for increasing TSH and increasing FT4; 2·45 (1·99-3·01) for decreasing TSH with decreasing FT4; and 1·94 (1·68-2·24) for decreasing TSH with stable or increasing FT4. INTERPRETATION:Ageing-related changes in thyroid function varied by sex and iodine status. Most individuals had stable thyroid function during ageing with a slight increase in TSH, although older adults displayed greater variability. Patterns of changing thyroid function were associated with an increased all-cause mortality risk, warranting further exploration of the underlying mechanisms and clinical management. FUNDING:None.

In this meta-analysis of international cohorts, current smoking is confirmed as a significant BMD-independent predictor of future fracture with a stronger relationship in men than in women. A causative and reversible effect of smoking on fracture risk is suggested by past smoking having a significantly lower risk than current smoking. In this meta-analysis of international cohorts, the aim was to examine the relationship of current and past smoking with fracture risk to provide an update for future iterations of the FRAX tool. The risk of fracture associated with current and past smoking was estimated using an extended Poisson model applied separately to each of 58 prospective international cohort studies. Covariates included current time since start of follow up, current age, and in an additional model, BMD at the femoral neck. The results of the different studies were merged by using inverse-variance weighted β-coefficients. This analysis included a total of 1,691,024 participants (61.2

AIMS:Both plasma levels of remnant cholesterol and low-density lipoprotein (LDL) cholesterol levels are independent risk factors for atherosclerotic cardiovascular disease. However, only remnant cholesterol has consistently been associated with systemic inflammation. In this study, we aimed to assess the extent to which inflammation mediates the effect of remnant and LDL cholesterol on (non)fatal major adverse cardiovascular events (MACE), comprising of coronary artery disease and ischaemic stroke. METHODS AND RESULTS:This prospective study included 16,445 participants without prior atherosclerotic cardiovascular disease from the EPIC-Norfolk study, with a mean age of 58.8 ± 9.1 years, of which 9,357 (56.9%) were women. Every 1 mmol/L higher remnant cholesterol was associated with 29.5% higher high-sensitivity C-reactive protein (hsCRP) levels [95% Confidence Interval (CI): 22.1, 37.4, P < 0.001], whereas LDL cholesterol was not significantly associated with hsCRP levels in the fully adjusted model. Additionally, each 1 mmol/L higher remnant cholesterol was associated with a hazard ratio (HR) of 1.31 (95% CI: 1.14, 1.50, P < 0.001) for MACE, compared with an HR of 1.21 (95% CI: 1.13, 1.31, P < 0.001) for LDL cholesterol. Mediation analysis showed that hsCRP mediated 5.9% (95% CI: 1.2, 10.6%, P < 0.001) of the effect of remnant cholesterol on MACE, whereas hsCRP did not mediate the effect of LDL cholesterol. CONCLUSION:Plasma remnant cholesterol levels are independently associated with systemic inflammation and cardiovascular events. Inflammation, as measured with hsCRP, contributed minorly to the association between remnant cholesterol and MACE. This underscores the need to address both remnant cholesterol and systemic inflammation separately in the clinical management of cardiovascular disease. LAY SUMMARY:This study finds that systemic inflammation does not influence the effect remnant cholesterol has on cardiovascular disease risk, suggesting the importance of addressing both remnant cholesterol and inflammation to manage cardiovascular health.

Antibodies are the principal effector proteins of humoral immunity. Dysregulated antibody production is a feature of a number of heritable immune-mediated diseases, such as the antibody deficiencies and IgA nephropathy. To characterize the common-variant architecture of serum antibody levels in the general population, we conducted the largest GWAS meta-analyses to date of serum IgA, IgM and IgG, attaining sample sizes of 85,204, 55,368 and 58,777, respectively. We identified 82 novel associations across three isotypes, including 38 novel IgA associations (of a total of 77), 36 novel IgM associations (of a total of 82) and 8 novel IgG associations (of a total of 14). We found that isotype-specific genetic architecture was largely disjoint, with few signals colocalising across isotypes in spite of their overall positive genetic correlation. We identified a large number of colocalisations between antibody phenotypes and immune-mediated diseases and 16 between antibody phenotypes and a lymphocyte count phenotype. We report a greatly expanded catalogue of serum antibody-associated variants and characterise these in terms of their pathway context and relation to immune pathology.

The relationship between bone mineral density (BMD) at the femoral neck and fracture risk was determined in a meta-analysis of primary data of 307205 men and women from 53 cohort studies. Low BMD was an important predictor of fracture risk, particularly for hip fracture. This study aimed to quantify the relationship between DXA-measured femoral neck BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value on fracture risk, with a view to updating FRAX®. We studied 307,205 men and women from within 53 predominately population-based cohorts followed up for an average of 8.7 years and a total of 2,683,185 person-years. The association of BMD and fracture risk was examined using a Poisson model in each cohort separately by sex. Results were expressed as a gradient of risk (GR, hazard ratio/standard deviation decrease in BMD). The different studies were then merged using weighted coefficients. Most hip fractures arose in men and women with low bone mass or osteoporosis at baseline (73 = 0.12 for women and p = 0.89 for men). A significant decrease in GR for hip fracture was observed with increasing duration of follow-up, but the magnitude of the effect was modest compared with the effect of age. For other fracture outcomes, including non-hip major osteoporotic fracture, the gradient of risk was lower than for hip fracture. Femoral neck BMD is a risk factor for fracture of substantial importance, particularly for future hip fracture. The lower magnitude of association at older age is consistent with other non-skeletal factors contributing to hip fracture risk with advancing age. Its validation on an international basis supports its use in case finding strategies. Its use should, however, take account of the variations in predictive value of BMD with age, sex, length of follow-up, and BMD.

The ‘European Prospective Investigation into Cancer and Nutrition’ cohort (EPIC) is a prospective study including 520,000 participants recruited across Europe (1991–2000) with in-depth baseline data on nutritional, lifestyle, medical, and anthropometric variables, and baseline blood samples. Here we introduce EPIC4ND, a case-cohort study within EPIC designed to identify biomarkers predicting a future onset of dementia, Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). EPIC4ND comprises 6415 initially non-diseased participants (aged 35–80 years, mean age at baseline: 54 ± 9, 64

In the largest meta-analysis of international cohorts to date, a family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. Parental and sibling histories of fracture carry the same significance for future fracture, including the impact of family hip fracture on future hip fracture risk. PURPOSE:We have undertaken a meta-analysis of international prospective cohorts to quantify the relationship between a family history of fracture and future fracture incidence. METHODS:The analysis dataset comprised 350,542 men and women from 42 cohorts in 29 countries followed for 2.8 million person-years. We investigated the relationship between family history of hip fracture or any fracture and the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture alone using an extended Poisson model in each cohort. Models were adjusted for current age, sex, BMD, and follow-up time. RESULTS:As no difference in influence of family history of fracture was seen between genders, results are presented for men and women combined. A parental history of hip fracture was associated with a higher risk of incident fracture across all fracture outcome categories, with a stronger relationship with future hip fracture (hazard ratios (HR, 95% CI) for hip and MOF 1.37, 1.23-1.52 and 1.19, 1.12-1.27, respectively). Associations were slightly reduced but remained significant when additionally adjusted for BMD and did not vary by baseline offspring age, follow-up time, or parent affected. In a more limited analysis, parental history of any fracture or a sibling history of hip or any fracture showed similar associations to those observed with parental history of hip fracture. CONCLUSIONS:A family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. While parental hip fracture appears the strongest factor for future hip fracture, a family history of other fractures might be appropriate for inclusion in future iterations of the FRAX tool.

Bladder cancer is the tenth most common cancer globally. Circulating proteins are key regulators of cellular functions, and proteomic analyses allow for a comprehensive investigation of proteins that may have causal roles in cancer development. We investigated the association between plasma proteins and bladder cancer risk in a case-cohort study within EPIC using a SomaLogic assay, comprising 4,047 sub-cohort members (15.3 years mean follow-up) and 254 bladder cancer cases (9.8 years mean follow-up), including 160 urothelial cell carcinoma (UCC) cases and 118 aggressive tumors. Prentice-weighted Cox regression models, with adjustment for smoking and other covariates, were conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with false discovery rate correction. Covariates included smoking status (never; former; current: ≤15 cigarettes/day, occasional or cigar smoker; current: >15 cigarettes/day), alcohol consumption (mL/day), BMI (kg/m2), diabetes (yes, no), physical activity (inactive; moderately inactive; moderately active; active), education (primary/none, secondary, university degree). Of 7,363 aptamers, we identified 31 significant associations with bladder cancer risk after false discovery rate correction. All HRs changed less than 15% when comparing the multivariable-adjusted to the minimally-adjusted model, and 11 proteins were also conventionally significant among never-smokers. Subgroup analyses identified nine proteins associated with UCC and 31 proteins associated with aggressive tumors. Twenty-five proteins were significant ≥10 years from blood collection. Notably, positive associations for I3L1E1 were observed for bladder cancer overall (HR: 1.23, 95% CI: 1.11-1.36), in never-smokers, and for cases diagnosed ≥10 years from blood collection, for WFIKKN1 in relation to UCC (HR: 1.33, 95% CI: 1.18-1.51), and for IRF4 in relation to aggressive tumors (HR: 1.29, 95% CI: 1.16-1.45). Evidence for several protein-cancer associations may suggest these could be used as novel biomarkers and provides insight into bladder cancer etiology. Alison Dillman, Zhe Huang, Joshua Atkins, Marc Gunter, Pietro Ferrari, Antonio Agudo, Carlotta Sacerdote, David C. Muller, Domenico Pali, Giovanna Masala, Monique Verschuren, Nicholas Wareham, Raul Zamora-Ros, Roel C. Zamora-Ros, Rosario Tumino, Salvatore Panico, Vivian Vallon, Elio Riboli, Karl Smith-Byrne, Ruth Travis. Prediagnostic circulating proteins and risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2337.