Spontaneous miscarriage and social support in predicting risks of depression and anxiety: a cohort study in UK Biobank.

BACKGROUND: It is still unclear whether social support can moderate the high risk of depression and anxiety due to spontaneous miscarriage. OBJECTIVE: This study prospectively investigated the associations of spontaneous miscarriage with risks of depression and anxiety, and evaluated the interactions between spontaneous miscarriage and the degree of social support in relation to depression and anxiety risks. STUDY DESIGN: A total of 179,000 participants from the UK Biobank with pregnancy experience and without depression or anxiety at baseline were included. Spontaneous miscarriage was defined by self-report from participants at enrollment or by International Classification of Diseases codes. The degree of social support was defined as the number of social support factors including living with a spouse or partner, participation in social activities, and confiding. Cox proportional hazards models were used to evaluate the joint association of spontaneous miscarriage and social support with the risks of depression and anxiety. RESULTS: During a median follow-up of 12.3 years, 4939 depression incidents and 5742 anxiety incidents were documented. For participants with 1, 2, and ≥3 spontaneous miscarriages, hazard ratios (95% confidence intervals) for depression were 1.10 (1.02-1.19), 1.31 (1.14-1.50), and 1.40 (1.18-1.67), respectively (P trend <.001), compared with participants without a history of spontaneous miscarriage, after adjustment for covariates. For anxiety, the hazard ratios (95% confidence intervals) were 1.07 (1.00-1.15), 1.04 (0.90-1.19), and 1.21 (1.02-1.44), respectively (P trend=.01). Moreover, we found that the risk of depression associated with a combination of spontaneous miscarriage and low degree of social support in later life was greater than the sum of the risks associated with each individual factor, indicating significant interactions on an additive scale (P interaction=.03). CONCLUSION: Spontaneous miscarriage is associated with higher risks of depression and anxiety, and the risk of depression is further increased when there is also low degree of social support.

Smoking timing, genetic susceptibility and the risk of incident type 2 diabetes: A cohort study from the UK Biobank.

AIM: To prospectively assess the association of smoking timing with the risk of type 2 diabetes (T2D) and examine whether smoking amount or genetic susceptibility might modify the relationship. MATERIALS AND METHODS: A total of 294 815 participants without diabetes from the UK Biobank, including non-smokers and smokers with data on the time from waking to first cigarette, were included. Cox proportional hazards models were used to evaluate the association between smoking timing and the risk of incident T2D. RESULTS: During a median follow-up time of 12 years, a total of 9937 incident cases of T2D were documented. Compared with non-smokers, a shorter time from waking to first cigarette was significantly associated with a higher risk of incident T2D (P for trend < .001). In the fully adjusted model, the hazard ratios (HRs) (95% confidence interval) associated with smoking timing were 1.46 (1.17-1.81) for more than 2 hours, 1.51 (1.21-1.87) for 1-2 hours, 1.58 (1.34-1.85) for 30-60 minutes, 1.86 (1.57-2.21) for 5-15 minutes and 2.01 (1.60-2.54) for less than 5 minutes. We found that even among those who reported being light smokers, those with the shortest time from waking to first cigarette had a 105% higher risk of T2D with an HR of 2.05 (1.52-2.76), which was comparable with heavy smokers. The genetic risk score for T2D did not modify this association (P-interaction = .51). CONCLUSIONS: Our findings indicate that shorter time from waking to first cigarette is significantly associated with a higher risk of incident T2D.

Changes in bile acid subtypes and improvements in lipid metabolism and atherosclerotic cardiovascular disease risk: the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial.

BACKGROUND: Distinct circulating bile acid (BA) subtypes may play roles in regulating lipid homeostasis and atherosclerosis. OBJECTIVES: We investigated whether changes in circulating BA subtypes induced by weight-loss dietary interventions were associated with improved lipid profiles and atherosclerotic cardiovascular disease (ASCVD) risk estimates. METHODS: This study included adults with overweight or obesity (n = 536) who participated in a randomized weight-loss dietary intervention trial. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 mo after the weight-loss diet intervention. The ASCVD risk estimates were calculated using the validated equations. RESULTS: At baseline, higher concentrations of specific BA subtypes were related to higher concentrations of atherogenic very low-density lipoprotein lipid subtypes and ASCVD risk estimates. Weight-loss diet-induced decreases in primary BAs were related to larger reductions in triglycerides and total cholesterol [every 1 standard deviation (SD) decrease of glycocholate, glycochenodeoxycholate, or taurochenodeoxycholate was related to ß (standard error) -3.3 (1.3), -3.4 (1.3), or -3.8 (1.3) mg/dL, respectively; PFDR < 0.05 for all]. Greater decreases in specific secondary BA subtypes were also associated with improved lipid metabolism at 6 mo; there was ß -4.0 (1.1) mg/dL per 1-SD decrease of glycoursodeoxycholate (PFDR =0.003) for changes in low-density lipoprotein cholesterol. We found significant interactions (P-interaction < 0.05) between dietary fat intake and changes in BA subtypes on changes in ASCVD risk estimates; decreases in primary and secondary BAs (such as conjugated cholate or deoxycholate) were significantly associated with improved ASCVD risk after consuming a high-fat diet, but not after consuming a low-fat diet. CONCLUSIONS: Decreases in distinct BA subtypes were associated with improved lipid profiles and ASCVD risk estimates, highlighting the importance of changes in circulating BA subtypes as significant factors linked to improved lipid metabolism and ASCVD risk estimates in response to weight-loss dietary interventions. Habitual dietary fat intake may modify the associations of changes in BAs with ASCVD risk. This trial was registered at clinicaltrials.gov as NCT00072995.

Association of white matter hyperintensities with BMD, incident fractures, and falls in the UK Biobank cohort.

Osteoporosis is the most common metabolic bone disease globally, which increases the healthcare service burden. Recent studies have linked higher white matter hyperintensities (WMH) to reduced BMD, increasing the risk of fractures and falls in older adults. However, limited evidence exists regarding the dose-response relationship between WMH and bone health in a larger and younger population. Our study aimed to examine the association of WMH volume with BMD, incident fractures and falls, focusing on dose-response relationship with varying levels of WMH volume. We included 26 410 participants from the UK Biobank. The association between WMH volume and BMD was analyzed using multiple linear regression. Cox regression models were used to estimate the hazard ratios of incident fractures and falls. Restricted cubic spline (RCS) fitted for linear and Cox regression models were employed to explore potential non-linearity. Over a mean follow-up time of 3.8 yr, we documented 59 hip fractures, 392 all fractures, and 375 fall incidents. When applying RCS, L-shaped relationships were identified between WMH volume and BMD across all 4 sites. Compared with those in the lowest fifth of WMH volume, individuals in the second to the highest fifths were associated with a reduction of 0.0102-0.0305 g/cm2 in femur neck BMD, 0.0075-0.0273 g/cm2 in femur troch BMD, 0.0173-0.0345 g/cm2 in LS BMD, and 0.0141-0.0339 g/cm2 in total body BMD. The association was more pronounced among women and younger participants under age 65 (Pinteraction < .05). Per 1 SD increment of WMH volume was associated with 36.9%, 20.1%, and 14.3% higher risks of incident hip fractures, all fractures, and falls. Genetically determined WMH or apolipoprotein E genotypes did not modify these associations. We demonstrated that a greater WMH was associated with BMD in an L-shaped dose-response manner, especially in women and those under 65 yr.

This study investigated the association between white matter hyperintensities (WMH) and bone health, focusing on BMD, incident fractures and falls. We included 26 410 participants from the UK Biobank and found that a greater WMH volume was associated with BMD in an L-shaped dose­response manner, especially in women and those under 65 yr. Additionally, per 1 SD increment of WMH volume was associated with 36.9%, 20.1%, and 14.3% higher risks of incident hip fractures, all fractures, and falls. These findings emphasize the significance of considering brain health when evaluating bone health.

Degree of joint risk factor control and hazard of mortality in diabetes patients: a matched cohort study in UK Biobank.

BACKGROUND: Diabetes patients are at higher risk for mortality than the general population; however, little is known about whether the excess mortality risk associated with diabetes could be mitigated or nullified via controlling for risk factors. METHODS: We included 18,535 diabetes patients and 91,745 matched individuals without diabetes without baseline cancer or cardiovascular disease (CVD), followed up from 2006 to 2021. The main exposure was the number of optimized risk factors including glycated hemoglobin < 53 mmol/mole, systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg, no albuminuria, non-current smoking and low-density lipoprotein cholesterol (LDL-C) < 2.5 mmol/L. We used Cox proportional hazards models to explore the association of the degree of risk factor control with all-cause mortality, cancer mortality, CVD mortality and other mortality. RESULTS: Each additional risk factor control was associated with a 16, 10, 21 and 15% lower risk of all-cause mortality, cancer mortality, CVD mortality and other mortality, respectively. Optimal risk factors control (controlling 5 risk factors) was associated with a 50% (HR 0.50, 95% CI 0.41-0.62), 74% (HR 0.26, 95% CI 0.16-0.43) and 38% (HR 0.62, 95% CI 0.44-0.87) lower risk of all-cause mortality, CVD mortality and other mortality, respectively. Diabetes patients with 4, 3 and 5 or more controlled risk factors, respectively, showed no excess risk of all-cause mortality, cancer mortality and CVD mortality compared to matched non-diabetes patients. CONCLUSIONS: The results from this study indicate that optimal risk factor control may eliminate diabetes-related excess risk of all-cause mortality, CVD mortality and other mortality.

Ready-to-Eat Food Environments and Risk of Incident Heart Failure: A Prospective Cohort Study.

BACKGROUND: Food environments have been linked to cardiovascular diseases; however, few studies have assessed the relationship between food environments and the risk of heart failure (HF). We aimed to evaluate the association between ready-to-eat food environments and incident HF at an individual level in a large prospective cohort. METHODS: Exposure to ready-to-eat food environments, comprising pubs or bars, restaurants or cafeterias, and fast-food outlets, were individually measured as both proximity and density metrics. We also developed a composite ready-to-eat food environment density score by summing the densities of 3 types of food environments. Cox proportional analyses were applied to assess the associations of each single type and the composite food environments with HF risk. RESULTS: Closer proximity to and greater density of ready-to-eat food environments, particularly for pubs and bars and fast-food outlets (P<0.05 for both proximity and density metric) were associated with an elevated risk of incident HF. Compared with those with no exposure to composite ready-to-eat food environments, participants in the highest density score category had a 16% (8%-25%; P<0.0001) higher risk of HF. In addition, we found significant interactions of food environments with education, urbanicity, and density of physical activity facilities on HF risk (all Pinteraction<0.05); the ready-to-eat food environments-associated risk of HF was stronger among participants who were poorly educated, living in urban areas, and without physical activity facilities. CONCLUSIONS: Exposure to ready-to-eat food environments is associated with a higher risk of incident HF, suggesting the potential importance of minimizing unfavorable food environments in the prevention of HF.

Circulating MicroRNA-19 and cardiovascular risk reduction in response to weight-loss diets.

OBJECTIVE: MicroRNA-19 (miR-19) plays a critical role in cardiac development and cardiovascular disease (CVD). We examined whether change in circulating miR-19 was associated with change in CVD risk during weight loss. METHODS: This study included 509 participants with overweight or obesity from the 24-month weight-loss diet intervention study (the POUNDS Lost trial) and with available data on circulating miR-19a-3p and miR-19b-3p at baseline and 6 months. The primary outcome for this analysis was the change in atherosclerotic CVD (ASCVD) risk at 6 and 24 months, which estimates the 10-year probability of hard ASCVD events. Secondary outcomes were the changes in ASCVD risk score components. RESULTS: Circulating miR-19a-3p and miR-19b-3p levels significantly decreased during the initial 6-month dietary intervention period (P = 0.008, 0.0004, respectively). We found that a greater decrease in miR-19a-3p or miR-19b-3p was related to a greater reduction in ASCVD risk (ß[SE] = 0.33 [0.13], P = 0.01 for miR-19a-3p; ß[SE] = 0.3 [0.12], P = 0.017 for miR-19b-3p) over 6 months, independent of concurrent weight loss. Moreover, we found significant interactions between change in miR-19 and sleep disturbance on change in ASCVD risk over 24 months of intervention (P interaction = 0.01 and 0.008 for miR-19a-3p and miR-19b-3p, respectively). Participants with a greater decrease in miR-19 without sleep disturbance had a greater reduction of ASCVD risk than those with slight/moderate/great amounts of sleep disturbance. In addition, change in physical activity significantly modified the associations between change in miR-19 and change in ASCVD risk over 24 months (P interaction = 0.006 and 0.004 for miR-19a-3p and miR-19b-3p, respectively). A greater decrease in miR-19 was significantly associated with a greater reduction in ASCVD risk among participants with an increase in physical activity, while non-significant inverse associations were observed among those without an increase in physical activity. CONCLUSIONS: In conclusion, decreased circulating miR-19 levels during dietary weight-loss interventions were related to a significant reduction in ASCVD risk, and these associations were more evident in people with no sleep disturbance or increase in physical activity. TRIAL REGISTRATION: ClinicalTrials.gov NCT00072995.

Degree of Risk Factor Control and Incident Cardiovascular Diseases in Patients With Hypertension.

OBJECTIVE: To investigate whether joint risk factor control could reduce the excess risk of cardiovascular disease (CVD) in patients with hypertension. PATIENTS AND METHODS: A total of 75,293 patients with diagnosed hypertension from the UK Biobank study were included, matched with 256,619 nonhypertensive controls, and followed up until May 31, 2021. Seven risk factors were measured to define joint risk factor control, including blood pressure, body mass index, low-density lipoprotein cholesterol, hemoglobin A1c, albuminuria, smoking, and physical activity. RESULTS: Among hypertensive patients, 14% to 24% lower risks of CVD outcomes were associated with each additional risk factor control. In the Cox proportional hazards models, adjusted hazard ratios for patients with 6 or more risk factor controls compared with patients having 2 or less risk factor controls were 0.49 (95% CI, 0.45 to 0.55) for CVD, 0.51 (95% CI, 0.45 to 0.57) for coronary heart disease, 0.48 (95% CI, 0.38 to 0.60) for stroke, and 0.34 (95% CI, 0.26 to 0.44) for CVD mortality. The excess risks of CVD outcomes in patients with hypertension were diminished to nonsignificant or even lower compared with controls if achieving 6 or more risk factor controls. Men experienced stronger protective associations of joint risk factor control on risks of CVD than women (P<.001 for interaction). CONCLUSION: The joint risk factor control is associated with lower risks of CVD, and a high degree of risk factor control may considerably attenuate the excess risk of CVD among patients with hypertension.

Body composition, lifestyle, and depression: a prospective study in the UK biobank.

BACKGROUND: Obesity has been related to depression and adhering healthy lifestyle was beneficial to lower the risk of depression; however, little is known about the relationship between body composition and fat distribution with depression risk and the influence of body composition and fat distribution on the association of lifestyle and depression. Therefore, we aimed to investigate whether body composition and fat distribution were associated with the adverse events of depression and the relationship between lifestyle and depression. METHODS: We included 330,131 participants without depression at baseline in the UK Biobank (mean age, 56.9 years; 53.83% females). The assessment of depression was sourced from health outcomes across self-report, primary care, hospital inpatient data, and death data. Body composition was determined by bioelectrical impedance. Seven lifestyles (no current smoking, moderate alcohol consumption, regular physical activity, healthy diet, less sedentary behavior, healthy sleep pattern, and appropriate social connection) were used to generate a lifestyle score. RESULTS: During a median of 11.7 years of follow-up, 7576 incident depression occurred. All the body composition measures were positively associated with depression risk, with the Hazard ratios (HR) for the uppermost tertile (T3) versus the lowest tertile (T1) ranging from 1.26 (95% CI: 1.15-1.39) for trunk fat-free mass (TFFM) to 1.78 (1.62-1.97) for leg fat percentage (LFP). In addition, we found significant interactions between fat mass-related indices, especially leg fat mass (LFM) (p = 1.65 × 10-9), and lifestyle score on the risk of depression, for which the beneficial associations of a healthy lifestyle with the risk of depression were more evident among participants with low body fat measurement. CONCLUSIONS: High levels of body composition measures were associated with an increased depression risk. Adverse body composition measures may weaken the link between a healthy lifestyle and a reduced risk of depression.

Food Insecurity and Premature Mortality and Life Expectancy in the US.

Importance: Food insecurity has been linked to multiple causes of disease and premature mortality; however, its association with mortality by sex and across racial and ethnic groups remains unknown in the US. Objective: To investigate the associations of the entire range of food security with all-cause premature mortality and life expectancy across racial and ethnic and sex groups in US adults. Design, Setting, and Participants: This cohort study included adults (aged ≥18 years) who participated in the National Health and Nutrition Examination Survey from 1999 to 2018, with linkage to the National Death Index through December 31, 2019. Data analysis was performed from August to November 2023. Exposures: Levels of food security were assessed with the US Department of Agriculture Adult Food Security Survey Module (full, marginal, low, and very low). Main Outcomes and Measures: All-cause premature mortality (death that occurs before age 80 years) and life expectancy. Results: The study included 57 404 adults (weighted mean [SE] age, 46.0 [0.19] years; 51.8% female; 12 281 Black individuals [21.4%]; 10 421 Mexican individuals [18.2%]; 4627 Other Hispanic individuals [8.1%]; 24 817 White individuals [43.2%]; and 5258 individuals of other races, including multiracial [9.2%]). During a median (IQR) of 9.3 (5.0-14.3) years of follow-up, 4263 premature deaths were documented. Compared with the full food security group, the adjusted hazard ratios were 1.50 (95% CI, 1.31-1.71), 1.44 (95% CI, 1.24-1.68), and 1.81 (95% CI, 1.56-2.10) across marginal, low, and very low food security groups, respectively (P < .001 for trend). The corresponding life expectancy at age 50 years in each group was 32.5 (95% CI, 32.4-32.6), 29.9 (95% CI, 28.9-30.9), 30.0 (95% CI, 28.9-31.0), and 28.0 (95% CI, 26.8-29.2) years. Equivalently, adults with marginal, low, or very low food security lived on average 2.6 (95% CI, 1.5-3.7), 2.5 (95% CI, 1.4-3.7), or 4.5 (95% CI, 3.2-5.8) fewer years at age 50 years, respectively, compared with those with full food security. The associations appeared to be stronger in women than in men (hazard ratios comparing very low food security with full food security, 2.29 [95% CI, 1.83-2.86] in women and 1.46 [95% CI, 1.19-1.78] in men; P = .009 for interaction) and stronger in White adults than in Black adults (hazard ratios comparing very low food security with full food security, 2.07 [95% CI, 1.70-2.53] in White adults and 1.33 [95% CI, 1.01-1.75] in Black adults; P < .001 for interaction) or in Hispanic adults (hazard ratios comparing very low food security with full food security, 1.06 [95% CI, 0.71-1.58]; P < .001 for interaction). Conclusions and Relevance: In this cohort study, although the association of food security and life expectancy varied across sex and racial and ethnic groups, overall, lower levels of food security were associated with a higher risk of premature mortality and a shorter life expectancy. The findings of this study highlight the potential importance of improving food security in promoting population health and health equity.

Improvement of Social Isolation and Loneliness and Excess Mortality Risk in People With Obesity.

Importance: Individuals with obesity experience markedly higher levels of social isolation and loneliness than those without obesity, but little is known about whether improvement of social isolation or loneliness might attenuate obesity-related excess risk of mortality. Objective: To investigate whether improvement of social isolation or loneliness is associated with lower obesity-related excess risk of mortality. Design, Setting, and Participants: This cohort study included individuals without cancer or cardiovascular disease (CVD) at baseline from the UK Biobank with follow-up beginning in March 2006 and ending in November 2021. Main Outcomes and Measures: All-cause, cancer-related, and CVD-related mortality were estimated. Results: A total of 398 972 participants were included in this study (mean [SD] age, 55.85 [8.08] years; 220 469 [55.26%] women; 13 734 [3.44%] Asian, 14 179 [3.55%] multiracial, and 363 685 [91.16%] White participants). Overall, 93 357 (23.40%) had obesity, and 305 615 (76.60%) did not. During a median (IQR) follow-up of 12.73 (12.01-13.43) years, a total of 22 872 incident deaths were recorded. Compared with participants with obesity with an index of 2 or greater for social isolation, the multivariable adjusted hazard ratios (HRs) for all-cause mortality were 0.85 (95% CI, 0.79-0.91) and 0.74 (95% CI, 0.69-0.80) for participants with obesity and a social isolation index of 1 and 0, respectively (P for trend < .001); compared with participants with obesity and an index of 2 for loneliness, the HRs and 0.97 (95% CI, 0.89-1.06) and 0.86 (95% CI, 0.79-0.94) for participants with obesity and a loneliness index of 1 and 0, respectively (P for trend < .001). As the index of social isolation and loneliness went from highest to lowest, the HR for all-cause mortality decreased by 36% and 9%, respectively, in people with obesity compared with people without obesity using the multivariable model. Social isolation was ranked higher than loneliness, depression, anxiety, and lifestyle-related risk factors including alcohol, physical activity, and healthy diet for estimating the risks of all-cause mortality, cancer-related mortality, and CVD-related mortality. Conclusions and Relevance: In this cohort study of UK Biobank participants, a lower index of social isolation or loneliness was associated with a decreased risk of all-cause mortality among people with obesity, and improvement of social isolation and loneliness attenuated obesity-related excess risk of all-cause mortality.

MTNR1B genotype and effects of carbohydrate quantity and dietary glycaemic index on glycaemic response to an oral glucose load: the OmniCarb trial.

AIMS/HYPOTHESIS: A type 2 diabetes-risk-increasing variant, MTNR1B (melatonin receptor 1B) rs10830963, regulates the circadian function and may influence the variability in metabolic responses to dietary carbohydrates. We investigated whether the effects of carbohydrate quantity and dietary glycaemic index (GI) on glycaemic response during OGTTs varied by the risk G allele of MTNR1B-rs10830963. METHODS: This study included participants (n=150) of a randomised crossover-controlled feeding trial of four diets with high/low GI levels and high/low carbohydrate content for 5 weeks. The MTNR1B-rs10830963 (C/G) variant was genotyped. Glucose response during 2 h OGTT was measured at baseline and the end of each diet intervention. RESULTS: Among the four study diets, carrying the risk G allele (CG/GG vs CC genotype) of MTNR1B-rs10830963 was associated with the largest AUC of glucose during 2 h OGTT after consuming a high-carbohydrate/high-GI diet (ß 134.32 [SE 45.69] mmol/l × min; p=0.004). The risk G-allele carriers showed greater increment of glucose during 0-60 min (ß 1.26 [0.47] mmol/l; p=0.008) or 0-90 min (ß 1.10 [0.50] mmol/l; p=0.028) after the high-carbohydrate/high-GI diet intervention, but not after consuming the other three diets. At high carbohydrate content, reducing GI levels decreased 60 min post-OGTT glucose (mean -0.67 [95% CI: -1.18, -0.17] mmol/l) and the increment of glucose during 0-60 min (mean -1.00 [95% CI: -1.67, -0.33] mmol/l) and 0-90 min, particularly in the risk G-allele carriers (pinteraction <0.05 for all). CONCLUSIONS/INTERPRETATION: Our study shows that carrying the risk G allele of MTNR1B-rs10830963 is associated with greater glycaemic responses after consuming a diet with high carbohydrates and high GI levels. Reducing GI in a high-carbohydrate diet may decrease post-OGTT glucose concentrations among the risk G-allele carriers.

Self-Reported Frequency of Adding Salt to Food and Risk of Incident Chronic Kidney Disease.

Importance: The self-reported frequency of adding salt to foods could reflect a person's long-term salt taste preference, and salt intake has been associated with increased risk of cardiovascular diseases (CVD). Whether self-reported adding of salt to foods is associated with increased risk of chronic kidney disease (CKD) remains unknown. Objective: To prospectively examine the association of self-reported frequency of adding salt to foods with incident CKD risk in a general population of adults. Design, Setting, and Participants: This population-based cohort study evaluated UK Biobank participants aged 37 to 73 years who were free of CKD at baseline. Participants were enrolled from 2006 to 2010 and prospectively followed up for disease diagnosis. Data were analyzed from October 2022 to April 2023. Exposure: Self-reported frequency of adding salt to foods, categorized into never or rarely, sometimes, usually, and always. Main Outcome and Measure: Incident CKD cases were defined by diagnostic codes. Hazard ratios (HRs) and 95% CIs were calculated by using Cox proportional hazards models. Models were adjusted for several potential confounders including age, sex, race and ethnicity, Townsend Deprivation Index, estimated glomerular filtration rate (eGFR), body mass index, (BMI), smoking status, alcohol drinking status, regular physical activity, high cholesterol, diabetes, CVD, hypertension, infectious disease, immune disease, and nephrotoxic drugs use at baseline. Results: Within a cohort of 465 288 individuals (mean [SD] age 56.32 [8.08] years; 255 102 female participants [54.83%]; 210 186 male participants [45.17%]), participants with higher self-reported frequency of adding salt to foods were more likely to have a higher BMI, higher Townsend Deprivation Index score, and diminished baseline eGFR compared with those who reported a lower frequency of adding salt to foods. Participants who added salt to their foods were also more likely than those who did not add salt to their foods to be current smokers and have diabetes or CVD at baseline. During a median (IQR) follow-up of 11.8 (1.4) years, 22 031 incident events of CKD were documented. Higher self-reported frequency of adding salt to foods was significantly associated with a higher CKD risk after adjustment for covariates. Compared with those who reported never or rarely adding salt to foods, those who reported sometimes adding salt to food (adjusted HR [aHR], 1.04; 95% CI, 1.00-1.07), those who reported usually adding salt to food (aHR, 1.07; 95% CI, 1.02-1.11), and those who reported always adding salt to food (aHR, 1.11; 95% CI, 1.05-1.18) had an increased risk of CKD (P for trend < .001). In addition, eGFR, BMI, and physical activity significantly modified the associations, which were more pronounced among participants with a higher eGFR, lower BMI, or lower level of physical activity. Conclusions and Relevance: In this cohort study of 465 288 individuals, a higher self-reported frequency of adding salt to foods was associated with a higher risk of CKD in the general population. These findings suggest that reducing the frequency of adding salt to foods at the table might be a valuable strategy to lower CKD risk in the general population.

Dietary Sodium Intake and Risk of Incident Type 2 Diabetes.

OBJECTIVE: To fill the knowledge gap of the relation between long-term dietary sodium intake and type 2 diabetes (T2D), we evaluate the association between the frequency of adding salt to foods, a surrogate marker for evaluating the long-term sodium intake, and incident T2D risk. METHODS: A total of 402,982 participants from UK Biobank (March 13, 2006 - October 10, 2010) who were free of diabetes, chronic kidney disease, cancer, or cardiovascular disease at baseline, and had completed information on adding salt were analyzed in this study. RESULTS: During a median of 11.9 years of follow-up, 13,120 incident cases of T2D were documented. Compared with participants who "never/rarely" added salt to foods, the adjusted HRs were 1.11 (95% CI, 1.06 to 1.15), 1.18 (95% CI, 1.12 to 1.24), and 1.28 (95% CI, 1.20 to 1.37) across the groups of "sometimes," "usually," and "always," respectively (P-trend<.001). We did not find significant interactions between the frequency of adding salt to foods and baseline hypertension status and other covariates on the risk of incident T2D. The observed positive association was partly mediated by body mass index, waist to hip ratio, and C-reactive protein, with a significant mediation effect of 33.8%, 39.9%, and 8.6%, respectively. The significant mediation effect of body mass index was largely driven by the body fat mass rather than the body fat-free mass. CONCLUSION: Our findings for the first time indicate that higher frequency of adding salt to foods, a surrogate marker for a person's long-term salt taste preference and intake, is associated with a higher T2D risk.

Adherence to a healthy sleep pattern is associated with lower risks of incident falls and fractures during aging.

Background: Autoimmune diseases are more common among people with unhealthy sleep behaviors, and these conditions have been linked to aging-related bone health. However, there have been few studies that examined the correlation between recently developed sleep patterns based on sleep duration, sleepiness, chronotype, snoring, insomnia, and the incidence of falls and fractures. Methods: We used a newly developed sleep pattern with components of sleep 7 to 8 h per day, absence of frequent excessive daytime sleepiness, early chronotype, no snoring, and no frequent insomnia as healthy factors to study their relationship with the incidence of falls and fractures. The analysis was conducted among 289,000 participants from the UK Biobank. Results: The mean follow-up period was 12.3 years (3.5 million person-years of follow-up), and 12,967 cases of falls and 16,121 cases of all fractures were documented. Compared to participants exhibiting an unfavorable sleep pattern, those adhering to a healthy sleep pattern experienced a 17% and 28% reduction in the risks of incident falls (hazard ratio [HR], 0.83; 95% CI, 0.74-0.93) and all fractures (HR, 0.72; 95% CI, 0.66-0.79) during follow-up. In addition, participants exhibiting a healthy sleep pattern, together with a high genetically determined bone mineral density (BMD), showed the lowest risks of falls and fractures. Conclusion: A healthy sleep pattern was significantly linked to decreased risks of incident falls and fractures. The protective association was not modified by genetically determined BMD.

Toward Precision Weight-Loss Dietary Interventions: Findings from the POUNDS Lost Trial.

The POUNDS Lost trial is a 2-year clinical trial testing the effects of dietary interventions on weight loss. This study included 811 adults with overweight or obesity who were randomized to one of four diets that contained either 15% or 25% protein and 20% or 40% fat in a 2 × 2 factorial design. By 2 years, participants on average lost from 2.9 to 3.6 kg in body weight in the four intervention arms, while no significant difference was observed across the intervention arms. In POUNDS Lost, we performed a series of ancillary studies to detect intrinsic factors particular to genomic, epigenomic, and metabolomic markers that may modulate changes in weight and other cardiometabolic traits in response to the weight-loss dietary interventions. Genomic variants identified from genome-wide association studies (GWASs) on obesity, type 2 diabetes, glucose and lipid metabolisms, gut microbiome, and dietary intakes have been found to interact with dietary macronutrients (fat, protein, and carbohydrates) in relation to weight loss and changes of body composition and cardiometabolic traits. In addition, we recently investigated epigenomic modifications, particularly blood DNA methylation and circulating microRNAs (miRNAs). We reported DNA methylation levels at NFATC2IP, CPT1A, TXNIP, and LINC00319 were related to weight loss or changes of glucose, lipids, and blood pressure; we also reported thrifty miRNA expression as a significant epigenomic marker related to changes in insulin sensitivity and adiposity. Our studies have also highlighted the importance of temporal changes in novel metabolomic signatures for gut microbiota, bile acids, and amino acids as predictors for achievement of successful weight loss outcomes. Moreover, our studies indicate that biochemical, behavioral, and psychosocial factors such as physical activity, sleep disturbance, and appetite may also modulate metabolic changes during dietary interventions. This review summarized our major findings in the POUNDS Lost trial, which provided preliminary evidence supporting the development of precision diet interventions for obesity management.

Adherence to Life's Essential 8 and incident chronic kidney disease: a prospective study of 147,988 UK Biobank participants.

BACKGROUND: The American Heart Association recently updated Life's Essential 8 (LE8) score. This amalgamation of health factors, recognized for their individual associations with chronic kidney disease (CKD) risk, provides a robust tool to assess overall cardiovascular health (CVH), which could potentially be extrapolated to predict CKD risk. OBJECTIVES: This study aimed to investigate the association between levels of CVH, as measured by the LE8 score, and risk of CKD in the UK Biobank. METHODS: A total of 147,988 participants free of CKD and cardiovascular disease from the UK Biobank were included in this prospective study. CVH levels were categorized as low (0-49), moderate (50-79), and high (80-100) using LE8 score. An adjusted Cox proportional hazard model was used to investigate the association between LE8 and CKD. The population attributable-risk (PAR) was also calculated. RESULTS: During a median follow-up of 10 y, 1936 CKD cases were documented. A higher LE8 score was associated with a significant lower risk of CKD (P < 0.001), and a linear dose-response relationship was observed. Similar patterns were also found in the associations of the LE8 behavior and biological subscale scores with CKD. Compared with participants with a low CVH category, participants with a moderate CVH were associated with a 39% lower risk of developing CKD (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.52, 0.72); and those with a high CVH had a 57% lower risk of CKD incidence (HR: 0.43; 95% CI: 0.35, 0.53) after adjustment for covariates. Among 8 distinct metrics of LE8 score, the BMI metric had the highest PAR (24.6%; 95% CI: 18.8, 30.2). Of the total CKD risk, 3.2% (95% CI: 1.4, 5.0) was attributable to inadequate or excessive sleep duration. CONCLUSIONS: High CVH, defined by LE8, is significantly associated with a lower risk of CKD. These results suggest that promoting optimal cardiovascular health may lower the burden of CKD.

BMI change during childhood, DNA methylation change at TXNIP, and glucose change during midlife.

OBJECTIVE: This study investigated whether changes in DNA methylation (DNAm) at TXNIP are associated with glycemic changes and whether such an association differs with early-life adiposity changes. METHODS: A total of 594 Bogalusa Heart Study participants who had blood DNAm measurements at two time points in midlife were included. Of them, 353 participants had at least four BMI measurements during childhood and adolescence. The incremental area under the curve was calculated as a measure of long-term trends of BMI during childhood and adolescence. RESULTS: Increase in DNAm at TXNIP was significantly associated with decrease in fasting plasma glucose (FPG) independent of covariates (p < 0.001). The study found that the strength of this relationship was significantly modified by a trend of increasing BMI during childhood and adolescence (p-interaction = 0.003). Each 1% increase in DNAm at TXNIP was associated with a 2.90- (0.77) mg/dL decrease in FPG among participants with the highest tertile of BMI incremental area under the curve and a 0.96- (0.38) mg/dL decrease among those with the middle tertile, whereas no association was observed among participants with the lowest tertile. CONCLUSIONS: These results indicate that changes in blood DNAm at TXNIP are significantly associated with changes in FPG in midlife, and this association was modified by BMI trends during childhood and adolescence.

Subtypes of Type 2 Diabetes and Incident Cardiovascular Disease Risk: UK Biobank and All of Us Cohorts.

OBJECTIVE: To characterize and validate the subtypes of type 2 diabetes (T2D) using a novel clustering algorithm and to further assess their associations with the risk of incident cardiovascular disease (CVD) events. METHODS: Unsupervised k-means clustering based on glycated hemoglobin level, age at onset of T2D, body mass index, and estimated glomerular filtration rate was conducted among participants with T2D from the UK Biobank (March 13, 2006, to October 1, 2010) and replicated in the All of Us cohort (May 30, 2017, to April 1, 2021). RESULTS: Five distinct T2D clusters were identified in the UK Biobank and validated in the All of Us cohort, characterizing the phenotypically heterogeneous subtypes. With a median follow-up of 11.69 years for patients with T2D in the UK Biobank, risks of incident CVD events varied considerably between the clusters after adjustment for potential confounders and multiple testing (all P<.001). With cluster 1 characterized by early onset of T2D and mild abnormalities of other variables as the reference, patients in cluster 5 characterized by poor renal function had the highest risk of CVD events (hazard ratio [95% CI], 1.72 [1.45 to 2.03], 2.41 [1.93 to 3.02], and 1.62 [1.35 to 1.94] for composite CVD event, CVD mortality, and CVD incidence, respectively; all P<.001), followed by cluster 4 characterized by poor glycemic control and cluster 3 characterized by severe obesity. No consistently significant difference was found between cluster 2 characterized by late onset of T2D and cluster 1. CONCLUSION: Our study, using a novel clustering algorithm to identify robust subtypes of T2D, found heterogeneous associations with incident CVD risk among patients with diabetes.