Associations of childhood and adulthood body size, and child-to-adult body size change with adult telomere length.

AIM: To comprehensively examine the associations of childhood and adulthood body size, and child-to-adult body size change with adult leucocyte telomere length (LTL). METHODS: We included 453 602 participants from the UK Biobank. Childhood body size at the age of 10 years was collected through a questionnaire. Adulthood body size was assessed using body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), fat mass index (FMI), and fat-free mass index (FFMI). RESULTS: Individuals with plumper body size in childhood exhibited shorter LTL in adulthood (-0.0086 [-0.0017, -0.0004]). Adulthood BMI (-0.0286 [-0.0315, -0.0258]), WC (-0.0271 [-0.0303, -0.0238]), WHR (-0.0269 [-0.0308, -0.0230]) and FMI (-0.0396 [-0.0438, -0.0351]) were negatively associated with LTL, whereas FFMI (0.0095 [0.0039, 0.0152]) was positively associated with LTL. Compared to individuals consistently having an average/normal weight in both childhood and adulthood, those who maintained or developed overweight/obesity from childhood to adulthood had a shorter adult LTL, regardless of childhood body size. Notably, the LTL shortening effect was not observed in individuals with plumper body size in childhood but normal weight in adulthood. CONCLUSIONS: Childhood and adulthood obesity are both associated with LTL shortening in adulthood. Transitioning to or maintaining overweight/obese status from childhood to adulthood is associated with shorter adult LTL, whereas this effect can be reversed if plumper children become normal weight.

Serum Uric Acid Levels Associated with Outcomes of Neurodegenerative Disorders and Brain Health: Findings from the UK Biobank.

BACKGROUND: The relationship between serum uric acid (SUA) levels and brain-related health remains uncertain. OBJECTIVES: This study aimed to investigate the relationship between SUA levels and some neurodegenerative disorders and brain structure. DESIGN: A longitudinal study. SETTING AND PARTICIPANTS: 384,517 participants who did not have stroke, dementia, and Parkinsonism, with complete urate testes and covariates were included. MEASUREMENTS: Cox proportional hazards models, competing risk models, and restricted cubic spine models were applied. RESULTS: During the median follow-up time of 12.7 years (interquartile range [IQR]:12.0, 13.5), 7821 (2.0%) participants developed stroke, 5103 (1.3%) participants developed dementia, and 2341 (0.6%) participants developed Parkinsonism. Nonlinear relationships were identified between SUA levels and stroke (J-shaped), dementia, and Parkinsonism (U-shaped). SUA levels of 4.2 mg/dl, 6.4 mg/dl, and 6.6 mg/dl yielded the lowest risk of stroke, dementia, and Parkinsonism, respectively. Besides, we found high SUA levels reduced the volumes of total brain, grey matter, white matter, grey matter in the hippocampus, and hippocampus, but increased lateral-ventricle volume. Inflammation accounted for 9.1% and 10.0% in the association of SUA with stroke and lateral-ventricle volume. CONCLUSIONS: Lower SUA levels increased the risk of Parkinsonism, while both lower and higher SUA levels were positively associated with increased risk of stroke and dementia. Moreover, high SUA levels reduced brain structure volumes. Our findings suggest the association between SUA levels and brain-related disorders and highlight the importance of SUA management.

Nonlinear relationships of circulating polyunsaturated fatty acids with the complications of liver cirrhosis: A prospective, longitudinal cohort study.

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.

Female-specific association between the APOE E4 allele and age at diagnosis of glaucoma in UK Biobank.

OBJECTIVE: To explore the impact of the apolipoprotein E (APOE) E4 allele in the gender-specific aging process in glaucoma by illustrating the interaction between risk factors, including the APOE E4 allele, gender and intraocular pressure (IOP), for age at diagnosis (AAD) of glaucoma. DESIGN: A cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis. Data were analyzed in December 2023. PARTICIPANTS: 2,236 glaucoma patients and 103,232 controls. METHODS: We evaluated multivariable-adjusted associations of AAD of glaucoma, APOE E4 allele (0: absence; 1: presence), and IOP using linear mixed model (LMM) analyses across groups stratified by AAD of mean age of menopause (50 years) and gender. MAIN OUTCOMES MEASURES: AAD of glaucoma, APOE E4 allele and IOP. RESULTS: Glaucoma patients were older and had a higher percentage of males and a higher mean IOP compared to controls (all P < 0.001). Further stratifying the glaucoma patients by AAD of 50 and gender, lower IOP (Model 1 adjusted by age, ßIOP=-0.096±0.041, P=0.019) and positive APOE E4 allele (Model 2 adjusted by age and IOP, ße4=1.093±0.488, P=0.026) were associated with an older AAD in females with an AAD < 50 years under univariate LMM. In multivariate LMM adjusted by age (Model 3), the effect size of both factors increased in the multivariate model as the beta-value increased. (ßIOP=-0.111±0.040, P=0.007; ße4=1.235±0.485, P=0.012) (Model 1 vs Model 3: P=0.011). In females with an AAD ≥50 years, only positive APOE E4 allele (adjusted by age and IOP, ße4=-1.121±0.412, P=0.007) was associated with a younger AAD. In males, only higher IOP was associated with an older AAD in those with an AAD ≥50 years (ßIOP=0.088±0.032, P=0.006). CONCLUSIONS: APOE E4 allele may initially delay and later accelerate the development of glaucoma in females around the transition period of 50 years, which is the mean age of menopause, and importantly, this is independent of IOP. Understanding the specific transition states and modifiable factors within each age phase is crucial for developing interventions or strategies that promote healthy aging.

Exploring pleiotropy in Mendelian randomisation analyses: What are genetic variants associated with 'cigarette smoking initiation' really capturing?

Genetic variants used as instruments for exposures in Mendelian randomisation (MR) analyses may have horizontal pleiotropic effects (i.e., influence outcomes via pathways other than through the exposure), which can undermine the validity of results. We examined the extent of this using smoking behaviours as an example. We first ran a phenome-wide association study in UK Biobank, using a smoking initiation genetic instrument. From the most strongly associated phenotypes, we selected those we considered could either plausibly or not plausibly be caused by smoking. We examined associations between genetic instruments for smoking initiation, smoking heaviness and lifetime smoking and these phenotypes in UK Biobank and the Avon Longitudinal Study of Parents and Children (ALSPAC). We conducted negative control analyses among never smokers, including children. We found evidence that smoking-related genetic instruments were associated with phenotypes not plausibly caused by smoking in UK Biobank and (to a lesser extent) ALSPAC. We observed associations with phenotypes among never smokers. Our results demonstrate that smoking-related genetic risk scores are associated with unexpected phenotypes that are less plausibly downstream of smoking. This may reflect horizontal pleiotropy in these genetic risk scores, and we would encourage researchers to exercise caution this when using these and genetic risk scores for other complex behavioural exposures. We outline approaches that could be taken to consider this and overcome issues caused by potential horizontal pleiotropy, for example, in genetically informed causal inference analyses (e.g., MR) it is important to consider negative control outcomes and triangulation approaches, to avoid arriving at incorrect conclusions.

Negative Emotions Are Associated With Older Self-perceived Age: A Cross-section Study From the UK Biobank.

BACKGROUND: Prior research has indicated a potential connection between psychological stress and how individuals perceive their own age. Building on this foundation, the current study explores the relationship between negative emotions and self-perceived age. METHODS: We conducted a cross-sectional analysis using data from the UK Biobank, a comprehensive cohort study representing the UK population. The analysis included 347 892 participants, aged between 39 and 73 years, of which 184 765 were women, accounting for 53.1% of the sample. Participants were categorized into three groups based on their self-perceived age: feeling younger than their chronological age (group Younger), feeling older than their chronological age (group Older), and feeling as old as their actual age (group Same). To investigate the relationship between negative emotions and self-perceived age, we utilized a multinomial logistic regression model with the Younger group serving as the reference category. RESULTS: Of 347 892 participants, after adjusted for covariates, the results showed that participants with irritability, nervous feelings, worrier/anxious feelings or fed-up feelings, worry too long and loneliness/isolation are more likely to be rated as "about your age" or "older than you are," with "younger than you are" as the reference group, indicating that negative emotions may influence one's self-perceived age. Among those negative emotions, irritability has the most significant impact self-perceived age, with the odds ratios (ORs) being 1.44 (95% CI: 1.35-1.54) and 1.11 (95% CI: 1.09-1.14). CONCLUSION: Negative emotions are associated with older self-perceived age, and irritability has the greatest impact. Further studies analyzing self-perceived age are needed to take psychological factors into consideration.

Association of triglyceride-glucose index with the risk of incident aortic dissection and aneurysm: a large-scale prospective cohort study in UK Biobank.

BACKGROUND: Triglyceride-glucose (TyG) index is an emerging surrogate indicator of insulin resistance, which has been demonstrated as a risk factor for various cardiovascular diseases including coronary syndrome, in-stent restenosis, and heart failure. However, association of TyG index with incident aortic dissection (AD) and aortic aneurysm (AA) remains to be investigated. METHODS: This study included 420,292 participants without baseline AD/AA from the large-scale prospective UK Biobank cohort. The primary outcome was incident AD/AA, comprising AD and AA. Multivariable-adjusted Cox proportional hazards regression models and restricted cubic spline (RCS) analyses were applied to assess the relationship between TyG index and the onset of AD/AA. In addition, the association between TyG index and incident AD/AA was examined within subgroups defined by age, gender, smoking status, drinking status, diabetes, hypertension, and BMI. RESULTS: Over a median follow-up period of 14.8 (14.1, 15.5) years, 3,481 AD/AA cases occurred. The incidence of AD/AA rose along with elevated TyG index. RCS curves showed a linear trend of TyG index with risk of incident AD/AA. TyG index was positively associated with risk of incident AD/AA after adjusting for age, gender, smoking status, drinking status, BMI, hypertension, LDL-c, and HbA1c, with adjusted HRs of 1.0 (reference), 1.20 (95% CI 1.08-1.35), 1.21 (95% CI 1.08-1.35), and 1.30 (95% CI 1.16-1.45) for TyG index quartiles 2, 3, and 4, respectively. Especially, participants in the highest TyG index quartile had highest risk of developing AA, with an adjusted HR of 1.35 (95% CI 1.20-1.52). CONCLUSIONS: TyG index is independently associated with a higher risk of incident AD/AA, indicating the importance of using TyG index for risk assessment of AD/AA, especially for AA.

Associations of age at diagnosis of breast cancer with incident myocardial infarction and heart failure: A prospective cohort study.

Background: The associations of age at diagnosis of breast cancer with incident myocardial infarction (MI) and heart failure (HF) remain unexamined. Addressing this problem could promote understanding of the cardiovascular impact of breast cancer. Methods: Data were obtained from the UK Biobank. Information on the diagnosis of breast cancer, MI, and HF was collected at baseline and follow-ups (median = 12.8 years). The propensity score matching method and Cox proportional hazards models were employed. Results: A total of 251,277 female participants (mean age: 56.8 ± 8.0 years), of whom 16,241 had breast cancer, were included. Among breast cancer participants, younger age at diagnosis (per 10-year decrease) was significantly associated with elevated risks of MI (hazard ratio [HR] = 1.36, 95% confidence interval [CI] 1.19-1.56, p<0.001) and HF (HR = 1.31, 95% CI 1.18-1.46, p<0.001). After propensity score matching, breast cancer patients with younger diagnosis age had significantly higher risks of MI and HF than controls without breast cancer. Conclusions: Younger age at diagnosis of breast cancer was associated with higher risks of incident MI and HF, underscoring the necessity to pay additional attention to the cardiovascular health of breast cancer patients diagnosed at younger age to conduct timely interventions to attenuate the subsequent risks of incident cardiovascular diseases. Funding: This study was supported by grants from the National Natural Science Foundation of China (82373665 and 81974490), the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (2021-RC330-001), and the 2022 China Medical Board-open competition research grant (22-466).

Associations of objective sleep duration and physical activity with risk of heart failure: A prospective cohort study.

OBJECTIVE: This study aimed to investigate the independent and joint associations of accelerometer-derived sleep duration and physical activity (PA) in different intensities with the risk of incident heart failure (HF). METHODS: The study included 89,572 participants (mean age 62.2 ± 7.8 years, 42.8% male) from the UK Biobank. Sleep duration (short: <6 h/day; normal: 6-8 h/day; long: >8 h/day) and PA [total PA, light PA (LPA), moderate-to-vigorous PA (MVPA), vigorous PA (VPA)] were measured using accelerometers over 7 days. MVPA and VPA were categorized according to the World Health Organization's recommended levels, while LPA and total PA were categorized based on the median. HF cases were identified through hospital records or death registries. RESULTS: Over a 7-year follow-up period, 1324 participants (2.1%; incidence rate, 2.1 per 1000 person-years) developed HF. Short, but not long, sleep duration was linked to a 33% increased risk of HF [hazard ratio (HR) 1.33, 95% confidence interval (CI): 1.11-1.59]. This increased risk associated with short sleep could be mitigated by increasing PA, especially to the levels of recommended MVPA or VPA. In joint analyses, compared to participants meeting the recommended MVPA and with normal sleep duration, those not meeting the MVPA recommendation and with short sleep had the highest HF risk (HR 1.78, 95% CI: 1.42-2.25). CONCLUSIONS: Accelerometer-derived short, but not long, sleep duration was associated with a higher risk of incident HF. Engaging in sufficient PA, especially recommended MVPA or VPA, can partially mitigate this risk.

Sex and population differences in the cardiometabolic continuum: a machine learning study using the UK Biobank and ELSA-Brasil cohorts.

BACKGROUND: The temporal relationships across cardiometabolic diseases (CMDs) were recently conceptualized as the cardiometabolic continuum (CMC), sequence of cardiovascular events that stem from gene-environmental interactions, unhealthy lifestyle influences, and metabolic diseases such as diabetes, and hypertension. While the physiological pathways linking metabolic and cardiovascular diseases have been investigated, the study of the sex and population differences in the CMC have still not been described. METHODS: We present a machine learning approach to model the CMC and investigate sex and population differences in two distinct cohorts: the UK Biobank (17,700 participants) and the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) (7162 participants). We consider the following CMDs: hypertension (Hyp), diabetes (DM), heart diseases (HD: angina, myocardial infarction, or heart failure), and stroke (STK). For the identification of the CMC patterns, individual trajectories with the time of disease occurrence were clustered using k-means. Based on clinical, sociodemographic, and lifestyle characteristics, we built multiclass random forest classifiers and used the SHAP methodology to evaluate feature importance. RESULTS: Five CMC patterns were identified across both sexes and cohorts: EarlyHyp, FirstDM, FirstHD, Healthy, and LateHyp, named according to prevalence and disease occurrence time that depicted around 95%, 78%, 75%, 88% and 99% of individuals, respectively. Within the UK Biobank, more women were classified in the Healthy cluster and more men in all others. In the EarlyHyp and LateHyp clusters, isolated hypertension occurred earlier among women. Smoking habits and education had high importance and clear directionality for both sexes. For ELSA-Brasil, more men were classified in the Healthy cluster and more women in the FirstDM. The diabetes occurrence time when followed by hypertension was lower among women. Education and ethnicity had high importance and clear directionality for women, while for men these features were smoking, alcohol, and coffee consumption. CONCLUSIONS: There are clear sex differences in the CMC that varied across the UK and Brazilian cohorts. In particular, disadvantages regarding incidence and the time to onset of diseases were more pronounced in Brazil, against woman. The results show the need to strengthen public health policies to prevent and control the time course of CMD, with an emphasis on women.

The AORTA Gene score for detection and risk stratification of ascending aortic dilation.

BACKGROUND AND AIMS: This study assessed whether a model incorporating clinical features and a polygenic score for ascending aortic diameter would improve diameter estimation and prediction of adverse thoracic aortic events over clinical features alone. METHODS: Aortic diameter estimation models were built with a 1.1 million-variant polygenic score (AORTA Gene) and without it. Models were validated internally in 4394 UK Biobank participants and externally in 5469 individuals from Mass General Brigham (MGB) Biobank, 1298 from the Framingham Heart Study (FHS), and 610 from All of Us. Model fit for adverse thoracic aortic events was compared in 401 453 UK Biobank and 164 789 All of Us participants. RESULTS: AORTA Gene explained more of the variance in thoracic aortic diameter compared to clinical factors alone: 39.5% (95% confidence interval 37.3%-41.8%) vs. 29.3% (27.0%-31.5%) in UK Biobank, 36.5% (34.4%-38.5%) vs. 32.5% (30.4%-34.5%) in MGB, 41.8% (37.7%-45.9%) vs. 33.0% (28.9%-37.2%) in FHS, and 34.9% (28.8%-41.0%) vs. 28.9% (22.9%-35.0%) in All of Us. AORTA Gene had a greater area under the receiver operating characteristic curve for identifying diameter ≥ 4 cm: 0.836 vs. 0.776 (P < .0001) in UK Biobank, 0.808 vs. 0.767 in MGB (P < .0001), 0.856 vs. 0.818 in FHS (P < .0001), and 0.827 vs. 0.791 (P = .0078) in All of Us. AORTA Gene was more informative for adverse thoracic aortic events in UK Biobank (P = .0042) and All of Us (P = .049). CONCLUSIONS: A comprehensive model incorporating polygenic information and clinical risk factors explained 34.9%-41.8% of the variation in ascending aortic diameter, improving the identification of ascending aortic dilation and adverse thoracic aortic events compared to clinical risk factors.

Cardiovascular Health, Polygenic Risk Score and Cancer Risk: A Prospective Cohort Study.

BACKGROUND: Cancer and cardiovascular disease shared common lifestyle risk factors. However, it remains unclear whether cardiovascular health (CVH) evaluated by Life's Essential 8 can predict cancer risk, and attenuate the influence of genetic susceptibility on cancer. OBJECTIVE: We aimed to evaluate independent and joint associations of CVH and polygenic risk score (PRS) with risks of overall and site-specific cancers. METHODS: We undertook a population-based cohort study based on the UK Biobank. The CVH score was constructed by physical activity, body mass index, nicotine exposure, sleep, diet, blood pressure, lipid profile, and blood glucose. PRSs were assessed individually for 18 cancer types by their independent single-nucleotide polymorphisms previously reported in genome-wide association studies. Multivariable Cox proportional hazards models were applied to explore the independent and joint associations of CVH and PRS with cancer incidence risk. The results were displayed as hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Compared with low CVH, high CVH was associated with decreased risks of overall cancer and the majority of common cancers, including digestive system [HRs (95% CI): 0.33 (0.23, 0.45)-0.66 (0.58, 0.75)], lung [HR (95% CI): 0.25 (0.21, 0.31)], renal [HR (95% CI): 0.42 (0.32, 0.56)], bladder [HR (95% CI): 0.55 (0.44, 0.69)], breast [HR (95% CI): 0.83 (0.74, 0.92)] and endometrial cancers [HR (95% CI): 0.39 (0.30, 0.51)]. For overall cancer in males, there was an interaction between CVH and PRS. Notably, individuals with high CVH across all levels of PRS had lower risks of overall cancer for females and eight site-specific cancers than those with low CVH and high PRS [HRs (95%CIs): 0.18 (0.12, 0.25)-0.79 (0.71, 0.87)]. CONCLUSIONS: High CVH was related to decreased risks of overall cancer and multiple cancers regardless of genetic predispositions. Our findings underscored the value of improving CVH for cancer prevention in the general population.

Association between dietary magnesium intake and incident chronic kidney disease : A prospective observational cohort study.

BACKGROUND: While serum magnesium deficiency is liked to higher cardiovascular disease risk, its association with chronic kidney disease (CKD) remains unclear. OBJECTIVE: To evaluate the relationship between dietary magnesium intake and CKD development in adults with clinically normal kidney function METHODS: The prospective observational cohort study evaluated 188,510 participants (median age, 57.0 years; female, 54.1%) from the UK Biobank. Dietary magnesium intake was assessed through a 24-hour dietary recall questionnaire compromising a list of 206 foods and 32 beverages, and categorized into quintiles. The primary outcome was incident CKD diagnosed through International Classification of Diseases (ICD)-10 and Office of Population Censuses and Surveys (OPCS)-4 codes. Incident CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, was also assessed in a sub-cohort with creatinine follow-up data. RESULTS: The median magnesium intake amount per person was 323.2 (interquartile range [IQR], 269.4-382.7) mg/day. During 1,826,038.1 person-years of follow-up (median, 9.6 years; IQR, 9.3-10.3 years), CKD developed in 5,878 participants. The incidence of CKD was progressively higher in participants with lower magnesium intake (2.8%, 2.8%, 3.0%, 3.2%, and 3.7% in Q5-1, respectively). Cox regression analysis revealed that the hazard ratios (HRs) for incident CKD increased in a stepwise manner towards lower magnesium intake quintiles (adjusted HR (95% CI); Q4, 0.97 (0.89, 1.06); Q3, 1.05 (0.96, 1.14); Q2, 1.12 (1.03, 1.21); Q1, 1.30 (1.20, 1.41)) relative to Q5 (P for linearity <0.001). Similar results were observed with eGFR-defined CKD outcome (adjusted HR (95% CI); Q4, 1.09 (0.92, 1.28); Q3, 1.15 (0.98, 1.35); Q2, 1.21 (1.03, 1.42); Q1, 1.41 (1.20, 1.65) relative to Q5; P for linearity <0.001). CONCLUSIONS: Lower dietary magnesium intake was associated with a higher risk of incident CKD in adults with clinically normal kidney function. Further controlled studies are required to establish the potential benefit of adequate magnesium intake.

Daytime napping and the incidence of Parkinson's disease: a prospective cohort study with Mendelian randomization.

BACKGROUND: The causal relationship between daytime napping and the risk of Parkinson's disease (PD) remains unclear, with prospective studies providing limited evidence. This study investigated the association between daytime napping frequency and duration and PD incidence and explored the causality relationship between this association by conducting Mendelian randomization (MR) analysis. METHODS: This prospective cohort study included 393,302 participants, and accelerometer-measured daytime napping data were available only for 78,141 individuals. Cox proportional hazards regression was used to estimate the association between the daytime napping frequency and duration and the PD risk. The role of the systemic immune-inflammation index (SII) in the association between daytime napping frequency and PD risk was assessed through mediation analyses. Moreover, the causal association between the daytime napping frequency and the PD risk was preliminarily explored by conducting two-sample MR analyses. RESULTS: The median follow-up duration was 12.18 years. The participants who reported napping sometimes or usually exhibited a significantly higher PD risk than those who never/rarely napped during the day [sometimes: hazard ratio (HR), 1.13; 95% confidence interval (CI), 1.03-1.23; usually: HR, 1.33; 95% CI, 1.14-1.55], and SII played a mediating role in this association. However, the MR analyses did not indicate that the daytime napping frequency and PD risk were significantly associated. The participants napping for over 1 h exhibited a significantly elevated PD risk (HR, 1.54; 95% CI, 1.11-2.16). Moreover, no significant interaction was identified between napping frequency or duration and genetic susceptibility to PD (P for interaction > 0.05). CONCLUSIONS: In this study, increased daytime napping frequency and duration were associated with an increased PD risk, but no causal relationship was observed between napping frequency and PD risk in the MR analysis. Larger GWAS-based cohort studies and MR studies are warranted to explore potential causal relationships.

An Exploration of Shared Risk Factors for Coronary Artery Disease and Cancer from 109 Traits: The Evidence from Two-Sample Mendelian Randomization Studies.

Background: Although observational studies have reported several common biomarkers related to coronary artery disease (CAD) and cancer, there is a shortage of traditional epidemiological data to establish causative linkages. Thus, we conducted a comprehensive two-sample Mendelian randomization (MR) analysis to systematically investigate the causal associations of 109 traits with both CAD and cancer to identify their shared risk and protective factors. Methods: The genetic association datasets pertaining to exposure and outcomes were reviewed using the most recent and public genome-wide association studies (GWAS). Inverse variance weighting (IVW), weighted median (WM), and MR-Egger strategies were implemented for the MR analyses. The heterogeneity and pleiotropy were measured utilizing leave-one-out sensitivity testing, MR-PRESSO outlier detection, and Cochran's Q test. Results: The IVW analyses revealed that genetic-predicted mean sphered cell volume (MSCV) is a protective factor for CAD, and weight is a risk factor. MSCV and weight also show similar effects on cancer. Furthermore, our study also identified a set of risk and protective factors unique to CAD and cancer, such as telomere length. Conclusions: Our Mendelian randomization study sheds light on shared and unique risk and protective factors for CAD and cancer, offering valuable insights that could guide future research and the development of personalized strategies for preventing and treating these two significant health issues.

Dietary flavonoid intake and risk of hormone-related cancers: A population-based prospective cohort study.

BACKGROUND: Dietary flavonoids may have potential effects on hormone-related cancers (HRCs) due to their anti-cancer properties via regulating hormones and suppressing inflammation and oxidative stress. We aimed to examine the association of flavonoid intake with risks of HRCs and whether this association was mediated by blood biomarkers involved in biological mechanisms. METHODS: This prospective cohort study from UK Biobank included 187,350 participants free of cancer when the last dietary recall was completed. The dietary intakes of flavonoids and subclasses were assessed using 24-hour dietary recalls. Venous blood was collected at baseline and assayed for biomarkers of inflammation, hormones, and oxidative stress. Hazard ratios (HR) and 95 % confidential intervals (CI) for the associations between flavonoid intake and HRCs risk were estimated by the cause-specific Cox proportional hazards model. The role of blood biomarkers in the flavonoids-HRCs association was investigated through mediation analysis. RESULTS: Over a median follow-up of 9.5 years, 3,392 female breast cancer, 417 ovarian cancer, 516 endometrial cancer, 4,305 prostate cancer, 45 testicular cancer, and 146 thyroid cancer cases were documented. Compared to the lowest quintile, multivariable-adjusted HRs (95 % CIs) in the highest quintile of total flavonoid intake were 0.89 (0.80-0.99) for breast cancer, 0.68 (0.50-0.92) for ovarian cancer, and 0.88 (0.80-0.98) for female-specific cancers. For subclasses, intakes of flavonols and anthocyanidins were inversely associated with the risk of female-specific cancers (Ptrend <0.05). Anthocyanidin intake was positively related to prostate cancer risk, whereas isoflavone intake was inversely linked to thyroid cancer risk (Ptrend <0.05). Additionally, certain biomarkers of inflammation, hormones and oxidative stress jointly mediated the association of flavonoid intake with the risk of female-specific cancers and prostate cancer. CONCLUSIONS: Our findings highlighted the importance of dietary flavonoids for the prevention of HRCs in the general population, providing epidemiological evidence for dietary guidelines.

Association between frailty and main work during the LIFE: A cross-sectional analysis of the UK Biobank.

BACKGROUND: The role of main work during the life course in predicting frailty, a typical geriatric syndrome, is still largely unknown. Therefore, with this research, we aimed to investigate the potential association between the main work done during the life with frailty and pre-frailty among participants 60 years and older of the UK Biobank study. METHODS: Frailty and pre-frailty presence were ascertained using a model including 5 indicators (weakness, slowness, weight loss, low physical activity, and exhaustion); the main employment status was ascertained using self-reported information. The association between frailty and main work was explored using an ordinal logistic regression model and reported as odds ratios (ORs) with their 95 % confidence intervals (CIs). RESULTS: The final sample comprised a total of 50,447 individuals (mean age: 64.2 years, females: 50.2 %). Individuals with higher qualifications had a reduced risk of frailty (OR = 0.881, 95%CI = 0.83-0.95, p-value<0.001 for pre-frail and OR = 0.681, 95%CI = 0.63-0.73, p-value<0.001 for frail) compared to those with lower qualifications. Moreover, active participation in the workforce, compared to being inactive, emerged as a protective factor from frailty (OR = 0.753, 95%CI = 0.70-0.81, p-value<0.001). The categories of Associate Professional and Technical Occupations exhibited protective effects against both pre-frailty and frailty. Similarly, occupations categorized as Professional and Management demonstrated protective effects against pre-frailty and frailty when compared to Elementary Occupations. Additionally, engagement in Trades and Services occupations, as opposed to Elementary Occupations, appeared to be protective against frailty. CONCLUSIONS: In this large cross-sectional investigation based on the data of the UK Biobank we found that work during lifetime could be an important factor in determining frailty later in life.

AI-based derivation of atrial fibrillation phenotypes in the general and critical care populations.

BACKGROUND: Atrial fibrillation (AF) is the most common heart arrhythmia worldwide and is linked to a higher risk of mortality and morbidity. To predict AF and AF-related complications, clinical risk scores are commonly employed, but their predictive accuracy is generally limited, given the inherent complexity and heterogeneity of patients with AF. By classifying different presentations of AF into coherent and manageable clinical phenotypes, the development of tailored prevention and treatment strategies can be facilitated. In this study, we propose an artificial intelligence (AI)-based methodology to derive meaningful clinical phenotypes of AF in the general and critical care populations. METHODS: Our approach employs generative topographic mapping, a probabilistic machine learning method, to identify micro-clusters of patients with similar characteristics. It then identifies macro-cluster regions (clinical phenotypes) in the latent space using Ward's minimum variance method. We applied it to two large cohort databases (UK-Biobank and MIMIC-IV) representing general and critical care populations. FINDINGS: The proposed methodology showed its ability to derive meaningful clinical phenotypes of AF. Because of its probabilistic foundations, it can enhance the robustness of patient stratification. It also produced interpretable visualisation of complex high-dimensional data, enhancing understanding of the derived phenotypes and their key characteristics. Using our methodology, we identified and characterised clinical phenotypes of AF across diverse patient populations. INTERPRETATION: Our methodology is robust to noise, can uncover hidden patterns and subgroups, and can elucidate more specific patient profiles, contributing to more robust patient stratification, which could facilitate the tailoring of prevention and treatment programs specific to each phenotype. It can also be applied to other datasets to derive clinically meaningful phenotypes of other conditions. FUNDING: This study was funded by the DECIPHER project (LJMU QR-PSF) and the EU project TARGET (10113624).

Association of healthy lifestyle factors and genetic liability with bipolar disorder: Findings from the UK Biobank.

BACKGROUND: The interplay between genetic and lifestyle factors in the development of bipolar disorder (BD) remains unclear. METHODS: A cohort study was carried out on 365,517 participants from the UK Biobank. Lifestyle scores, based on smoking, physical activity, diet, alcohol consumption, sedentary behavior, sleep duration, and social contact, were grouped as favorable (scores 6-7), intermediate (scores 4-5), or unfavorable (scores 0-3). The BD polygenic risk score (PRS) was also categorized into high, intermediate, and low-risk groups using PRS tertiles. Cox regression models determined hazard ratios (HRs) and 95 % confidence intervals (CIs) for BD. RESULTS: During the 12.9-year follow-up, 529 individuals developed BD. Comparing those with favorable lifestyles to those with unfavorable participants, the HR of developing BD was 3.28 (95 % CI, 2.76-3.89). Similarly, individuals with a high PRS had a risk of 3.20 (95 % CI, 2.83-3.63) compared to those with a low PRS. Notably, individuals with both a high PRS and an unfavorable lifestyle had a significantly higher risk of BD (HR = 6.31, 95 % CI, 4.14-9.63) compared to those with a low PRS and a favorable lifestyle. Additionally, the interaction between PRS and lifestyle contributed an additional risk, with a relative excess risk of 1.74 (95 % CI, 0.40-3.07) and an attributable proportion due to the interaction of 0.37 (95 % CI, 0.16-0.58). CONCLUSIONS: Our findings suggest that genetic liability for BD, measured as PRS, and lifestyle have an additive effect on the risk of developing BD. A favorable lifestyle was associated with a reduced risk of developing BD.

The role of aspirin in the prevention of pancreatic cancer: A nested case-control study in the UK Biobank.

BACKGROUND: Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) usage has been associated with pancreatic ductal adenocarcinoma (PDAC) prevention, though epidemiological data have not reliably demonstrated this. The aim of this study is to identify if aspirin and other NSAIDs are effective in the primary prevention of PDAC in a large UK prospective cohort. METHODS: A nested case-control study was conducted using the UK Biobank cohort. Incident PDAC cases (n = 1129 of whom 239 (21.2 %) were using aspirin) were age and sex-matched with cancer-free controls (n = 8822 of whom 1752 (19.9 %) were using aspirin). Conditional logistic regression models were used to generate odds ratios (ORs) and 95 % confidence intervals (CI) for risk of PDAC with and without regular use of aspirin, non-aspirin NSAIDs and all NSAIDs respectively. Exploratory analyses were carried out assessing interactions with diabetes mellitus (DM) as a condition with increased pancreatic cancer risk. RESULTS: Regular aspirin use at initial recruitment was independently associated with a decreased risk of PDAC (OR [95 % CI] = 0.80 [0.68-0.95] P = 0.01). Regular non-aspirin NSAID use was not associated with a risk reduction of PDAC (OR [95 % CI] = 1.01 [0.84-1.23] P = 0.88). Exploratory analyses showed that in those with DM; regular aspirin use reduced risk of PDAC (OR [95 % CI] = 0.60 [0.42-0.85] P = 0.004) compared to non-use. DISCUSSION: Regular aspirin use is associated with a reduction in risk of PDAC. The reduced risk is more apparent in participants with DM.