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Dysregulation of the urea cycle (UC) has been detected in colorectal cancer (CRC). However, the impact of the UC's end product, urea, on CRC development remains unclear. We investigated the association between serum urea and CRC risk based on the data of 348 872 participants cancer‐free at recruitment from the UK Biobank. Multivariable Cox proportional hazards models were fitted to conduct risk estimates. Stratification analyses based on sex, diet pattern, metabolic factors (including body mass index [BMI], the estimated glomerular filtration rate [eGFR] and type 2 diabetes [T2D]) and genetic profiles (the polygenic risk score [PRS] of CRC) were conducted to find potential modifiers. During an average of 9.0 years of follow‐up, we identified 3408 (1.0%) CRC incident cases. Serum urea showed a nonlinear relationship with CRC risk (P‐nonlinear:.035). Lower serum urea levels were associated with a higher CRC risk, with a fully‐adjusted hazard ratio (HR) of 1.26 (95% confidence interval [CI]: 1.13‐1.41) in the first quartile (Q1) of urea, compared to the Q4. This association was largely consistent across subgroups of sex, protein diet, BMI, eGFR and CRC‐PRSs (P‐interaction >.05); however, it was stronger in the T2D, with an interaction between urea and T2D on both additive (synergy index: 3.32, [95% CI: 1.24‐8.88]) and multiplicative scales (P‐interaction:.019). Lower serum urea concentrations were associated with an increased risk of CRC, with a more pronounced effect observed in individuals with T2D. Maintaining stable levels of serum urea has important implications for CRC prevention, particularly in individuals with T2D. [ABSTRACT FROM AUTHOR]

Background and Aim: Aberrant sleep parameters are associated with the risk of nonalcoholic fatty liver disease (NAFLD). However, existing information is inconsistent among studies and involves reverse causation. Therefore, we aimed to investigate the observational associations and causations between sleep traits and NAFLD. Methods: We performed multivariable regression to assess observational associations of seven sleep traits (sleep duration, easiness of getting up in the morning, chronotype, nap during day, snoring, insomnia, and narcolepsy), and NAFLD in the UK Biobank (1,029 NAFLD). The Cox proportional hazards model was applied to derive hazard ratios and 95% confidence intervals (CIs). Furthermore, a bidirectional two-sample Mendelian randomization (MR) approach was used to explore the causal relationships between sleep traits and NAFLD. Results: In the multivariable regression model adjusted for potential confounders, getting up in the morning not at all easy (HR, 1.51; 95% CI, 1.27–1.78) and usually insomnia (HR, 1.46; 95% CI, 1.21–1.75) were associated with the risk of NAFLD. Furthermore, the easiness of getting up in the morning and insomnia showed a dose–response association with NAFLD (Ptrend <0.05). MR analysis found consistent causal effects of NAFLD on easiness of getting up in the morning (OR, 0.995; 95% CI, 0.990–0.999; p = 0.033) and insomnia (OR, 1.006; 95% CI, 1.001–1.011; p = 0.024). These results were robust to weak instrument bias, pleiotropy, and heterogeneity. Conclusions: Findings showed consistent evidence of observational analyses and MR analyses that trouble getting up in the morning and insomnia were associated with an increased risk of NAFLD. Bidirectional MR demonstrated causal effects of NAFLD on sleep traits. [ABSTRACT FROM AUTHOR]

Viral hepatitis has been recognized as a leading cause of deaths worldwide. We aimed to analyse the disease burden of viral hepatitis at the global, regional and national levels. We collected the data of death number, mortality rate, and disability‐adjusted life years (DALYs) of viral hepatitis by sex, age, geography and type of disease from the Global Health Data Exchange platform. Estimated average percentage change (EAPC) was used to quantify the age‐standardized mortality rate (ASMR) of viral hepatitis between 1990 and 2017. Globally, the number of deaths from viral hepatitis increased from 980.9 thousand in 1990 to 1412.3 thousand in 2017, accompanying by the DALYs increased from 35.2 million to 43.1 million in the same period. Hepatitis B and C accounted for 97.6% of total viral hepatitis‐related deaths worldwide in 2017. While the death number and DALYs were decreased in acute hepatitis A, B, C and E, a significant increase was found in liver cancer and cirrhosis due to hepatitis B and C. The ASMRs of liver cancer and cirrhosis caused by hepatitis B and C were decreased at the global level and in most regions. However, a significant increase was observed in several developed countries, such as the USA and the UK. The disease burden of viral hepatitis continues to increase worldwide, which was driven by the increase in burden of chronic hepatitis B and C. [ABSTRACT FROM AUTHOR]

Unhealthy sleep behaviors are associated with higher risks of osteoporosis (OP), while prospective evidence is limited. This study aimed to prospectively investigate this association, quantify the attributable burden of OP incidence reduction due to unhealthy sleep behaviors, and explore potential modifications by genetic risk factors. This longitudinal cohort study was conducted utilizing data from the UK Biobank, comprising 293,164 participants initially free of OP and with requisite sleep behaviors data at baseline. We followed the participants after recruitment until November 30, 2022, to ascertain incident OP. We assessed the associations of five sleep behaviors including sleep duration, chronotype, insomnia, daytime napping, and morning wake-up difficulties, as well as sleep behavior patterns identified based on the above sleep behaviors, with the risk of OP, using Cox models adjusted for multiple confounders. The analyses were then performed separately among individuals with different OP susceptibility, indexed by standard polygenetic risk scores(PRS) for OP. Our secondary outcome was OP with pathologic fracture. Subgroup and sensitivity analyses were performed. Additionally, attributable risk percent in the exposed population (AR%) and population attributable fraction (PAF) of sleep behaviors were calculated. Over a median follow-up of 13.7 years, 8253 new-onset OP cases were documented. Unhealthy sleep behaviors, such as long or short sleep duration, insomnia, daytime napping, morning wake-up difficulties, and unhealthy sleep patterns, were associated with elevated risks of OP (HRs ranging from 1.14 to 1.46, all P -value <0.001) compared to healthy sleep behaviors. Similar associations were observed for OP with pathologic fractures. Insomnia exhibited the largest AR% of 39.98 % (95%CI: 36.46, 43.31) and PAF of 33.25 % (95%CI: 30.00, 36.34) among healthy sleep patterns and components. A statistically significant multiplicative interaction was noted between sleep behaviors and OP PRS on OP risk (all P -interaction <0.001). Four unhealthy sleep behaviors and sleep behavior patterns were associated to increased OP risk, with insomnia contributing the most to OP incidence, while genetic risk for OP modified this association. These findings underscore the crucial role of adhering to healthy sleep behaviors for effective OP prevention. • Unhealthy sleep behaviors were associated with higher risks of osteoporosis. • Insomnia's attributable risk for osteoporosis was the highest among sleep behaviors. • Genetic risk modified the association between sleep behaviors and osteoporosis. [ABSTRACT FROM AUTHOR]

Accelerated biological aging may be associated with increased risk of esophageal adenocarcinoma (EAC). However, its relationship with genetic variation, and its effect on improving risk population stratification, remains unknown. We performed an exposome association study to determine potential associated factors associated with EAC. To quantify biological age and its difference from chronological age, we calculated the BioAge10 and Biological Age Acceleration (BioAgeAccel) based on chronological age and nine biomarkers. Multivariable Cox regression models for 362,310 participants from the UK Biobank with a median follow-up of 13.70 years were performed. We established a weighted polygenic risk score (wPRS) associated with EAC, to assess joint and interaction effects with BioAgeAccel. Four indicators were used to evaluate their interaction effects, and we fitted curves to evaluate the risk stratification ability of BioAgeAccel. Compared with biologically younger participants, those older had higher risk of EAC, with adjusted HR of 1.79 (95%CI: 1.52-2.10). Compared with low wPRS and biologically younger group, the high wPRS and biologically older group had a 4.30-fold increase in HR (95% CI: 2.78-6.66), at meanwhile, 1.15-fold relative excess risk was detected (95% CI: 0.30-2.75), and 22% of the overall EAC risk was attributable to the interactive effects (95% CI: 12%-31%). The 10-year absolute incidence risk indicates that biologically older individuals should begin screening procedures 4.18 years in advance, while youngers can postpone screening by 4.96 years, compared with general population. BioAgeAccel interacted positively with genetic variation and increased risk of EAC, it could serve as a novel indicator for predicting incidence., (© 2024 UICC.)

Background & Aims: The role of circulating polyunsaturated fatty acids (PUFAs) in preventing liver cirrhosis complications remains unclear., Methods: Between 2006 and 2010, 273,834 UK Biobank participants with plasma PUFA quantification data were enrolled and followed up until October 31, 2022. Plasma PUFAs were quantified using a high-throughput nuclear magnetic resonance-based metabolic profiling platform. Liver cirrhosis complications were defined as hospitalization for liver cirrhosis or presentation with hepatocellular carcinoma., Results: During a median follow-up of 13.9 years, 2026 participants developed liver cirrhosis complications. Total plasma PUFAs, omega-3 PUFAs, docosahexaenoic acid (DHA), omega-6 PUFAs, and linoleic acid (LA) were inversely associated with the risk of liver cirrhosis complications, whereas the plasma omega-6/omega-3 ratio was positively associated. Nonparametrically restricted cubic spline regression showed nonlinear associations of plasma PUFAs with liver cirrhosis complications. The inflection points were 4.78 mmol/L for total PUFAs, 0.73 mmol/L for omega-3 PUFAs, 0.25 mmol/L for DHA, 4.07 mmol/L for omega-6 PUFAs, and 2.99 mmol/L for LA. Plasma omega-3 PUFAs were negatively associated with the risk of liver cirrhosis complications when omega-3 PUFAs were <0.73 mmol/L (adjusted hazard ratio [HR], 0.11 [0.08-0.16]), whereas the association was inverted when omega-3 PUFAs were ≥0.73 mmol/L (adjusted HR, 1.87 [1.20-2.92])., Conclusions: The protective effect of plasma omega-3 PUFAs on liver cirrhosis complications is reversed after passing the corresponding inflection point, suggesting an optimal dietary omega-3 PUFA supplementation dose., Competing Interests: Conflict of interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Mitochondrial (MT) dysfunction is a hallmark of liver diseases. However, the effects of functional variants such as protein truncating variants (PTVs) in MT-related genes on the risk of liver diseases have not been extensively explored., Methods: We extracted 60,928 PTVs across 2466 MT-related nucleus genes using whole-exome sequencing data obtained from 442,603 participants in the UK Biobank. We examined their associations with liver dysfunction that represented by the liver-related biomarkers and the risks of chronic liver diseases and liver-related mortality., Results: 96.10% of the total participants carried at least one PTV. We identified 866 PTVs that were positively associated with liver dysfunction at the threshold of P value < 8.21e - 07. The coding genes of these PTVs were mainly enriched in pathways related to lipid, fatty acid, amino acid, and carbohydrate metabolisms. The 866 PTVs were presented in 1.07% (4721) of participants. Compared with participants who did not carry any of the PTVs, the carriers had a 5.33-fold (95% CI 4.15-6.85), 2.82-fold (1.69-4.72), and 4.41-fold (3.04-6.41) increased risk for fibrosis and cirrhosis of liver, liver cancer, and liver disease-related mortality, respectively. These adverse effects were consistent across subgroups based on age, sex, body mass index, smoking status, and presence of hypertension, diabetes, dyslipidemia, and metabolic syndrome., Conclusions: Our findings revealed a significant impact of PTVs in MT-related genes on liver disease risk, highlighting the importance of these variants in identifying populations at risk of liver diseases and facilitating early clinical interventions., (© 2024. The Author(s).)

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant health issue closely associated with multiple metabolic dysfunctions. The association between MAFLD and cancer risk is yet unknown., Methods: UK Biobank study participants were diagnosed for the presence of MAFLD at baseline. A multivariable Cox regression model was performed to examine the associations of MAFLD with incident events in 24 specific cancers., Results: We included 352,911 individuals (37.2% with MAFLD), among whom 23,345 developed cancers. Compared with non-MAFLD, MAFLD was significantly associated with 10 of the 24 examined cancers, including corpus uteri (hazard ratio [HR] = 2.36, 95% CI 1.99-2.80), gallbladder (2.20, 1.14-4.23), liver (1.81, 1.43-2.28), kidney (1.77, 1.49-2.11), thyroid (1.69, 1.20-2.38), esophagus (1.48, 1.25-1.76), pancreas (1.31, 1.10-1.56), bladder (1.26, 1.11-1.43), breast (1.19, 1.11-1.27), and colorectal and anus cancers (1.14, 1.06-1.23). The associations of MAFLD with liver, esophageal, pancreatic, colorectal and anal and bladder cancers and malignant melanoma were strengthened in males, and associations with kidney, thyroid, and lung cancers were increased in females. The associations of MAFLD with the risk of liver, kidney, and thyroid cancers remained significant after further adjusting for the waist circumference or body mass index and the number of metabolic syndrome components based on the main models. The risk-increasing allele of PNPLA3 rs738409 significantly amplified the association of MAFLD with the risk of liver and kidney cancers., Conclusion: MAFLD is associated with an increased risk of a set of cancers, but the effect substantially varies by site. MAFLD deserves higher priority in the current scheme of cancer prevention., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)