Causal effect of thyroid cancer on secondary primary malignancies: findings from the UK Biobank and FinnGen cohorts.

Background: Existing epidemiological data indicated a correlation between thyroid cancer (THCA) and the risk of secondary primary malignancies (SPMs). However, the correlation does not always imply causality. Methods: The Mendelian randomization (MR) analyses were performed to investigate the causal relationships between THCA and SPMs based on international multicenter data. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. The Cancer Genome Atlas (TCGA) was used to explore potential mechanisms shared by THCA and bladder cancer (BLCA). Results: Summary datasets of genome-wide association studies (GWAS) on 30 types of cancers were obtained from the United Kingdom Biobank (UKB) and FinnGen database. Meta-analysis of the UKB and FinnGen results revealed that THCA was significantly positively correlated with BLCA (OR = 1.140; 95% CI, 1.072-1.212; P < 0.001). Four genes, including WNT3, FAM171A2, MLLT11, and ULBP1, were identified as key genes shared by both TCHA and BLCA. Correlation analysis indicated that THCA may increase the risk of secondary BLCA through augmentation of N2 neutrophil infiltration. Conclusions: This study showed that THCA was causally related to BLCA. It is recommended to conduct more rigorous screenings for BLCA during the follow-up of THCA patients.

Artificial intelligence driven definition of food preference endotypes in UK Biobank volunteers is associated with distinctive health outcomes and blood based metabolomic and proteomic profiles.

BACKGROUND: Specific food preferences can determine an individual's dietary patterns and therefore, may be associated with certain health risks and benefits. METHODS: Using food preference questionnaire (FPQ) data from a subset comprising over 180,000 UK Biobank participants, we employed Latent Profile Analysis (LPA) approach to identify the main patterns or profiles among participants. blood biochemistry across groups/profiles was compared using the non-parametric Kruskal-Wallis test. We applied the Limma algorithm for differential abundance analysis on 168 metabolites and 2923 proteins, and utilized the Database for Annotation, Visualization and Integrated Discovery (DAVID) to identify enriched biological processes and pathways. Relative risks (RR) were calculated for chronic diseases and mental conditions per group, adjusting for sociodemographic factors. RESULTS: Based on their food preferences, three profiles were termed: the putative Health-conscious group (low preference for animal-based or sweet foods, and high preference for vegetables and fruits), the Omnivore group (high preference for all foods), and the putative Sweet-tooth group (high preference for sweet foods and sweetened beverages). The Health-conscious group exhibited lower risk of heart failure (RR = 0.86, 95%CI 0.79-0.93) and chronic kidney disease (RR = 0.69, 95%CI 0.65-0.74) compared to the two other groups. The Sweet-tooth group had greater risk of depression (RR = 1.27, 95%CI 1.21-1.34), diabetes (RR = 1.15, 95%CI 1.01-1.31), and stroke (RR = 1.22, 95%CI 1.15-1.31) compared to the other two groups. Cancer (overall) relative risk showed little difference across the Health-conscious, Omnivore, and Sweet-tooth groups with RR of 0.98 (95%CI 0.96-1.01), 1.00 (95%CI 0.98-1.03), and 1.01 (95%CI 0.98-1.04), respectively. The Health-conscious group was associated with lower levels of inflammatory biomarkers (e.g., C-reactive Protein) which are also known to be elevated in those with common metabolic diseases (e.g., cardiovascular disease). Other markers modulated in the Health-conscious group, ketone bodies, insulin-like growth factor-binding protein (IGFBP), and Growth Hormone 1 were more abundant, while leptin was less abundant. Further, the IGFBP pathway, which influences IGF1 activity, may be significantly enhanced by dietary choices. CONCLUSIONS: These observations align with previous findings from studies focusing on weight loss interventions, which include a reduction in leptin levels. Overall, the Health-conscious group, with preference to healthier food options, has better health outcomes, compared to Sweet-tooth and Omnivore groups.

Multimorbidity and the risk of malnutrition, frailty and sarcopenia in adults with cancer in the UK Biobank.

BACKGROUND: Malnutrition, sarcopenia and frailty are distinct, albeit interrelated, conditions associated with adverse outcomes in adults with cancer, but whether they relate to multimorbidity, which affects up to 90% of people with cancer, is unknown. This study investigated the relationship between multimorbidity with malnutrition, sarcopenia and frailty in adults with cancer from the UK Biobank. METHODS: This was a cross-sectional study including 4122 adults with cancer (mean [SD] age 59.8 [7.1] years, 50.7% female). Malnutrition was determined using the Global Leadership Initiative on Malnutrition criteria. Probable sarcopenia and sarcopenia were defined using the European Working Group on Sarcopenia in Older People 2 criteria. (Pre-)frailty was determined using the Fried frailty criteria. Multimorbidity was defined as ≥2 long-term conditions with and without the cancer diagnosis included. Logistic regression models were fitted to estimate the odds ratios (ORs) of malnutrition, sarcopenia and frailty according to the presence of multimorbidity. RESULTS: Genitourinary (28.9%) and breast (26.1%) cancers were the most common cancer diagnoses. The prevalence of malnutrition, (probable-)sarcopenia and (pre-)frailty was 11.1%, 6.9% and 51.2%, respectively. Of the 11.1% of participants with malnutrition, the majority (9%) also had (pre-)frailty, and 1.1% also had (probable-)sarcopenia. Of the 51.2% of participants with (pre-)frailty, 6.8% also had (probable-)sarcopenia. No participants had (probable-)sarcopenia alone, and 1.1% had malnutrition, (probable-)sarcopenia plus (pre-)frailty. In total, 33% and 65% of participants had multimorbidity, including and excluding the cancer diagnosis, respectively. The most common long-term conditions, excluding the cancer diagnosis, were hypertension (32.5%), painful conditions such as osteoarthritis or sciatica (17.6%) and asthma (10.4%). Overall, 80% of malnourished, 74% of (probable-)sarcopenia and 71.5% of (pre-)frail participants had multimorbidity. Participants with multimorbidity, including the cancer diagnosis, had higher odds of malnutrition (OR 1.72 [95% confidence interval, CI, 1.31-2.30; P < 0.0005]) and (pre-)frailty (OR 1.43 [95% CI 1.24-1.68; P < 0.0005]). The odds increased further in people with ≥2 long-term conditions in addition to their cancer diagnosis (malnutrition, OR 2.41 [95% CI 1.85-3.14; P < 0.0005]; (pre-)frailty, OR 2.03 [95% CI 1.73-2.38; P < 0.0005]). There was little evidence of an association of multimorbidity with sarcopenia. CONCLUSIONS: In adults with cancer, multimorbidity was associated with increased odds of having malnutrition and (pre-)frailty but not (probable-)sarcopenia. This highlights that multimorbidity should be considered a risk factor for these conditions and evaluated during nutrition and functional screening and assessment to support risk stratification within clinical practice.

Association between surgical admissions, cognition, and neurodegeneration in older people: a population-based study from the UK Biobank.

BACKGROUND: Previous studies have shown that major surgical and medical hospital admissions are associated with cognitive decline in older people (aged 40-69 years at recruitment), which is concerning for patients and caregivers. We aimed to validate these findings in a large cohort and investigate associations with neurodegeneration using MRI. METHODS: For this population-based study, we analysed data from the UK Biobank collected from March 13, 2006, to July 16, 2023, linked to the National Health Service Hospital Episode Statistics database, excluding participants with dementia diagnoses. We constructed fully adjusted models that included age, time, sex, Lancet Commission dementia risk factors, stroke, and hospital admissions with a participant random effect. Primary outcomes were hippocampal volume and white matter hyperintensities, both of which are established markers of neurodegeneration, and exploratory analyses investigated the cortical thickness of Desikan-Killiany-Tourville atlas regions. The main cognitive outcomes were reaction time, fluid intelligence, and prospective and numeric memory. Surgeries were calculated cumulatively starting from 8 years before the baseline evaluation. FINDINGS: Of 502 412 participants in the UK Biobank study, 492 802 participants were eligible for inclusion in this study, of whom 46 706 underwent MRI. Small adverse associations with cognition were found per surgery: reaction time increased by 0·273 ms, fluid intelligence score decreased by 0·057 correct responses, prospective memory (scored as correct at first attempt) decreased (odds ratio 0·96 [95% CI 0·95 to 0·97]), and numeric memory maximum correct matches decreased by 0·025 in fully adjusted models. Surgeries were associated with smaller hippocampal volume (ß=-5·76 mm³ [-7·89 to -3·64]) and greater white matter hyperintensities volume (ß=100·02 mm³ [66·17 to 133·87]) in fully adjusted models. Surgeries were also associated with neurodegeneration of the insula and superior temporal cortex. INTERPRETATION: This population-based study corroborates that surgeries are generally safe but cumulatively are associated with cognitive decline and neurodegeneration. Perioperative brain health should be prioritised for older and vulnerable patients, particularly those who have multiple surgical procedures. FUNDING: The Australian and New Zealand College of Anaesthetists (ANZCA) Foundation and the University of Sydney.

Association between personality, lifestyle behaviors, and cardiovascular diseases in type 2 diabetes mellitus: a population-based cohort study of UK Biobank data.

INTRODUCTION: Various strategies aim to better assess risks and refine prevention for patients with type 2 diabetes mellitus (T2DM), who vary in cardiovascular disease (CVD) risk. However, the prognostic value of personality and its association with lifestyle factors remain elusive. RESEARCH DESIGN AND METHODS: We identified 8794 patients with T2DM from the UK Biobank database between 2006 and 2010 and followed them up until the end of 2021. We assessed personality traits using the Big Five proxies derived from UK Biobank data: sociability, warmth, diligence, curiosity, and nervousness. Healthy lifestyle behaviors were determined from information about obesity, smoking status, and physical activity. The primary outcome was a composite of incident CVD, including myocardial infarction (MI), ischemic stroke (IS), atrial fibrillation (AF), and heart failure (HF). RESULTS: During a median follow-up of 13.6 years, a total of 2110 patients experienced CVDs. Among personality traits, diligence was significantly associated with a reduced risk of primary and secondary outcomes. The adjusted HRs with 95% CIs were: composite CVD, 0.93 (0.89-0.97); MI 0.90 (0.82-1.00); IS 0.83 (0.74-0.94); AF 0.92 (0.85-0.98); HF 0.84 (0.76-0.91). Healthy lifestyle behaviors significantly reduced the risk of composite CVDs in groups with high and low diligence. The findings of a structural equation model showed that diligence directly affected the risk of the primary outcome or indirectly by modifying lifestyle behaviors. CONCLUSION: This study revealed which personality traits can influence CVD risk during T2DM and how patients might benefit from adopting healthy lifestyle behaviors in relation to personality.

Diurnal timing of physical activity and risk of colorectal cancer in the UK Biobank.

BACKGROUND: Physical activity reduces colorectal cancer risk, yet the diurnal timing of physical activity in colorectal cancer etiology remains unclear. METHODS: This study used 24-h accelerometry time series from UK Biobank participants aged 42 to 79 years to derive circadian physical activity patterns using functional principal component analysis. Multivariable Cox proportional hazard models were used to examine associations with colorectal cancer risk. RESULTS: Among 86,252 participants (56% women), 529 colorectal cancer cases occurred during a median 5.3-year follow-up. We identified four physical activity patterns that explained almost 100% of the data variability during the day. A pattern of continuous day-long activity was inversely associated with colorectal cancer risk (hazard ratio (HR) = 0.94, 95% confidence interval (CI) = 0.89-0.99). A second pattern of late-day activity was suggestively inversely related to risk (HR = 0.93, 95% CI = 0.85-1.02). A third pattern of early- plus late-day activity was associated with decreased risk (HR = 0.89, 95% CI = 0.80-0.99). A fourth pattern of mid-day plus night-time activity showed no relation (HR = 1.02, 95% CI = 0.88-1.19). Our results were consistent across various sensitivity analyses, including the restriction to never smokers, the exclusion of the first 2 years of follow-up, and the adjustment for shift work. CONCLUSIONS: A pattern of early- plus late-day activity is related to reduced colorectal cancer risk, beyond the benefits of overall activity. Further research is needed to confirm the role of activity timing in colorectal cancer prevention.

Genetic links between ovarian ageing, cancer risk and de novo mutation rates.

Human genetic studies of common variants have provided substantial insight into the biological mechanisms that govern ovarian ageing1. Here we report analyses of rare protein-coding variants in 106,973 women from the UK Biobank study, implicating genes with effects around five times larger than previously found for common variants (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1). The SAMHD1 association reinforces the link between ovarian ageing and cancer susceptibility1, with damaging germline variants being associated with extended reproductive lifespan and increased all-cause cancer risk in both men and women. Protein-truncating variants in ZNF518A are associated with shorter reproductive lifespan-that is, earlier age at menopause (by 5.61 years) and later age at menarche (by 0.56 years). Finally, using 8,089 sequenced trios from the 100,000 Genomes Project (100kGP), we observe that common genetic variants associated with earlier ovarian ageing associate with an increased rate of maternally derived de novo mutations. Although we were unable to replicate the finding in independent samples from the deCODE study, it is consistent with the expected role of DNA damage response genes in maintaining the genetic integrity of germ cells. This study provides evidence of genetic links between age of menopause and cancer risk.

Cardiovascular health and cancer mortality: evidence from US NHANES and UK Biobank cohort studies.

BACKGROUND: The American Heart Association recently introduced a novel cardiovascular health (CVH) metric, Life's Essential 8 (LE8), for health promotion. However, the relationship between LE8 and cancer mortality risk remains uncertain. METHODS: We investigated 17,076 participants from US National Health and Nutrition Examination Survey (US NHANES) and 272,727 participants from UK Biobank, all free of cancer at baseline. The CVH score, based on LE8 metrics, incorporates four health behaviors (diet, physical activity, smoking, and sleep) and four health factors (body mass index, lipid, blood glucose, and blood pressure). Self-reported questionnaires assessed health behaviors. Primary outcomes were mortality rates for total cancer and its subtypes. The association between CVH score (continuous and categorical variable) and outcomes was examined using Cox model with adjustments. Cancer subtypes-related polygenic risk score (PRS) was constructed to evaluate its interactions with CVH on cancer death risk. RESULTS: Over 141,526 person-years in US NHANES, 424 cancer-related deaths occurred, and in UK Biobank, 8,872 cancer deaths were documented during 3,690,893 person-years. High CVH was associated with reduced overall cancer mortality compared to low CVH (HR 0.58, 95% CI 0.37-0.91 in US NHANES; 0.51, 0.46-0.57 in UK Biobank). Each one-standard deviation increase in CVH score was linked to a 19% decrease in cancer mortality (HR: 0.81; 95% CI: 0.73-0.91) in US NHANES and a 19% decrease (HR: 0.81; 95% CI: 0.79-0.83) in UK Biobank. Adhering to ideal CVH was linearly associated with decreased risks of death from lung, bladder, liver, kidney, esophageal, breast, colorectal, pancreatic, and gastric cancers in UK Biobank. Furthermore, integrating genetic data revealed individuals with low PRS and high CVH exhibited the lowest mortality from eight cancers (HRs ranged from 0.36 to 0.57) compared to those with high PRS and low CVH. No significant modification of the association between CVH and mortality risk for eight cancers by genetic predisposition was observed. Subgroup analyses showed a more pronounced protective association for overall cancer mortality among younger participants and those with lower socio-economic status. CONCLUSIONS: Maintaining optimal CVH is associated with a substantial reduction in the risk of overall cancer mortality. Adherence to ideal CVH correlates linearly with decreased mortality risk across multiple cancer subtypes. Individuals with both ideal CVH and high genetic predisposition demonstrated significant health benefits. These findings support adopting ideal CVH as an intervention strategy to mitigate cancer mortality risk and promote healthy aging.

Higher ultraviolet light exposure is associated with lower mortality: An analysis of data from the UK biobank cohort study.

We aimed to examine associations between ultraviolet (UV) exposure and mortality among older adults in the United Kingdom (UK). We used data from UK Biobank participants with two UV exposures, validated with measured vitamin D levels: solarium use and annual average residential shortwave radiation. Associations between the UV exposures, all-cause and cause-specific mortality were examined as adjusted hazard ratios. The UV exposures were inversely associated with all-cause, cardiovascular disease (CVD) and cancer mortality. Solarium users were also at a lower risk of non-CVD/non-cancer mortality. The benefits of UV exposure may outweigh the risks in low-sunlight countries.

Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences.

Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.

Plasma n6 polyunsaturated fatty acid levels and risk for total and cause-specific mortality: A prospective observational study from the UK Biobank.

BACKGROUND: The potential role of n-6 PUFAs in major health outcomes remains controversial. OBJECTIVES: To examine the relationship between the major plasma n6 PUFA, linoleic acid (LA), as well as the non-LA n6 PUFAs, and total and cause-specific mortality. METHODS: This was a prospective, observational, biomarker-based study in the UK Biobank. Individuals with complete information on baseline demographic, covariate and plasma PUFA levels (percent ot total fatty acids) and mortality outcomes were included (n=257,925). Multivariable-adjusted, Cox-proportional hazards models were used to predict risk of death from all-causes, and from cardiovascular disease (CVD), cancer, and other causes as a function of plasma LA and non-LA n6 levels, both continuously and by PUFA quintile (Q). RESULTS: Comparing LA Q5 to Q1, the hazard ratio (HR, 95% CI) for total mortality was 0.80 (0.76, 0.84; p<0.001), and this was similar for all three cause-specific death categories. On the other hand, mortality HR for non-LA n6 was 1.12 (1.08,1.17; p<0.001), and this was primarily due to increased risk for non-CVD, noncancer deaths [HR 1.29 (1.19,1.40; p<0.001)]. Exploratory analyses among the eight next most common other causes of death suggested that both the decreased risk associated with higher LA and the increased risk associated with non-LA n6 were confined to deaths from respiratory and digestive diseases. CONCLUSIONS: These findings highlight the profound differences in mortality risk related to LA and non-LA n6 PUFA levels and underscore the inappropriateness of treating n-6 PUFAs as a homogenous class with respect to health outcomes. They also support recommendations to maintain (if not increase) current LA intakes.

Change in physical activity and its association with decline in kidney function: A UK Biobank-based cohort study.

BACKGROUND: Previous research on the association between physical activity (PA) and kidney function is inconsistent. The association between muscle mass and serum creatinine (SCr) may have implications for interpreting the effect of PA on estimated glomerular filtration rate (eGFR). Few studies have reported changes in physical activity and changes in kidney function. METHODS: A cohort study was constructed using the UK Biobank. Changes in physical activity were self-reported as metabolic equivalent task (MET) minutes/week. eGFR was calculated using SCr and cystatin C (CysC). Cox and nonlinear regressions with restricted cubic splines were applied to explore the association between changes in physical activity and rapid decline of kidney function (RDKF, eGFR annual decrease ≥3 mL/min/1.73 m2), and the annual change of eGFR. An exploratory analysis of cardiorespiratory fitness as the exposure was conducted. RESULTS: Among 11 757 participants, the median follow-up time was 4.4 years. Participants whose PA decreased by 1000 MET minutes/week at the follow-up assessment had a 2% reduction in risk of developing RDKFSCr (HR = 0.98, 95% CI: 0.96, 1.00). In contrast, a 1000 MET minutes/week increase in PA was associated with a 4% reduction in risk of developing RDKFCysC (HR = 0.96, 95% CI: 0.93, 0.99). A PA increase of 1000 MET minutes/week was associated with eGFRCysC annual increase of 0.04 mL/min/1.73 m2 (95% CI: 0.03, 0.06) but no significant changes in eGFRSCr. CONCLUSIONS: In this general population study, there are differing associations between changes in PA and changes in kidney function depending on the kidney biomarker used. Increasing PA is modestly associated with improving annual eGFRCysC and reduced risk of RDKF.

Association between four insulin resistance surrogates and the risk of esophageal cancer: a prospective cohort study using the UK Biobank.

PURPOSE: This study explored the association between triglyceride-glucose (TyG), TyG index with body mass index (TyG-BMI), triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C), metabolic score for insulin resistance (IR) (METS-IR) and the risk of esophageal cancer. METHODS: A total of 388,900 participants from the United Kingdom Biobank from 2006 to 2010 were included. Fine-Gray models, restricted cubic spline (RCS), and receiver operating characteristic (ROC) curves were used to assess the association between the four IR surrogates and the risk of esophageal cancer, specifically, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). RESULTS: Ten years after recruitment, 0.16% (95%CI 0.11-0.26%) had esophageal cancer and 4.17% (95%CI 3.86-4.46%) are deceased. For each standard deviation increase in the TyG index, TyG-BMI, TG/HDL-C, and METS-IR, the risk of EAC increased by Hazard ratios (HR)1.16, 1.37, 1.08, and 1.36, respectively (all P < 0.05), while the risk of ESCC decreased by HRs 0.80, 0.67, 0.77, and 0.65, respectively. RCS analysis indicated that most relationships were nonlinear (P < 0.05). ROC curves showed that METS-IR had a more robust diagnostic efficacy than TyG, TyG-BMI, and TG/HDL-C. CONCLUSION: TyG index, TyG-BMI, TG/HDL-C, and METS-IR were closely associated with the risk of EAC and ESCC. Additionally, METS-IR surpassed the other three IR indices in predicting and diagnosing the risks of EAC and ESCC. The METS-IR is expected to become a more effective metric for identifying populations at early risk of esophageal cancer and for improving risk stratification.

The Association between the Substitution of Red Meat with Legumes and the Risk of Primary Liver Cancer in the UK Biobank: A Cohort Study.

Primary liver cancer is globally on the rise, partially due to poor diets and sedentary lifestyles. Shifting to more plant-based diets may lower the risk. We aimed to estimate the effect of replacing total red meat, unprocessed red meat and processed red meat with legumes on primary liver cancer in a free-living population. We analyzed data from 126,744 UK Biobank participants who completed ≥ two 24 h diet recalls. Baseline characteristics were collected from the initial assessment visit. Information on liver cancer diagnoses was collected via external linkage to inpatient hospital episodes or central cancer registries. Cox proportional hazards regression models were used to estimate the substitution of 15 g/day of legumes with 15 g/day of total red meat, unprocessed red meat or processed red meat on liver cancer risk, using the leave-one-out food substitution model. During a median follow-up time of 11.1 years, 173 participants developed liver cancer. In the fully adjusted models, no association was observed when substituting 15 g/day of legumes with total red meat (HR: 1.02 (95% CI 0.96-1.08)), unprocessed red meat (HR: 1.00 (95% CI 0.94-1.06)) or processed red meat (HR: 1.09 (95% CI 0.99-1.21)). Overall, little evidence of an association between replacing red meat with legumes and liver cancer was observed. Further research in other study populations with longer follow-up time is warranted.

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.

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.

Osteoarthritis, osteoarthritis treatment and risk of incident dementia: a prospective cohort study based on UK Biobank.

BACKGROUND: We aimed to investigate the association between OA and treatment with dementia risk and structural brain abnormalities. METHODS: We recruited a total of 466,460 individuals from the UK Biobank to investigate the impact of OA on the incidence of dementia. Among the total population, there were 63,081 participants diagnosed with OA. We subsequently categorised the OA patients into medication and surgery groups based on treatment routes. Cox regression models explored the associations between OA/OA treatment and dementia risk, with the results represented as hazard ratios (HRs) and 95% confidence intervals (95% CI). Linear regression models assessed the associations of OA/OA therapy with alterations in cortical structure. RESULTS: During an average of 11.90 (± 1.01) years of follow-up, 5,627 individuals were diagnosed with all-cause dementia (ACD), including 2,438 AD (Alzheimer's disease), and 1,312 VaD (vascular dementia) cases. Results revealed that OA was associated with the elevated risk of ACD (HR: 1.116; 95% CI: 1.039-1.199) and AD (HR: 1.127; 95% CI: 1.013-1.254). OA therapy lowered the risk of dementia in both medication group (HR: 0.746; 95% CI: 0.652-0.854) and surgery group (HR: 0.841; 95% CI: 0.736-0.960). OA was negatively associated with cortical area, especially precentral, postcentral and temporal regions. CONCLUSIONS: Osteoarthritis increased the likelihood of developing dementia, and had an association with regional brain atrophy. OA treatment lowered the dementia risk. OA is a promising modifiable risk factor for dementia.

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.