Associations of birth weight, plasma metabolome in adulthood and risk of type 2 diabetes.

AIMS: We aimed to examine the longitudinal associations of birth weight with plasma metabolites in adulthood, and further quantify the proportions of the links between birth weight and incident adult type 2 diabetes (T2D) that were mediated by plasma metabolites. MATERIALS AND METHODS: A total of 62,033 participants with complete nuclear magnetic resonance metabolomics and birth weight data from the UK Biobank were included in this study. Linear regression was used to assess the associations between birth weight and metabolites. Cox regression was used to estimate hazard ratios for T2D associated with metabolites. We further performed mediation analyses to estimate the extent to which metabolites might mediate the association between birth weight and T2D risk. RESULTS: Low birth weight was associated with the adverse metabolic responses across multiple metabolic pathways, including lipoprotein subclasses, amino acids, fatty acids (FA), and inflammation. Metabolites associated with higher birth weight tended to be associated with a lower risk of T2D (Pearson correlation coefficient: -0.85). A total of 62 metabolites showed statistically significant mediation effects in the protective association of higher birth weight and T2D risk, including large-sized very low-density lipoprotein particles and triglyceride concentrations as well as saturated, and monounsaturated FA and glycoprotein acetyls. CONCLUSIONS: We identified a range of metabolites that reflect the adult metabolic response to birth weight, some of which might lie on the pathway between birth weight and adult T2D risk.

Effects of genetically proxied lipid-lowering drugs on acute myocardial infarction: a drug-target mendelian randomization study.

OBJECTIVE: High low-density-lipoprotein (LDL) cholesterol has been associated with an increased risk of coronary artery diseases (CAD) including acute myocardial infarction (AMI). However, whether lipids lowering drug treatment is causally associated with decreased risk of AMI remains largely unknown. We used Mendelian randomization (MR) to evaluate the influence of genetic variation affecting the function of lipid-lowering drug targets on AMI. METHODS: Single-nucleotide polymorphisms (SNPs) associated with lipids as instruments were extracted from the Global Lipids Genetics Consortium (GLGC). The genome-wide association study (GWAS) data for AMI were obtained from UK Biobank. Two sample MR analysis was used to study the associations between high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) with AMI (n = 3,927). Genetic variants associated with LDL cholesterol at or near drug target gene were used to mimic drug effects on the AMI events in drug target MR. RESULTS: Genetically predicted higher LDL-C (per one SD increase in LDL-C of 38.67 mg/dL, OR 1.006, 95% CI 1.004-1.007) and TG (per one SD increase in TG of 90.72 mg/dL, 1.004, 1.002-1.006) was associated with increased risk of AMI, but decreased risk for higher HDL-C (per one SD increase in HDL-C of 15.51 mg/dL, 0.997, 0.995-0.999) in univariable MR. Association remained significant for LDL-C, but attenuated toward the null for HDL-C and TG in multivariable MR. Genetically proxied lower LDL-C with genetic variants at or near the PCSK9 region (drug target of evolocumab) and NPC1L1 (drug target of ezetimibe) were associated with decreased risk of AMI (0.997, 0.994-0.999 and 0.986, 0.975-0.998, respectively), whereas genetic variants at HMGCR region (drug target of statin) showed marginal association with AMI (0.995, 0.990-1.000). After excluding drug target-related SNPs, LDL-C related SNPs outside the drug target region remained a causal effect on AMI (0.994, 0.993-0.996). CONCLUSIONS: The findings suggest that genetically predicted LDL-C may play a predominant role in the development of AMI. The drug MR results imply that ezetimibe and evolocumab may decrease the risk of AMI due to their LDL-C lowering effect, and there are other non-drug related lipid lowering pathways that may be causally linked to AMI.

Leisure-Time Television Viewing and Computer Use, Family History, and Incidence of Dementia.

INTRODUCTION: Time spent on screen-based sedentary activities is significantly associated with dementia risk, however, whether the associations vary by family history (FHx) of dementia is currently unknown. We aimed to examine independent associations of two prevalent types of screen-based sedentary activities (television [TV] viewing and computer use) with dementia and assess the modifying effect of FHx. METHODS: We included 415,048 individuals free of dementia from the UK Biobank. Associations of TV viewing, computer use, and FHx with dementia risk were determined using Cox regression models. We estimated both multiplicative- and additive-scale interactions between TV viewing and computer use and FHx. RESULTS: During a median follow-up of 12.6 years, 5,549 participants developed dementia. After adjusting for potential confounding factors, we observed that moderate (2-3 h/day; hazard ratio [HR] 1.13, 95% confidence interval 0.03-1.23) and high (>3 h/day; 1.33, 1.21-1.46) TV viewing was associated with a higher dementia risk, compared with low (0-1 h/day) TV viewing. Using restricted cubic spline models, the relationship of TV viewing with dementia was nonlinear (relative to 0 h/day; p for nonlinear = 0.005). We found that >3 h/day of TV viewing was associated with a 42% (1.42, 1.18-1.71) higher dementia risk in participants with FHx while a 30% (1.30, 1.17-1.45) in those without FHx. For computer use, both low (0 h/day; 1.41, 1.33-1.50) and high (>2 h/day; 1.17, 1.05-1.29) computer use were associated with elevated dementia risk, compared with moderate (1-2 h/day) computer use. We observed a J-shaped relationship with dementia (relative to 2 h/day; p for nonlinear <0.001). Compared with 1-2 h/day of computer use, the HRs of dementia were 1.46 (1.29-1.65) and 1.10 (0.90-1.36) for 0 h/day and >2 h/day of computer use in participants with FHx, respectively, while the corresponding HRs were 1.40 (1.30-1.50) and 1.19 (1.06-1.33) in those without FHx. We observed a positive additive interaction (RERI 0.29, 0.06-0.53) between computer use and FHx, while little evidence of interaction between TV viewing and FHx. CONCLUSIONS: The time spent on TV viewing and computer use were independent risk factors for dementia, and the adverse effects of computer use and FHx were additive. Our findings point to new behavioral targets for intervention on preventing an early onset of dementia, especially for those with FHx.

The effects of blood pressure and antihypertensive drugs on heart failure: A Mendelian randomization study.

BACKGROUND AND AIMS: Heart failure (HF) is often triggered by hypertension and can benefit from antihypertensive treatment. We aimed to investigate whether pulse pressure (PP) could independently raise the risk of HF beyond systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as explore the potential mechanisms of antihypertensives in HF prevention. METHODS AND RESULTS: We generated genetic proxies for SBP, DBP, PP, and five drug classes based on a massive genome-wide association study. We applied two-sample Mendelian randomization (MR) using summary statistics derived from European individuals and conducted summary data-based MR (SMR) with gene expression data. In univariate analysis, PP showed an obvious association with HF risk (OR, 1.24 per 10 mm Hg increment; 95% CI, 1.16 to 1.32), which was largely attenuated in multivariable analysis when adjusted for SBP (0.89; 0.77 to 1.04). A significant decrease in HF risk was obtained with genetically proxied ß-blockers (equivalent to a 10 mm Hg reduction in SBP, 0.71; 0.62 to 0.82) and calcium channel blockers (0.71; 0.65 to 0.78), but not with genetically proxied angiotensin-converting enzyme inhibitors (0.69; 0.40 to 1.19) and thiazide diuretics (0.80; 0.47 to 1.37). Additionally, the enrichment of expression for the KCNH2 gene, a target gene of ß-blockers, in blood vessels and nerves was significantly associated with HF risk. CONCLUSION: Our findings suggest that PP may not be an independent risk factor for HF. ß-blockers and calcium channel blockers have a protective effect against HF, which at least partly depends on their blood pressure-lowering effect.

Genetic modification effects of physical frailty on the morbidity of mental disorders in the UK Biobank.

Objectives: Depression and anxiety are two major categories of mental disorders that are highly prevalent in the general population. This study aims to explore the genetic modification effects of physical frailty on the morbidity of mental disorders.Methods: Using data from UK Biobank, we calculate genetic risk scores for depression, anxiety and mental disorders based on 37/44 single-nucleotide polymorphisms (SNPs) of Major Depressive Disorder (MDD) and 9/10 SNPs of anxiety. Frailty status was defined by a modified version of the frailty phenotype based on five individual components. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of depression and anxiety risk among groups with different frailty status.Results: Of 267,755 participants in UK Biobank, 4,905 (2%) were considered frail, 98,907 (37%) pre-frail and 163,943 (61%) not frail. Compared with the non-frail group, the pre-frail group (HR = 1.53; [95% CI:1.47-1.61]), and frail group (HR = 2.75; [95% CI:2.46-3.07]) were significantly associated with increased risk of depression. Per 1-number increment in frailty component counts were significantly associated with increased risk of mental disorders. In each genetic risk score (GRS) strata, people with pre-frailty and frailty suffered higher risks of mental disorders than the non-frail group.Conclusion: Our results indicate that physical frailty plays an important role in the incidence of mental disorders, even after adjustments for covariates, and patients with genetic individual differences are also affected. Therefore, it is crucial that while diagnosing mental disorders, professionals pay closer attention to those patients who present symptoms of frailty.

Association of TyG index with hypertension in Chinese adults: the China Health Examination Collaborative Study (CHEC Study).

BACKGROUND AND OBJECTIVES: We aimed to investigate the association of triglyceride-glucose (TyG) index with hypertension and compare the discriminative power of the TyG index, lipid, glycemic parameters for hypertension using the China Health Examination Collaborative study (CHEC Study). METHODS AND STUDY DESIGN: Data were collected at Ningbo Mingzhou Hospital and Beijing physical examination center from the CHEC Study during 2014 and 2021. Participants with ≥2 medical check-up times were included. The TyG index is the logarithmized product of fasting triglyceride and glucose. Generalised estimation equation (GEE) model was used to evaluate the association between the TyG index, lipid parameters, glycemic parameters and hypertension. Receiver operating characteristic (ROC) analysis was performed to explore the predictive ability of TyG index on hypertension at different years of medical check-up. RESULTS: 112,902 participants with an average age of 42.8 years were recruited in the study, 36,839 participants developed hypertension over the 8-year period. GEE model analysis showed that the ORs with 95% CI of hypertension were 3.35 (3.15-3.57), 1.86 (1.76-1.95), 1.67 (1.58-1.78), 1.45 (1.33-1.58), 1.24 (1.19-1.29), 0.92 (0.86-0.99), and 1.90 (1.83-1.97) in the highest versus lowest quintiles of TyG index, TG/HDL-C ratio, TG, TC, LDL-C, HDL-C and FPG in model 2. The area under the ROC curve of the overall years of medical check-up was signifi-cantly higher than a particular year in predicting hypertension (AUC: 0.883, p < 0.05). CONCLUSIONS: TyG index is associated with hypertension and shows the superior discriminative ability for hypertension compared with lipid and glycemic parameters.

Association between birth weight/joint exposure to ambient air pollutants and type 2 diabetes: a cohort study in the UK Biobank.

Early life events and environmental factors are associated with type 2 diabetes (T2D) development. We assessed the combined effect of birth weight andambient air pollutants, and effect of their interaction on T2D risk. Totally, 6,474 T2D incidents were recorded over an 8.7-year follow-up period. The adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were 1.31 (1.26, 1.36) for each kilogram decrease in birth weight, and 1.08 (1.05, 1.11) for each standard deviation increase in air pollution score (APS). Birth weight<3000 g amplified the T2D risk associated with high APS. A combination of the lowest birth weight (<2500 g) and the highest quintile of APS led to over two-fold increase in T2D risk (aHR: 2.17; 95% CI: 1.79-2.64). There was a significant additive interaction between them. In conclusion, ambient air pollutants increase the risk for T2D, particularly in populations with low birth weight.

Associations of reproductive risk score and joint exposure to ambient air pollutants with chronic obstructive pulmonary disease: a cohort study in UK Biobank.

BACKGROUND: Reproductive risk factors and air pollution for developing chronic obstructive pulmonary disease (COPD) have been documented separately. However, the combined effects of overall reproductive risk status on COPD and the extent to which this can be impacted by air pollution are unknown. The aim of this study was to construct a reproductive risk score (RRS) and an air pollution score (APS) and assess independent and joint associations between the two with incident COPD risk. METHODS: 78,027 female participants aged 40-69 years without baseline COPD from UK Biobank recruited between 2006 to 2010 were included in this study. RRS was constructed by 17 women's reproductive health-related items, and APS incorporating PM2.5, PM2.5-10, PM10, NO2, and NOx was calculated to assess the joint exposure level. The outcome of the incident COPD was identified through the in-patient hospital register. The associations of RRS and APS with COPD were examined by Cox proportional hazards regression. RESULTS: The risk of COPD reached its highest in the fourth quartile of the RRS (adjusted HR: 2.23, 95% CI: 1.76-2.82, P for trend < 0.001). A dose-response manner can also be observed between higher tertile APS with increased COPD risk and the highest risk was found in the third tertile of the APS (adjusted HR: 1.37, 95% CI: 1.19-1.58, P for trend < 0.001). The relative excess risk due to interaction (RERI) of 0.030 (95% CI: 0.012-0.048) showed additive interaction between RRS and APS on COPD was significant. In the joint analysis, the combinations of both higher RRS and APS signified higher incident COPD risk. CONCLUSION: High RRS and high APS were jointly associated with increased COPD risks in a dose-response pattern. Using comprehensive indicators to identify women's reproductive risk factors, together with the control of air pollution, is effective for COPD prevention.

Associations of polysocial risk score, lifestyle and genetic factors with incident type 2 diabetes: a prospective cohort study.

AIM/HYPOTHESIS: We aimed to investigate the association between polysocial risk score (PsRS), an estimator of individual-level exposure to cumulative social risks, and incident type 2 diabetes in the UK Biobank study. METHODS: This study includes 319,832 participants who were free of diabetes, cardiovascular disease and cancer at baseline in the UK Biobank study. The PsRS was calculated by counting the 12 social determinants of health from three social risk domains (namely socioeconomic status, psychosocial factors, and neighbourhood and living environment) that had a statistically significant association with incident type 2 diabetes after Bonferroni correction. A healthy lifestyle score was calculated using information on smoking status, alcohol intake, physical activity, diet quality and sleep quality. A genetic risk score was calculated using 403 SNPs that showed significant genome-wide associations with type 2 diabetes in people of European descent. The Cox proportional hazards model was used to analyse the association between the PsRS and incident type 2 diabetes. RESULTS: During a median follow-up period of 8.7 years, 4427 participants were diagnosed with type 2 diabetes. After adjustment for major confounders, an intermediate PsRS (4-6) and high PsRS (≥7) was associated with higher risks of developing type 2 diabetes with the HRs being 1.38 (95% CI 1.26, 1.52) and 2.02 (95% CI 1.83, 2.22), respectively, compared with those with a low PsRS (≤3). In addition, an intermediate to high PsRS accounted for approximately 34% (95% CI 29, 39) of new-onset type 2 diabetes cases. A healthy lifestyle slightly, but significantly, mitigated PsRS-related risks of type 2 diabetes (pinteraction=0.030). In addition, the additive interactions between PsRS and genetic predisposition led to 15% (95% CI 13, 17; p<0.001) of new-onset type 2 diabetes cases (pinteraction<0.001). CONCLUSIONS/INTERPRETATION: A higher PsRS was related to increased risks of type 2 diabetes. Adherence to a healthy lifestyle may attenuate elevated diabetes risks due to social vulnerability. Genetic susceptibility and disadvantaged social status may act synergistically, resulting in additional risks for type 2 diabetes.

Mortality and morbidity risk prediction for older former smokers based on a score of smoking history: evidence from UK Biobank and ESTHER cohorts.

BACKGROUND: Rapid population ageing has raised the proportion of older former smokers considerably, but a comprehensive assessment tool of former smoking-related health risks is absent. OBJECTIVE: We utilised the large-scale data of UK Biobank and ESTHER study to build a former smoking score (FSS) for older former smokers using three major former smoking traits: pack-years, smoking duration and time since smoking cessation. DESIGN: UK Biobank and ESTHER study are two cohorts of older adults with 502,528 and 9,940 participants from the UK and Germany, respectively. METHODS: Smoking history and covariates were retrieved from the self-administrated questionnaires and mortality and morbidity data were obtained through regular linkages to hospital records. RESULTS: We constructed the FSS based on the 94,446 former smokers of UK Biobank by retrieving the averaged effect estimates of each trait with a 100-time random sampling. This score was robustly associated with higher risks of mortality and incidence of major smoking-related diseases, outperforming each trait. In the validation panel of 2,683 former smokers from ESTHER study, the FSS was highly predictive of mortality and morbidities. Particularly, compared with the 1st quartile of the FSS group, the 4th quartile group had 114.1, 104.5 and 158.9% higher risks of all-cause, CVD and cancer mortality, respectively, and 41.9, 31.9, 52.4 and 831.3% higher risks of incident CVD, type 2 diabetes, any cancers and lung cancer, respectively. CONCLUSIONS: Our study demonstrates the large potential of refined risk assessment of former smokers by more comprehensive consideration of the major traits of former smoking.

Modification effect of ideal cardiovascular health metrics on genetic association with incident heart failure in the China Kadoorie Biobank and the UK Biobank.

BACKGROUND: Both genetic and cardiovascular factors contribute to the risk of developing heart failure (HF), but whether idea cardiovascular health metrics (ICVHMs) offset the genetic association with incident HF remains unclear. OBJECTIVES: To investigate the genetic association with incident HF as well as the modification effect of ICVHMs on such genetic association in Chinese and British populations. METHODS: An ICVHMs based on smoking, drinking, physical activity, diets, body mass index, waist circumference, blood pressure, blood glucose, and blood lipids, and a polygenic risk score (PRS) for HF were constructed in the China Kadoorie Biobank (CKB) of 96,014 participants and UK Biobank (UKB) of 335,782 participants which were free from HF and severe chronic diseases at baseline. RESULTS: During the median follow-up of 11.38 and 8.73 years, 1451 and 3169 incident HF events were documented in CKB and UKB, respectively. HF risk increased monotonically with the increase of PRS per standard deviation (CKB: hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07, 1.32; UKB: 1.07; 1.03, 1.11; P for trend < 0.001). Each point increase in ICVHMs was associated with 15% and 20% lower risk of incident HF in CKB (0.85; 0.81, 0.90) and UKB (0.80; 0.77, 0.82), respectively. Compared with unfavorable ICVHMs, favorable ICVHMs was associated with a lower HF risk, with 0.71 (0.44, 1.15), 0.41 (0.22, 0.77), and 0.48 (0.30, 0.77) in the low, intermediate, and high genetic risk in CKB and 0.34 (0.26, 0.44), 0.32 (0.25, 0.41), and 0.37 (0.28, 0.47) in UKB (P for multiplicative interaction > 0.05). Participants with low genetic risk and favorable ICVHMs, as compared with high genetic risk and unfavorable ICVHMs, had 56~72% lower risk of HF (CKB 0.44; 0.28, 0.70; UKB 0.28; 0.22, 0.37). No additive interaction between PRS and ICVHMs was observed (relative excess risk due to interaction was 0.05 [-0.22, 0.33] in CKB and 0.04 [-0.14, 0.22] in UKB). CONCLUSIONS: In CKB and UKB, genetic risk and ICVHMs were independently associated with the risk of incident HF, which suggested that adherence to favorable cardiovascular health status was associated with a lower HF risk among participants with all gradients of genetic risk.

Association of healthy lifestyle including a healthy sleep pattern with incident type 2 diabetes mellitus among individuals with hypertension.

BACKGROUND: Evidence is limited regarding the association of healthy lifestyle including sleep pattern with the risk of complicated type 2 diabetes mellitus (T2DM) among patients with hypertension. We aimed to investigate the associations of an overall healthy lifestyle including a healthy sleep pattern with subsequent development of T2DM among participants with hypertension compared to normotension, and to estimate how much of that risk could be prevented. METHODS: This study examined six lifestyle factors with T2DM cases among hypertension (227,966) and normotension (203,005) and their interaction in the UK Biobank. Low-risk lifestyle factors were defined as standard body mass index (BMI), drinking alcohol in moderation, nonsmoking, engaging in moderate- to vigorous-intensity physical activity, eating a high-quality diet, and maintaining a healthy sleep pattern. RESULTS: There were 12,403 incident T2DM cases during an average of 8.63 years of follow-up. Compared to those with 0 low-risk lifestyle factors, HRs for those with 5-6 were 0.14 (95% CI 0.10 to 0.19) for hypertensive participants, 0.13 (95% CI 0.08 to 0.19) for normotensive participants, respectively (ptrend < 0.001). 76.93% of hypertensive participants were considerably less likely to develop T2DM if they adhered to five healthy lifestyle practices, increased to 81.14% if they followed 6-factors (with a healthy sleep pattern). Compared with hypertension adults, normotensive people gain more benefits if they stick to six healthy lifestyles [Population attributable risk (PAR%) 83.66%, 95% CI 79.45 to 87.00%, p for interaction = 0.0011]. CONCLUSIONS: Adherence to a healthy lifestyle pattern including a healthy sleep pattern is associated with lower risk of T2DM in hypertensives, and this benefit is even further in normotensives.

Associations of daily sedentary behavior, physical activity, and sleep with irritable bowel syndrome: A prospective analysis of 362,193 participants.

BACKGROUND: Irritable bowel syndrome (IBS) substantially affects quality of life and requires early prevention. This study aimed to elucidate the relationships between IBS and daily behaviors, including sedentary behavior (SB), physical activity (PA), and sleep. In particular, it seeks to identify healthy behaviors to reduce IBS risk, which previous studies have rarely addressed. METHODS: Daily behaviors were retrieved from self-reported data of 362,193 eligible UK Biobank participants. Incident cases were determined by self-report or health care data according to Rome IV criteria. RESULTS: A total of 345,388 participants were IBS-free at baseline, during a median follow-up of 8.45 years, 19,885 incident IBS cases were recorded. When examined individually, SB and shorter (≤7 h/day) or longer (>7 h/day) sleep duration were each positively associated with increased IBS risk, and PA was associated with lower IBS risk. The isotemporal substitution model suggested that replacing SB with other activities could provide further protective effects against IBS risk. Among people sleeping ≤7 h/day, replacing 1 h of SB with equivalent light PA, vigorous PA, or sleep was associated with 8.1% (95% confidence interval (95%CI): 0.901-0.937), 5.8% (95%CI: 0.896-0.991), and 9.2% (95%CI: 0.885-0.932) reduced IBS risk, respectively. For people sleeping >7 h/day, light and vigorous PA were associated with a 4.8% (95%CI: 0.926-0.978) and a 12.0% (95%CI: 0.815-0.949) lower IBS risk, respectively. These benefits were mostly independent of genetic risk for IBS. CONCLUSION: SB and unhealthy sleep duration are risk factors for IBS. A promising way to mitigate IBS risk for individuals sleeping ≤7 h/day and for those sleeping >7 h/day appears to be by replacing SB with adequate sleep or vigorous PA, respectively, regardless of the genetic predisposition of IBS.

Fetal/maternal-determined birth weight and adulthood type 2 diabetes and its subtypes: a Mendelian randomization study.

BACKGROUND: Lower birth weight (BW) might increase the risk of adulthood type 2 diabetes, but its associations with the highly heterogeneous type 2 diabetes subtypes remain to be studied. In addition, whether the associations between lower BW and adulthood type 2 diabetes risks depend on fetal or maternal effect is largely unknown. METHODS: In this study, we performed a two-sample Mendelian Randomization analysis to study the associations between overall, fetal-determined, and maternal-determined BW and the risks of type 2 diabetes and its subtypes, namely mild age-related diabetes (MARD), mild obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD), and severe insulin-resistant diabetes (SIRD). RESULTS: Lower BW was genetically associated with increased risks of type 2 diabetes (odds ratio (OR): 1.86; 95% confidence interval (CI): 1.53, 2.26), MARD (OR: 2.15; 95%CI: 1.43, 3.23), MOD (OR: 1.75; 95%CI: 1.10, 2.77), SIDD (OR: 1.86; 95%CI: 1.11, 3.10), and SIRD (OR: 1.66; 95%CI: 1.06, 2.60). When examining the fetal-determined genetic effects independently, lower BW remained associated with type 2 diabetes and its subtypes, except for MOD. Using maternal-determined BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it raised offspring risks of type 2 diabetes. CONCLUSIONS: Fetal-determined but not maternal-determined lower BW were associated with increased risks of adulthood type 2 diabetes and its subtypes. Our results underscored the importance of early targeted management among people with a low BW in the prevention of type 2 diabetes.

Associations of healthy aging index and all-cause and cause-specific mortality: a prospective cohort study of UK Biobank participants.

The healthy aging index (HAI) has been recently developed as a surrogate measure of biological age. However, to what extent the HAI is associated with all-cause and cause-specific mortality and whether this association differs in younger and older adults remains unknown. We aimed to quantify the association between the HAI and mortality in a population of UK adults. In the prospective cohort study, data are obtained from the UK Biobank. Five HAI components (systolic blood pressure, reaction time, cystatin C, serum glucose, forced vital capacity) were scored 0 (healthiest), 1, and 2 (unhealthiest) according to sex-specific tertiles or clinically relevant cut-points and summed to construct the HAI (range 0-10). Cox proportional hazard regression models were used to estimate the associations of the HAI with the risk of all-cause and cause-specific mortality. 387,794 middle-aged and older participants were followed up for a median of 8.9 years (IQR 8.3-9.5). A total of 14,112 all-cause deaths were documented. After adjustments, each 1-point increase in the HAI was related to a higher risk of all-cause mortality (hazards ratio [HR], 1.17; 95%CI, 1.15-1.18). Such association was stronger among adults younger than 60 years (1.19, 1.17-1.21) than that among those 60 years and older (1.15, 1.14-1.17) (P interaction < 0.001). For each unit increment of the HAI, the multivariate-adjusted HRs for risk of death were 1.28 (1.25-1.31) for cardiovascular diseases, 1.09 (1.07-1.10) for cancer, 1.36 (1.29-1.44) for digestive disease, 1.42 (1.35-1.48) for respiratory disease, 1.42 (1.33-1.51) for infectious diseases, and 1.15 (1.09-1.21) for neurodegenerative disease, respectively. Our findings indicate that the HAI is positively associated with all-cause and cause-specific mortality independent of chronological age. Our results further underscore the importance of effective early-life interventions to slow aging and prevent premature death.

Identifying Potential Causal Effects of Telomere Length on Health Outcomes: A Phenome-Wide Investigation and Mendelian Randomization Study.

BACKGROUND: Telomere length has been linked to various health outcomes. To comprehensively investigate the causal effects of telomere length throughout the human disease spectrum, we conducted a phenome-wide Mendelian randomization study (MR-PheWAS) and a systematic review of MR studies. METHODS: We conducted a PheWAS to screen for associations between telomere length and 1 035 phenotypes in the UK Biobank (n = 408 354). The exposure of interest was the genetic risk score (GRS) of telomere length. Observed associations passing multiple testing corrections were assessed for causality by 2-sample MR analysis. A systematic review of MR studies on telomere length was performed to harmonize the published evidence and complement our findings. RESULTS: Of the 1 035 phenotypes tested, PheWAS identified 29 and 78 associations of telomere length GRS at a Bonferroni- and false discovery rate-corrected threshold; 24 and 66 distinct health outcomes were causal in the following principal MR analysis. The replication MR using data from the FinnGen study provided evidence of causal effects of genetically instrumented telomere length on 28 out of 66 outcomes, including decreased risks of 5 diseases in respiratory diseases, digestive diseases, and myocardial infarction, and increased risks of 23 diseases, mainly comprised neoplasms, diseases of the genitourinary system, and essential hypertension. A systematic review of 53 MR studies found evidence to support 16 out of the 66 outcomes. CONCLUSIONS: This large-scale MR-PheWAS identified a wide range of health outcomes that were possibly affected by telomere length, and suggested that susceptibility to telomere length may vary across disease categories.

Women's reproductive risk and genetic predisposition in type 2 diabetes: A prospective cohort study.

OBJECTIVE: To assess synergistic effects of reproductive factors and gene-reproductive interaction on type 2 diabetes (T2D) risk, also the extent to which the genetic risk of T2D can be affected by reproductive risk. METHODS: 84,254 women with genetic data and reproductive factors were enrolled between 2006 and 2010 in the UK Biobank. The reproductive risk score (RRS) was conducted based on 17 reproductive items, and genetic risk score (GRS) was based on 149 genetic variants. RESULTS: There were 2300 (2.8 %) T2D cases during an average follow-up of 4.49 years. We found a significant increase in T2D risk across RRS categories (Ptrend < 0.001). Compared with low reproductive risk, high-mediate (adjusted hazard ratio [aHR] 1.38, 95 % CI 1.20-1.58) and high (aHR 1.84, 95 % CI 1.54-2.19) reproductive risk could increase the risk of T2D. We further observed a significant additive interaction between reproductive risk and genetic predisposition. In the situation of high genetic predisposition, women with low reproductive risk had lower risk of T2D than those with high reproductive risk (aHR 0.47, 95 % CI 0.30-0.76), with an absolute risk reduction of 2.98 %. CONCLUSIONS: Our novo developed RRS identified high reproductive risk is associated with elevated risk of women's T2D, which can be magnified by gene-reproductive interaction.

Joint association and interaction of birth weight and lifestyle with hypertension: A cohort study in UK Biobank.

Low birth weight and unhealthy lifestyle are both associated with an increased risk of hypertension. The authors aimed to assess the joint association and interaction of birth weight and lifestyle with incident hypertension. The authors included 205 522 participants free of hypertension at baseline from UK Biobank. A healthy lifestyle score was constructed using information on body mass index, physical activity, diet, smoking status and alcohol intake. Cox proportional hazard models were used to investigate the impact of birth weight, healthy lifestyle score and their joint effect on hypertension. The authors documented 13 548 (6.59%) incident hypertension cases during a median of 8.6 years of follow-up. The multivariate adjusted hazard ratios and 95% confidence intervals were 1.12 (1.09, 1.15) per kg lower birth weight and 0.76 (0.75, 0.77) per score increment in healthy lifestyle score. Healthy lifestyle reduced the risk of hypertension in any category of different birth weight groups. The preventive effect of healthy lifestyle on hypertension was the most pronounced at lower birth weight with <2500 g and 2500-2999 g, respectively. Addictive interaction between birth weight and healthy lifestyle score was observed with the relative excess risk due to interaction of 0.04 (0.03, 0.05). Our findings emphasized the importance of healthy lifestyle for hypertension prevention, especially among the high-risk population with lower birth weight.

Women's reproductive risk score and healthy lifestyle modification in cardiovascular disease: Findings from the UK Biobank.

BACKGROUND AND AIMS: Reproductive risk factors are associated with increased risk of cardiovascular disease (CVD) in women. However, the combined effects of the composite reproductive risk factors on CVD are unknown. This study was performed to construct a reproductive risk score (RRS) to measure reproductive status, examine the association between RRS and CVD, and explore the modification effect of healthy lifestyle on the association in women in the UK Biobank cohort. METHODS: The RRS was constructed in 74,141 female participants with data about the items derived for the RRS in the UK Biobank. The RRS was derived from 17 baseline variables, all of which indicated women's reproductive health status. We defined four categories of RRS status: low-risk group (score 0-1); low-intermediate group (score 2-3); high-intermediate group (score 4-5); and high-risk group (score 6-13). We also constructed a healthy lifestyle score (HLS) with five related factors, and categorized into unhealthy lifestyle group (score: 0-1), intermediate lifestyle group (score: 2-3) and healthy lifestyle group (score: 4-5). RESULTS: Each point increase in the RRS was associated with a 22 % higher risk of CVD (adjusted hazard ratio (aHR): 1.22; 95 % confidence interval (CI): 1.16 to 1.28), 23 % higher risk of IHD (1.23; 1.17 to 1.31) and 19 % higher risk of stroke (1.19; 1.07 to 1.32). The percentage population-attribution risks (PAR%) were 16 % (95 % CI: 8 to 24) for CVD, 15 % (95 % CI: 6 to 24) for IHD and 18 % (95 % CI: 1 to 33) for stroke. A healthy lifestyle significantly attenuated RRS associations with the incidence of CVD and IHD. The attributable proportions due to additive interaction (p < 0.001) between RRS and HLS were 0.14 (95 % CI: 0.07 to 0.22) for CVD and 0.15 (95 % CI: 0.09 to 0.23) for IHD, respectively. CONCLUSIONS: High RRS was associated with increased risks of CVD, IHD and stroke in female participants in the UK Biobank. The early-stage identification of women with reproductive risk using synthesised indicators and appropriate healthy lifestyle interventions could be useful for the prevention of early CVD and the extension of healthy active life expectancy.

Elevated blood remnant cholesterol and triglycerides are causally related to the risks of cardiometabolic multimorbidity.

The connection between triglyceride-rich lipoproteins and cardiometabolic multimorbidity, characterized by the concurrence of at least two of type 2 diabetes, ischemic heart disease, and stroke, has not been definitively established. We aim to examine the prospective associations between serum remnant cholesterol, triglycerides, and the risks of progression from first cardiometabolic disease to multimorbidity via multistate modeling in the UK Biobank. We also evaluate the causality of these associations via Mendelian randomization using 13 biologically relevant SNPs as the genetic instruments. Here we show that elevated remnant cholesterol and triglycerides are significantly associated with gradually higher risks of cardiometabolic multimorbidity, particularly the progression of ischemic heart disease to the multimorbidity of ischemic heart disease and type 2 diabetes. These results advocate for effective management of remnant cholesterol and triglycerides as a potential strategy in mitigating the risks of cardiometabolic multimorbidity.