Abstract
Although GWASs have been conducted to investigate genetic variation of bladder tumorigenesis, little is known about genetic interactions that may influence bladder cancer (BC) risk. By ...leveraging large‐scale participants from UK Biobank, we established a discovery database with 4000 Caucasian participants (2000 cases vs 2000 non‐cases), a database with 1648 Caucasian participants (824 cases vs 824 non‐cases) and 856 non‐Caucasian participants (428 cases vs 428 non‐cases) as validation. We then performed a genome‐wide SNP‐SNP interaction investigation related to BC risk based a machine learning approach (ie, GenEpi). Moreover, we used the selected interactions to build a BC screening model with an integrated interaction‐empowered polygenic risk score (iPRS) based on Cox proportional hazard model. With Bonferroni correction, we identified 10 statistically significant pairs of SNPs, which located in 17 chromosomes. Of these, four SNP‐SNP interactions were found to be positively associated with BC risk among Caucasian participants (ORs 1.57‐2.03), while six SNP‐SNP interactions showed negatively associated with BC risk (ORs 0.54‐0.65). Only four of the SNP‐SNP interactions were consistently identified in non‐Caucasian participants located in
ST7L
‐
ADSS2, FHIT
‐
CHDH, LARP4B
‐
LHPP
and
RBFOX3
‐
MPRIP
. In addition, the iPRS showed a HR of 1.81 (95% CI: 1.46‐2.09) compared the highest tertile to the lowest tertile, with an enhanced AUC (0.91; 95% CI:0.85‐0.97) than PRS (AUC: 0.86; 95% CI:0.76‐0.95;
P
‐
DeLong test
= 2.2 × 10
−4
). In summary, this study identified several important SNP‐SNP interactions for BC risk, and developed an iPRS model for BC screening, which may help to identify the people at high‐risk state of BC before early manifestation.
Objectives
To investigate the association of polygenic risk score (PRS) and bladder cancer (BC) risk and whether this PRS can be offset by a healthy lifestyle.
Methods
Individuals with BC (n = 563) ...and non‐BC controls (n = 483 957) were identified in the UK Biobank, and adjusted Cox regression models were used. A PRS was constructed based on 34 genetic variants associated with BC development, while a healthy lifestyle score (HLS) was constructed based on three lifestyle factors (i.e., smoking, physical activity, and diet).
Results
Overall, a negative interaction was observed between the PRS and the HLS (P = 0.02). A 7% higher and 28% lower BC risk per 1‐standard deviation (SD) increment in PRS and HLS were observed, respectively. A simultaneous increment of 1 SD in both HLS and PRS was associated with a 6% lower BC risk. In addition, individuals with a high genetic risk and an unfavourable lifestyle showed an increased BC risk compared to individuals with low genetic risk and a favourable lifestyle (hazard ratio 1.55, 95% confidence interval 1.16–1.91; P for trend <0.001). Furthermore, population‐attributable fraction (PAF) analysis showed that 12%–15% of the BC cases might have been prevented if individuals had adhered to a healthy lifestyle.
Conclusion
This large‐scale cohort study shows that a genetic predisposition combined with unhealthy behaviours have a joint negative effect on the risk of developing BC. Behavioural lifestyle changes should be encouraged for people through comprehensive, multifactorial approaches, although high‐risk individuals may be selected based on genetic risk.
Proteomic profiling of extracellular vesicles (EVs) represents a promising approach for early detection and therapeutic monitoring of diseases such as cancer. The focus of this study was to apply ...robust EV isolation and subsequent data-independent acquisition mass spectrometry (DIA-MS) for urinary EV proteomics of prostate cancer and prostate inflammation patients. Urinary EVs were isolated by functionalized magnetic beads through chemical affinity on an automatic station, and EV proteins were analyzed by integrating three library-base analyses (Direct-DIA, GPF-DIA, and Fractionated DDA-base DIA) to improve the coverage and quantitation. We assessed the levels of urinary EV-associated proteins based on 40 samples consisting of 20 cases and 20 controls, where 18 EV proteins were identified to be differentiated in prostate cancer outcome, of which three (i.e., SERPINA3, LRG1, and SCGB3A1) were shown to be consistently upregulated. We also observed 6 out of the 18 (33%) EV proteins that had been developed as drug targets, while some of them showed protein-protein interactions. Moreover, the potential mechanistic pathways of 18 significantly different EV proteins were enriched in metabolic, immune, and inflammatory activities. These results showed consistency in an independent cohort with 20 participants. Using a random forest algorithm for classification assessment, including the identified EV proteins, we found that SERPINA3, LRG1, or SCGB3A1 add predictable value in addition to age, prostate size, body mass index (BMI), and prostate-specific antigen (PSA). In summary, the current study demonstrates a translational workflow to identify EV proteins as molecular markers to improve the clinical diagnosis of prostate cancer.
Observational studies suggests that diets and medications affect bladder cancer (BC) development, which are subject to confounding and difficult to make causal inference. Here we aimed to investigate ...whether those observational associations are causal and determining the potential directions and pathways.
We used 2-sample Mendelian randomization (MR) analysis to assess associations of dietary intakes, medication uses and molecules with BC risk. Genetic summary data were derived from participants of predominantly European ancestry with rigorous instruments selection, where univariable MR, mediation MR and multivariable MR were performed.
The results of univariable MR showed 4 dietary intakes and 4 medication uses having a protective effect on BC, while 4 circulating metabolites, 440 circulating proteins and 2 gut microbes were observed to be causally associated with BC risk. Through mediation MR, we found 572 analytes showing consistent mediating effects between dietary intakes or medication uses and BC risk. Furthermore, 9 out of 16 diet-medication pairs showed significant interactions and alterations on BC when consumed jointly.
In summary, the findings obtained from the current study have important implications for informing prevention strategies that point to potential lifestyle interventions or medication prescriptions to reduce the risk of developing BC.
Highlights
The current study extends observational literature in showing the importance of diets and medications on bladder cancer prevention.
The associations of diets and medications on bladder cancer prevention might be through circulating metabolites, circulating proteins and gut microbiota
Our results provide a new understanding of interactions in certain diet-medication pairs which should be taken into account by both physicians and patients during the development of a treatment strategy.
Objectives
To quantify the health‐related quality of life (HRQoL) of patients with bladder cancer around the time of diagnosis and to test the hypotheses of a two‐factor model for the HRQoL ...questionnaire QLQ‐C30.
Methods
From participants in the Bladder Cancer Prognoses Programme, a multicentre cohort study, sociodemographic data were collected using semi‐structured face‐to‐face interviews. Answers to the QLQ‐C30 were transformed into a scale from 0 to 100. HRQoL data were analysed in multivariate analyses. The hypothesized two‐factor (Physical and Mental Health) domain structure of the QLQ‐C30 was also tested with confirmatory factor analyses (CFA).
Results
A total of 1160 participants (78%) completed the questionnaire after initial visual diagnosis and before pathological confirmation. Despite non‐muscle‐invasive bladder cancer (NMIBC) being associated with a higher HRQoL than carcinoma invading bladder muscle, only the domain Role Functioning was clinically significantly better in patients with NMIBC. Age, gender, bladder cancer stage and comorbidity all had a significant influence on QLQ‐C30 scores. The CFA showed an overall good fit of the hypothesized two‐factor model.
Conclusion
This study identified a baseline reference value for HRQoL for patients with bladder cancer, which allows better evaluation of any changes in HRQoL as disease progresses or after treatment. In addition, a two‐factor (Physical and Mental Health) model was developed for the QLQ‐C30.
Background
The incidence of acute pancreatitis (AP) is increasing over years, which brings enormous economy and health burden. However, the aetiologies of AP and underlying mechanisms are still ...unclear. Here, we performed a two‐sample Mendelian randomization (MR) analysis to investigate the associations between all reported possible risk factors and AP using publicly available genome‐wide association study summary statistics.
Methods
A series of quality control steps were taken in our analysis to select eligible instrumental single nucleotide polymorphisms which were strongly associated with exposures. To make the conclusions more robust and reliable, we utilized several analytical methods (inverse‐variance weighting, MR‐PRESSO method, weighted median, MR‐Egger regression) that are based on different assumptions of two‐sample MR analysis. The MR‐Egger intercept test, radial regression and leave‐one‐out sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on each exposure. A two‐step MR method was applied to explore mediators in significant associations.
Results
Genetic predisposition to cholelithiasis (effect estimate: 17.30, 95% CI: 12.25–22.36, p = 1.95 E‐11), body mass index (0.32, 95% CI: 0.13–0.51, p < 0.001), body fat percentage (0.57, 95% CI: 0.31–0.83, p = 1.31 E‐05), trunk fat percentage (0.36, 95% CI: 0.14–0.59, p < 0.005), ever smoked (1.61, 95% CI: 0.45–2.77, p = 0.007), and limbs fat percentage (0.55, 95% CI: 0.41–0.69, p < 0.001) were associated with an increased risk of AP. In addition, whole‐body fat‐free mass (−0.32, 95% CI: −0.55 to −0.10, p = 0.004) was associated with a decrease risk of AP.
Conclusion
Genetic predisposition to cholelithiasis, obesity and smoking could be causally associated with an increased risk of AP, and whole body fat‐free mass could be associated with a decreased risk of AP.
The incidence of acute pancreatitis is increasing over years especially in western countries, but the etiologies of acute pancreatitis have not been well understood. And it is unclear whether the reported possible risk factors are real causes of acute pancreatitis. To our knowledge, our research is the first to explore the associations of all reported possible risk factors and acute pancreatitis using public data from the UK biobank and the FinnGen consortium.
Although observational studies have shown positive associations between body mass index (BMI) and the risk of atrial fibrillation (AF), the causal relationship is still uncertain owing to the ...susceptibility to confounding and reverse causation. This study aimed to examine the potential causality of BMI on AF by conducting a two-sample Mendelian randomization (TSMR) study.
The independent genetic variants associated with BMI (
= 303) at the genome-wide significant level were derived as instrumental variables (IV) from the Genetic Investigation of Anthropometric Traits (GIANT) consortium consisting of 681,275 individuals of European ancestry. We then derived the outcome data from a GWAS meta-analysis comprised of 60,620 cases and 970,216 controls of European ancestry. The TSMR analyses were performed in five methods, namely inverse variance weighted (IVW) method, MR-Egger regression, the weighted median estimator (WME), the generalized summary data-based Mendelian randomization (GSMR), and the robust adjusted profile score (RAPS), to investigate whether BMI was causally associated with the risk of AF.
We found a genetically determined 1-standard deviation (SD) increment of BMI causally increased a 42.5% risk of AF (OR = 1.425; 95% CI, 1.346 to 1.509) based on the IVW method, which was consistent with the results of MR-Egger regression, WME, GSMR, as well as RAPS. The Mendelian randomization assumptions did not seem to be violated.
This study provides evidence that higher BMI causally increased the risk of AF, suggesting control of BMI and obesity for prevention of AF.
Identification of protein quantitative trait loci (pQTL) helps understand the underlying mechanisms of diseases and discover promising targets for pharmacological intervention. For most important ...class of drug targets, genetic evidence needs to be generalizable to diverse populations. Given that the majority of the previous studies were conducted in European ancestry populations, little is known about the protein-associated genetic variants in East Asians. Based on data-independent acquisition mass spectrometry technique, we conduct genome-wide association analyses for 304 unique proteins in 2,958 Han Chinese participants. We identify 195 genetic variant-protein associations. Colocalization and Mendelian randomization analyses highlight 60 gene-protein-phenotype associations, 45 of which (75%) have not been prioritized in Europeans previously. Further cross-ancestry analyses uncover key proteins that contributed to the differences in the obesity-induced diabetes and coronary artery disease susceptibility. These findings provide novel druggable proteins as well as a unique resource for the trans-ancestry evaluation of protein-targeted drug discovery.
Objectives: The molecular landscape of non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) bladder cancer based on molecular characteristics is essential but poorly understood. In this pilot study ...we aimed to identify a multi-omics signature that can distinguish MIBC from NMIBC. Such a signature can assist in finding potential mechanistic biomarkers and druggable targets. Methods: Patients diagnosed with NMIBC (n = 15) and MIBC (n = 11) were recruited at a tertiary-care hospital in Nanjing from 1 April 2021, and 31 July 2021. Blood, urine and stool samples per participant were collected, in which the serum metabolome, urine metabolome, gut microbiome, and serum extracellular vesicles (EV) proteome were quantified. The differences of the global profiles and individual omics measure between NMIBC vs. MIBC were assessed by permutational multivariate analysis and the Mann–Whitney test, respectively. Logistic regression analysis was used to assess the association of each identified analyte with NMIBC vs. MIBC, and the Spearman correlation was used to investigate the correlations between identified analytes, where both were adjusted for age, sex and smoking status. Results: Among 3168 multi-omics measures that passed the quality control, 159 were identified to be differentiated in NMIBC vs. MIBC. Of these, 46 analytes were associated with bladder cancer progression. In addition, the global profiles showed significantly different urine metabolome (p = 0.029), gut microbiome (p = 0.036), and serum EV (extracellular vesicles) proteome (p = 0.039) but not serum metabolome (p = 0.059). We also observed 17 (35%) analytes that had been developed as drug targets. Multiple interactions were obtained between the identified analytes, whereas for the majority (61%), the number of interactions was at 11–20. Moreover, unconjugated bilirubin (p = 0.009) and white blood cell count (p = 0.006) were also shown to be different in NMIBC and MIBC, and associated with 11 identified omics analytes. Conclusions: The pilot study has shown promising to monitor the progression of bladder cancer by integrating multi-omics data and deserves further investigations.
Although a potential inverse association between vegetable intake and bladder cancer risk has been reported, epidemiological evidence is inconsistent. This research aimed to elucidate the association ...between vegetable intake and bladder cancer risk by conducting a pooled analysis of data from prospective cohort studies.
Vegetable intake in relation to bladder cancer risk was examined by pooling individual-level data from 13 cohort studies, comprising 3203 cases among a total of 555,685 participants. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were estimated using Cox proportional hazards regression models stratified by cohort for intakes of total vegetable, vegetable subtypes (i.e. non-starchy, starchy, green leafy and cruciferous vegetables) and individual vegetable types. In addition, a diet diversity score was used to assess the association of the varied types of vegetable intake on bladder cancer risk.
The association between vegetable intake and bladder cancer risk differed by sex (P-interaction = 0.011) and smoking status (P-interaction = 0.038); therefore, analyses were stratified by sex and smoking status. With adjustment of age, sex, smoking, energy intake, ethnicity and other potential dietary factors, we found that higher intake of total and non-starchy vegetables were inversely associated with the risk of bladder cancer among women (comparing the highest with lowest intake tertile: HR = 0.79, 95% CI = 0.64-0.98, P = 0.037 for trend, HR per 1 SD increment = 0.89, 95% CI = 0.81-0.99; HR = 0.78, 95% CI = 0.63-0.97, P = 0.034 for trend, HR per 1 SD increment = 0.88, 95% CI = 0.79-0.98, respectively). However, no evidence of association was observed among men, and the intake of vegetable was not found to be associated with bladder cancer when stratified by smoking status. Moreover, we found no evidence of association for diet diversity with bladder cancer risk.
Higher intakes of total and non-starchy vegetable are associated with reduced risk of bladder cancer for women. Further studies are needed to clarify whether these results reflect causal processes and potential underlying mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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