Nuclear Magnetic Resonance-Based Metabolomics and Risk of CKD.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) leads to lipid and metabolic abnormalities, but a comprehensive investigation of lipids, lipoprotein particles, and circulating metabolites associated with the risk of CKD has been lacking. We examined the associations of nuclear magnetic resonance (NMR)-based metabolomics data with CKD risk in the UK Biobank study. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: A total of 91,532 participants in the UK Biobank Study without CKD and not receiving lipid-lowering therapy. EXPOSURE: Levels of metabolites including lipid concentration and composition within 14 lipoprotein subclasses, as well as other metabolic biomarkers were quantified via NMR spectroscopy. OUTCOME: Incident CKD identified using ICD codes in any primary care data, hospital admission records, or death register records. ANALYTICAL APPROACH: Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals. RESULTS: We identified 2,269 CKD cases over a median follow-up period of 13.1 years via linkage with the electronic health records. After adjusting for covariates and correcting for multiple testing, 90 of 142 biomarkers were significantly associated with incident CKD. In general, higher concentrations of very-low-density lipoprotein (VLDL) particles were associated with a higher risk of CKD whereas higher concentrations of high-density lipoprotein (HDL) particles were associated with a lower risk of CKD. Higher concentrations of cholesterol, phospholipids, and total lipids within VLDL were associated with a higher risk of CKD, whereas within HDL they were associated with a lower risk of CKD. Further, higher triglyceride levels within all lipoprotein subclasses, including all HDL particles, were associated with greater risk of CKD. We also identified that several amino acids, fatty acids, and inflammatory biomarkers were associated with risk of CKD. LIMITATIONS: Potential underreporting of CKD cases because of case identification via electronic health records. CONCLUSIONS: Our findings highlight multiple known and novel pathways linking circulating metabolites to the risk of CKD. PLAIN-LANGUAGE SUMMARY: The relationship between individual lipoprotein particle subclasses and lipid-related traits and risk of chronic kidney disease (CKD) in general population is unclear. Using data from 91,532 participants in the UK Biobank, we evaluated the associations of metabolites measured using nuclear magnetic resonance testing with the risk of CKD. We identified that 90 out of 142 lipid biomarkers were significantly associated with incident CKD. We found that very-low-density lipoproteins, high-density lipoproteins, the lipid concentration and composition within these lipoproteins, triglycerides within all the lipoprotein subclasses, fatty acids, amino acids, and inflammation biomarkers were associated with CKD risk. These findings advance our knowledge about mechanistic pathways that may contribute to the development of CKD.

Associations of lipoprotein subclasses with risk of all-cause and cardiovascular disease mortality in individuals with type 2 diabetes: A prospective cohort study.

AIM: Although lipoproteins are well-established risk factors for cardiovascular disease (CVD) mortality, conventional measurements failed to identify lipoprotein particle sizes. This study aimed to investigate associations of lipoprotein subclasses categorized by particle sizes with risk of all-cause and CVD mortality in individuals with type 2 diabetes. METHODS: This study included 6575 individuals with type 2 diabetes from the UK Biobank. Concentrations of very low-, low-, intermediate- and high-density lipoprotein [very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), intermediate-density lipoprotein and high-density lipoprotein (HDL)] particles in 14 subclasses and lipid constituents within each subclass were measured by quantitative nuclear magnetic resonance. Multivariable-adjusted Cox proportional-hazard regression models were used to estimate the hazard ratio (HR) for per standard deviation increment of log-transformed lipoprotein subclasses with risk of mortality. All p-values were adjusted by the false discovery rate method. RESULTS: During a median follow-up of 11.4 years, 943 deaths were documented, including 310 CVD deaths. Small HDL particles were inversely associated with CVD mortality, with HR (95% CI) of 0.78 (0.69, 0.87), whereas very large and large HDL particles were positively associated with CVD mortality with HR (95% CI) of 1.28 (1.12, 1.45) and 1.19 (1.05, 1.35), respectively. A similar pattern was observed for all-cause mortality [small HDL particle (HR, 95% CI): 0.79, 0.74-0.85; large HDL particle: 1.15, 1.07-1.24; very large HDL particle: 1.26, 1.17-1.36]. For VLDL and LDL, very small VLDL particle was positively, while medium LDL particle was inversely associated with all-cause mortality, but not associated with CVD mortality. The pattern of association with all-cause and CVD mortality for cholesterol and triglyceride within lipoprotein particles was similar to those for lipoprotein particles themselves. CONCLUSIONS: The associations between lipoprotein particles, particularly HDL particles, with all-cause and CVD mortality among patients with type 2 diabetes were significantly varied by particle sizes, highlighting the importance of particle size as a lipoprotein metric in mortality risk discrimination.

Associations of combined healthy lifestyles with cancer morbidity and mortality among individuals with diabetes: results from five cohort studies in the USA, the UK and China.

AIMS/HYPOTHESIS: Cancer has contributed to an increasing proportion of diabetes-related deaths, while lifestyle management is the cornerstone of both diabetes care and cancer prevention. We aimed to evaluate the associations of combined healthy lifestyles with total and site-specific cancer risks among individuals with diabetes. METHODS: We included 92,239 individuals with diabetes but without cancer at baseline from five population-based cohorts in the USA (National Health and Nutrition Examination Survey and National Institutes of Health [NIH]-AARP Diet and Health Study), the UK (UK Biobank study) and China (Dongfeng-Tongji cohort and Kailuan study). Healthy lifestyle scores (range 0-5) were constructed based on current nonsmoking, low-to-moderate alcohol drinking, adequate physical activity, healthy diet and optimal bodyweight. Cox regressions were used to calculate HRs for cancer morbidity and mortality, adjusting for sociodemographic, medical and diabetes-related factors. RESULTS: During 376,354 person-years of follow-up from UK Biobank and the two Chinese cohorts, 3229 incident cancer cases were documented, and 6682 cancer deaths were documented during 1,089,987 person-years of follow-up in the five cohorts. The pooled multivariable-adjusted HRs (95% CIs) comparing participants with 4-5 vs 0-1 healthy lifestyle factors were 0.73 (0.61, 0.88) for incident cancer and 0.55 (0.46, 0.67) for cancer mortality, and ranged between 0.41 and 0.63 for oesophagus, lung, liver, colorectum, breast and kidney cancers. Findings remained consistent across different cohorts and subgroups. CONCLUSIONS/INTERPRETATION: This international cohort study found that adherence to combined healthy lifestyles was associated with lower risks of total cancer morbidity and mortality as well as several subtypes (oesophagus, lung, liver, colorectum, breast and kidney cancers) among individuals with diabetes.

Overall lifestyles and socioeconomic inequity in mortality and life expectancy in China: the China health and nutrition survey.

BACKGROUND: socioeconomic inequity in mortality and life expectancy remains inconclusive in low- and middle-income countries, and to what extent the associations are mediated or modified by lifestyles remains debatable. METHODS: we included 21,133 adults from China Health and Nutrition Survey (1991-2011) and constructed three parameters to reflect participants' overall individual- (synthesising income, education and occupation) and area-level (urbanisation index) socioeconomic status (SES) and lifestyles (counting the number of smoking, physical inactivity and unhealthy diet and bodyweight). HRs for mortality and life expectancy were estimated by time-dependent Cox model and life table method, respectively. RESULTS: during a median follow-up of 15.2 years, 1,352 deaths were recorded. HRs (95% CIs) for mortality comparing low versus high individual- and area-level SES were 2.38 (1.75-3.24) and 1.84 (1.51-2.24), respectively, corresponding to 5.7 (2.7-8.6) and 5.0 (3.6-6.3) life-year lost at age 50. Lifestyles explained ≤11.5% of socioeconomic disparity in mortality. Higher lifestyle risk scores were associated with higher mortality across all socioeconomic groups. HR (95% CI) for mortality comparing adults with low individual-level SES and 3-4 lifestyle risk factors versus those with high SES and 0-1 lifestyle risk factors was 7.06 (3.47-14.36), corresponding to 19.1 (2.6-35.7) life-year lost at age 50. CONCLUSION: this is the first nationwide cohort study reporting that disadvantaged SES was associated with higher mortality and shorter life expectancy in China, which was slightly mediated by lifestyles. Risk lifestyles were related to higher mortality across all socioeconomic groups, and those with risk lifestyles and disadvantaged SES had much higher mortality risks.

Quality diet indexes and risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study.

There is limited research on the effect of dietary quality on hepatocellular carcinoma (HCC) risk in populations with relatively high risk of HCC. Using data from Singapore Chinese Health Study, a prospective cohort study, of 63 257 Chinese aged 45 to 74, we assessed four diet-quality index (DQI) scores: the Alternative Health Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH) and Heathy Diet Indicator (HDI). We identified 561 incident HCC cases among the cohort participants after a mean of 17.6 years of follow-up. Cox proportional hazard regression model was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for HCC in relation to these DQI scores. Unconditional logistic regression method was used to evaluate the associations between DQIs and HCC risk among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg). High scores of AHEI-2010, aMED and DASH, representing higher dietary quality, were associated with lower risk of HCC (all Ptrend < .05). Compared with the lowest quartile, HRs (95% CIs) of HCC for the highest quartile of AHEI-2010, aMED and DASH were 0.69 (0.53-0.89), 0.70 (0.52-0.95) and 0.67 (0.51-0.87), respectively. No significant association between HDI and HCC risk was observed. Among HBsAg-negative individuals, similar inverse associations were observed, and the strongest inverse association was for aMED (HRQ4vsQ1 = 0.46, 95% CI: 0.23-0.94, Ptrend = .10). These findings support the notion that adherence to a healthier diet may lower the risk of HCC, suggesting that dietary modification may be an effective approach for primary prevention of HCC.

Long-term incense use and the risk of end-stage renal disease among Chinese in Singapore: the Singapore Chinese health study.

BACKGROUND: Experimental studies have shown that exposure to incense burning may have deleterious effects on kidney function and architecture. However, the association between chronic exposure to incense smoke and risk of end-stage renal disease (ESRD) has not been reported in epidemiologic studies. METHODS: We investigated this association in the Singapore Chinese Health Study, a prospective population-based cohort of 63,257 Chinese men and women of 45-74 years of age in Singapore during recruitment from 1993 to 1998. Information on the practice of incense burning at home, diet, lifestyle and medical history was collected at baseline interviews. ESRD cases were identified through linkage with the nationwide Singapore Renal Registry through 2015. We used Cox proportional hazards regression analysis to estimate hazard ratio (HR) and 95% confidence interval (CI) of ESRD associated with domestic incense burning. RESULTS: Among cohort participants, 76.9% were current incense users. After an average 17.5 years of follow-up, there were 1217 incident ESRD cases. Compared to never users, the multivariable-adjusted HR for ESRD risk was 1.05 (95% CI, 0.80 to 1.38) for former users and 1.26 (95% CI, 1.02 to1.57) for current users of incense. In analysis by daily or non-daily use and duration, the increased ESRD risk was observed in daily users who had used incense for > 20 years; HR was 1.25 (95% CI, 1.07 to 1.46). Conversely, the risk was not increased in those who did not use incense daily or who had used daily but for ≤20 years. CONCLUSIONS: Our findings demonstrate that long-term daily exposure to domestic incense burning could be associated with a higher risk of ESRD in the general population.

Maternal central obesity and birth size: a Mendelian randomization analysis.

BACKGROUND: Observational studies have illustrated that maternal central obesity is associated with birth size, including of birth weight, birth length and head circumference, but the causal nature of these associations remains unclear. Our study aimed to test the causal effect of maternal central obesity on birth size and puberty height growth using a Mendelian randomization (MR) analysis. METHODS: We performed two-sample MR using summary-level genome-wide public data. Thirty-five single nucleotide polymorphisms (SNPs), 25 SNPs and 41 SNPs were selected as instrumental variables for waist-to-hip ratio adjusted for BMI, waist circumference adjusted for BMI and hip circumference adjusted for BMI, respectively to test the causal effects of maternal central obesity on birth size and puberty height using an inverse-variance-weighted approach. RESULTS: In this MR analysis, we found no evidence of a causal association between waist circumference or waist-to-hip ratio and the outcomes. However, we observed that one standard deviation (SD) increase in hip circumference (HIP) was associated with a 0.392 SD increase in birth length (p = 1.1 × 10- 6) and a 0.168 SD increase in birth weight (p = 7.1 × 10- 5), respectively at the Bonferroni-adjusted level of significance. In addition, higher genetically predicted maternal HIP was strongly associated with the puberty heights (0.835 SD, p = 8.4 × 10- 10). However, HIP was not associated with head circumference (p = 0.172). CONCLUSIONS: A genetic predisposition to higher maternal HIP was causally associated with larger offspring birth size independent of maternal BMI. However, we found no evidence of a causal association between maternal waist circumference, waist-to-hip ratio and birth size.

Serum 25-hydroxyvitamin D concentrations, vitamin D receptor polymorphisms, and risk of infections among individuals with type 2 diabetes: a prospective cohort study.

BACKGROUND: Evidence on the association between serum 25-hydroxyvitamin D [25(OH)D] and infections among patients with type 2 diabetes (T2D), a group susceptible to vitamin D deficiency and infections, is limited. OBJECTIVES: We aimed to examine this association in individuals with T2D, and to evaluate whether genetic variants in vitamin D receptor (VDR) would modify this association. METHODS: This study included 19,851 participants with T2D from UK Biobank. Infections were identified by linkage to hospital inpatient and death registers. Negative binomial regression models were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs), with adjustment of potential confounders. RESULTS: In patients with T2D, the incidence rate of infections was 29.3/1000 person-years. Compared to those with 25(OH)D of 50.0-74.9 nmol/L, the multivariable-adjusted IRRs and 95% CIs of total infections, pneumonia, gastrointestinal infections and sepsis were 1.44 (1.31, 1.59), 1.49 (1.27, 1.75), 1.47 (1.22, 1.78), and 1.41 (1.14, 1.73), respectively, in patients with 25(OH)D <25.0 nmol/L. Nonlinear inverse associations between 25(OH)D concentrations and the risks of total infections (P-overall <0.001; P-nonlinear = 0.002) and gastrointestinal infections (P-overall <0.001; P-nonlinear = 0.040) were observed, with a threshold effect at ∼50.0 nmol/L. The vitamin D-infection association was not modified by genetic variants in VDR (all P-interaction >0.050). CONCLUSIONS: In patients with T2D, lower serum 25(OH)D concentration (<50 nmol/L) was associated with higher risks of infections, regardless of genetic variants in VDR. Notably, nonlinear inverse associations between 25(OH)D concentrations and the risks of infections were found, with a threshold effect at ∼50.0 nmol/L. These findings highlighted the importance of maintaining adequate vitamin D in reducing the risk of infections in patients with T2D.

RTEL1 and TERT polymorphisms are associated with astrocytoma risk in the Chinese Han population.

Common variants of multiple genes play a role in glioma onset. However, research related to astrocytoma, the most common primary brain neoplasm, is rare. In this study, we chose 21 tagging SNPs (tSNPs), previously reported to be associated with glioma risk in a Chinese case-control study from Xi'an, China, and identified their contributions to astrocytoma susceptibility. We found an association with astrocytoma susceptibility for two tSNPs (rs6010620 and rs2853676) in two different genes: regulator of telomere elongation helicase 1 (RTEL1) and telomerase reverse transcriptase (TERT), respectively. We confirmed our results using recessive, dominant, and additive models. In the recessive model, we found two tSNPs (rs2297440 and rs6010620) associated with increased astrocytoma risk. In the dominant model, we found that rs2853676 was associated with increased astrocytoma risk. In the additive model, all three tSNPs (rs2297440, rs2853676, and rs6010620) were associated with increased astrocytoma risk. Our results demonstrate, for the first time, the potential roles of RTEL1 and TERT in astrocytoma development.

Adherence to a Planetary Health Diet, Environmental Impacts, and Mortality in Chinese Adults.

Importance: Although the EAT-Lancet Commission has recently proposed a planetary health diet (PHD) to promote human and environmental health, little is known about how PHD affects environment and mortality risk among an Asian population. Objective: To investigate whether a PHD score is associated with environmental impacts and mortality outcomes in a Chinese cohort living in Singapore. Design, Setting, and Participants: This cohort study used data from the Singapore Chinese Health Study. Eligible participants were without known cardiovascular disease and cancer at baseline; they were recruited between 1993 and 1998 and followed up using record linkage data until 2020. Data were analyzed from September 2022 to April 2023. Exposures: PHD score was calculated based on the reference consumption of 14 dietary components in PHD and individual energy intake assessed using a validated food frequency questionnaire in this cohort. Main Outcomes and Measures: Diet-related environmental impacts were estimated using a food frequency questionnaire. Mortality outcomes (all-cause, cardiovascular disease, cancer, and respiratory disease) were identified via linkage with a nationwide registry. Results: A total of 57 078 participants were included in this study (mean [SD] age, 56.1 (7.9) years; 31 958 women [56.0%]). During a median (IQR) follow-up of 23.4 (18.7-26.2) years, 22 599 deaths occurred. Comparing the highest and lowest quintiles, higher PHD scores were associated with lower greenhouse gas emissions (ß = -0.13 kg CO2 equivalent; 95% CI, -0.14 to -0.12 kg CO2 equivalent), but with higher total water footprint (ß = 0.12 m3; 95% CI, 0.11-0.13 m3) and land use (ß = 0.29 m2; 95% CI, 0.28-0.31 m2). In the adjusted multivariable model, compared with the lowest quintile, participants in the highest quintile of PHD score had lower risk of all-cause mortality (hazard ratio [HR], 0.85; 95% CI, 0.81-0.89), cardiovascular disease mortality (HR, 0.79; 95% CI, 0.73-0.85), cancer mortality (HR, 0.93; 95% CI, 0.86-1.00), and respiratory disease mortality (HR, 0.81; 95% CI, 0.74-0.89). Conclusions and Relevance: In this study of Singapore Chinese adults, higher adherence to PHD was associated with reduced risk of chronic disease mortality. However, environmental impacts were uncertain, as higher adherence was associated with lower greenhouse gas emissions but higher total water footprint and land use.

Trends in Self-Reported Adherence to Healthy Lifestyle Behaviors Among US Adults, 1999 to March 2020.

Importance: Adherence to a healthy lifestyle is associated with lower risks of adverse outcomes. However, trends in multiple lifestyle factors and overall healthy lifestyle status among US adults in recent years are unknown. Objective: To examine trends in multiple lifestyle factors and overall healthy lifestyle among US adults. Design, Setting, and Participants: This serial cross-sectional study used nationally representative data from 10 National Health and Nutrition Examination Survey (NHANES) cycles (nine 2-year cycles from 1999 to 2016 and 1 combined cycle from 2017 to March 2020) among adults 20 years or older. Data were analyzed from December 10, 2021, to January 11, 2023. Exposure: Survey cycle. Main Outcomes and Measures: Five healthy lifestyle factors: never smoking, moderate or lighter alcohol consumption (for women: ≤7 drinks/wk; for men: ≤14 drinks/wk), healthy diet (Healthy Eating Index-2015 scores ≥60.0), sufficient physical activity (≥150 min/wk of equivalent moderate physical activity), and healthy weight (body mass index [calculated as weight in kilograms divided by height in meters squared] 18.5-24.9). Results: A total of 47 852 adults were included in this study. The weighted mean [SE] age was 47.3 [0.2] years; 24 539 (weighted proportion, 51.5%) were women. From the 1999-2000 cycle to the 2017 to March 2020 cycle, the estimated prevalence of the 5 lifestyle factors showed divergent trends, with increasing prevalence of never smoking (from 49.4% [95% CI, 46.4%-52.4%] to 57.7% [95% CI, 55.5%-59.9%]; difference, 8.2% [95% CI, 4.5%-12.0%]), healthy diet (from 19.3% [95% CI, 16.0%-22.6%] to 24.5% [95% CI, 21.5%-27.5%]; difference, 5.2% [95% CI, 0.8%-9.7%]), and sufficient physical activity (from 55.7% [95% CI, 51.8%-59.6%] to 69.1% [95% CI, 67.2%-71.1%]; difference, 13.4% [95% CI, 9.0%-17.8%]), while prevalence of healthy weight decreased from 33.1% (95% CI, 30.5%-35.6%) to 24.6% (95% CI, 22.6%-26.7%; difference, -8.4% [95% CI, -11.8% to -5.1%]) (all P < .001 for trend). Meanwhile, there was no significant trend in moderate or lighter alcohol consumption. Overall, the estimated prevalence of at least 4 healthy lifestyle factors increased from 15.7% (95% CI, 12.8%-18.7%) to 20.3% (95% CI, 17.8%-22.7%; difference, 4.5% [95% CI, 0.7%-8.4%]; P < .001 for trend). Disparities in healthy lifestyle were widened by age group, with little improvement among adults 65 years and older (difference, 0.04% [95% CI, -4.28% to 4.35%]). There were persistent disparities in healthy lifestyle by race and ethnicity, educational level, and income level. Conclusions and Relevance: The findings of this cross-sectional study of NHANES data over a 22-year period suggest diverse change patterns across 5 healthy lifestyle factors and a modest improvement in overall lifestyle existed among US adults, with worsening or persistent disparities in lifestyle.

Trends in the Prevalence of Metabolically Healthy Obesity Among US Adults, 1999-2018.

Importance: Improved understanding of trends in the proportion of individuals with metabolically healthy obesity (MHO) may facilitate stratification and management of obesity and inform policy efforts. Objectives: To characterize trends in the prevalence of MHO among US adults with obesity, overall and by sociodemographic subgroups. Design, Setting, and Participants: This survey study included 20 430 adult participants from 10 National Health and Nutrition Examination Survey (NHANES) cycles between 1999-2000 and 2017-2018. The NHANES is a series of cross-sectional and nationally representative surveys of the US population conducted continuously in 2-year cycles. Data were analyzed from November 2021 to August 2022. Exposures: National Health and Nutrition Examination Survey cycles from 1999-2000 to 2017-2018. Main Outcomes and Measures: Metabolically healthy obesity was defined as a body mass index of 30.0 (calculated as weight in kilograms divided by height in meters squared) without any metabolic disorders in blood pressure, fasting plasma glucose (FPG), high-density lipoprotein cholesterol (HDL-C), or triglycerides based on established cutoffs. Trends in the age-standardized prevalence of MHO were estimated using logistic regression analysis. Results: This study included 20 430 participants. Their weighted mean (SE) age was 47.1 (0.2) years; 50.8% were women, and 68.8% self-reported their race and ethnicity as non-Hispanic White. The age-standardized prevalence (95% CI) of MHO increased from 3.2% (2.6%-3.8%) in the 1999-2002 cycles to 6.6% (5.3%-7.9%) in the 2015-2018 cycles (P < .001 for trend). There were 7386 adults with obesity. Their weighted mean (SE) age was 48.0 (0.3) years, and 53.5% were women. The age-standardized proportion (95% CI) of MHO among these 7386 adults increased from 10.6% (8.8%-12.5%) in the 1999-2002 cycles to 15.0% (12.4%-17.6%) in the 2015-2018 cycles (P = .02 for trend). Substantial increases in the proportion of MHO were observed for adults aged 60 years or older, men, non-Hispanic White individuals, and those with higher income, private insurance, or class I obesity. In addition, there were significant decreases in the age-standardized prevalence (95% CI) of elevated triglycerides (from 44.9% [40.9%-48.9%] to 29.0% [25.7%-32.4%]; P < .001 for trend) and reduced HDL-C (from 51.1% [47.6%-54.6%] to 39.6% [36.3%-43.0%]; P = .006 for trend). There was also a significant increase in elevated FPG (from 49.7% [95% CI, 46.3%-53.0%] to 58.0% [54.8%-61.3%]; P < .001 for trend) but no significant change in elevated blood pressure (from 57.3% [53.9%-60.7%] to 54.0% [50.9%-57.1%]; P = .28 for trend). Conclusions and Relevance: The findings of this cross-sectional study suggest that the age-standardized proportion of MHO increased among US adults from 1999 to 2018, but differences in trends existed across sociodemographic subgroups. Effective strategies are needed to improve metabolic health status and prevent obesity-related complications in adults with obesity.

Association of Combined Healthy Lifestyles With Cardiovascular Disease and Mortality of Patients With Diabetes: An International Multicohort Study.

OBJECTIVE: To prospectively examine the associations of combined lifestyle factors with incident cardiovascular disease (CVD) and mortality in patients with diabetes. PATIENTS AND METHODS: Patients with prevalent diabetes were included from 5 prospective, population-based cohorts in China (Dongfeng-Tongji cohort and Kailuan study), the United Kingdom (UK Biobank study), and the United States (National Health and Nutrition Examination Survey and National Institutes of Health-AARP Diet and Health Study). Healthy lifestyle scores were constructed according to non-current smoking, low to moderate alcohol drinking, regular physical activity, healthy diet, and optimal body weight; the healthy level of each lifestyle factor was assigned 1 point, or 0 for otherwise, and the range of the score was 0 to 5. Cox proportional hazards models were used to estimate hazard ratios for incident CVD, CVD mortality, and all-cause mortality adjusting for sociodemographic, medical, and diabetes-related factors, and outcomes were obtained by linkage to medical records and death registries. Data were collected from October 18, 1988, to September 30, 2020. RESULTS: A total of 6945 incident CVD cases were documented in 41,350 participants without CVD at baseline from the 2 Chinese cohorts and the UK Biobank during 389,330 person-years of follow-up, and 40,353 deaths were documented in 101,219 participants from all 5 cohorts during 1,238,391 person-years of follow-up. Adjusted hazard ratios (95% CIs) comparing patients with 4 or 5 vs 0 or 1 healthy lifestyle factors were 0.67 (0.60 to 0.74) for incident CVD, 0.58 (0.50 to 0.68) for CVD mortality, and 0.60 (0.53 to 0.68) for all-cause mortality. Findings remained consistent across different cohorts, subgroups, and sensitivity analyses. CONCLUSION: The international analyses document that adherence to multicomponent healthy lifestyles is associated with lower risk of CVD and premature death of patients with diabetes.

Association between serum 25-hydroxy vitamin D concentrations and mortality among individuals with metabolic dysfunction-associated fatty liver disease: a prospective cohort study.

BACKGROUND: The association between serum 25-hydroxyvitamin D [25(OH)D] concentrations and mortality among patients with metabolic dysfunction-associated fatty liver disease (MAFLD) or nonalcoholic fatty liver disease (NAFLD) remains unclear. OBJECTIVE: The aim was to evaluate the association between serum 25(OH)D concentrations and mortality among individuals with MAFLD/NAFLD. METHODS: The study included 4651 individuals with fatty liver disease (FLD; 3964 had MAFLD and 3968 had NAFLD) from NHANES III. Fatty liver disease was identified by ultrasonographic detection of hepatic steatosis. Mortality was ascertained by linkage to the National Death Index up to 31 December 2019. Cox proportional hazards models were used to estimate the HRs and 95% CIs, with adjustment of potential confounders. RESULTS: Of 4651 individuals with FLD, 3427 individuals (69.7%) had both MAFLD and NAFLD. During median follow-ups of 25.8 and 26.1 y, we identified 1809 and 1665 deaths among 3964 participants with MAFLD and 3968 participants with NAFLD, respectively. Compared with participants with serum 25(OH)D concentrations ≤30.0 nmol/L, the multivariable-adjusted HRs and 95% CIs of all-cause mortality were 0.62 (0.43, 0.89) for participants with MAFLD having serum 25(OH)D >75.0 nmol/L (P-trend = 0.001) and 0.63 (0.42, 0.95) for participants with NAFLD having serum 25(OH)D >75.0 nmol/L (P-trend = 0.002). A nonlinear inverse association was observed between serum 25(OH)D concentrations and all-cause mortality among participants with MAFLD (Poverall < 0.001; Pnonlinear = 0.003) or NAFLD (Poverall < 0.001; Pnonlinear = 0.009), with a threshold effect at ∼50.0 nmol/L. The inverse association was stronger among participants with MAFLD aged <60 y (P-interaction = 0.001). CONCLUSIONS: This study suggested a nonlinear inverse association between serum 25(OH)D concentrations and all-cause mortality among patients with MAFLD/NAFLD, with a threshold effect at ∼50.0 nmol/L of serum 25(OH)D.

Differential roles of RIG-I like receptors in SARS-CoV-2 infection.

Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) sense viral RNA and activate antiviral immune responses. Herein we investigate their functions in human epithelial cells, the primary and initial target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A deficiency in MDA5, RIG-I or mitochondrial antiviral signaling protein (MAVS) enhanced viral replication. The expression of the type I/III interferon (IFN) during infection was impaired in MDA5-/- and MAVS-/-, but not in RIG-I-/-, when compared to wild type (WT) cells. The mRNA level of full-length angiotensin-converting enzyme 2 (ACE2), the cellular entry receptor for SARS-CoV-2, was ~ 2.5-fold higher in RIG-I-/- than WT cells. These data demonstrate MDA5 as the predominant SARS-CoV-2 sensor, IFN-independent induction of ACE2 and anti-SARS-CoV-2 role of RIG-I in epithelial cells.

Healthful dietary patterns and risk of end-stage kidney disease: the Singapore Chinese Health Study.

BACKGROUND: Although adherence to healthful dietary patterns has been associated with a lower risk of kidney function decline in Western populations, evidence in Asian populations remains scanty. OBJECTIVES: We examined predefined dietary patterns, namely, the Alternate Healthy Eating Index-2010 (AHEI-2010), the Dietary Approaches to Stop Hypertension (DASH), and the alternate Mediterranean diet (aMED), in relation to risk of end-stage kidney disease (ESKD). METHODS: We included 56,985 Chinese adults (aged 45-74 y) in the Singapore Chinese Health Study who were free of cancer, stroke, coronary artery disease, and ESKD at recruitment (1993-1998). Dietary pattern scores were calculated based on a validated 165-item FFQ. AHEI-2010 and aMED scores were modified by excluding the alcohol intake component because daily drinking has been associated with a higher risk of ESKD in our study population. We identified 1026 ESKD cases over a median follow-up of 17.5 y via linkage with the nationwide Singapore Renal Registry. Multivariable Cox regression models were used to compute HRs and their 95% CIs. RESULTS: Higher scores of all 3 dietary patterns were associated with lower ESKD risk in a dose-dependent manner. Compared with the lowest quintiles, the multivariable-adjusted HRs (95% CIs) of ESKD were 0.75 (0.61, 0.92) for the highest quintile of AHEI-2010, 0.67 (0.54, 0.84) for DASH, and 0.73 (0.59, 0.91) for aMED (all P-trend ≤ 0.004). These inverse associations were stronger with increasing BMI (in kg/m2), and the HRs for the diet-ESKD association were lowest in the obese (BMI ≥ 27.5), followed by the overweight (BMI = 25 to <27.5) participants, compared with those in lower BMI categories; the P-interaction values between BMI and diet scores were 0.03 for AHEI-2010, 0.004 for aMED, and 0.06 for DASH. CONCLUSIONS: Adherence to healthful dietary patterns was associated with a lower ESKD risk in an Asian population, especially in overweight or obese individuals.

The impact of diabetes on the association between alcohol intake and the risk of end-stage kidney disease in the Singapore Chinese Health Study.

BACKGROUND: The relationship between alcohol intake and end-stage kidney disease (ESKD) risk is controversial. Moreover, while evidence has shown that the relationship between alcohol and atherosclerosis may be modified by diabetes, whether this applies to ESKD is unknown. METHODS: We examined these associations in the Singapore Chinese Health Study, a prospective cohort of 63 257 adults aged 45 to 74 years. Information on alcohol intake, diet, lifestyle factors, and medical history was collected at recruitment. We identified 1217 ESKD cases via linkage with the Singapore Renal Registry after a mean follow-up of 17.5 years. Cox regression models were used to estimate hazard ratios (HRs) and 95% CI of ESKD. RESULTS: Among the participants without diabetes at baseline, monthly to weekly drinking was associated with a decreased risk of ESKD (HR 0.69; 95% CI, 0.54-0.87) compared to nondrinkers. In contrast, this association was attenuated and not significant among those with diabetes (HR 0.82; 95% CI, 0.58-1.16; Pinteraction = .19). Comparatively, alcohol intake of ≥2 drinks per day was significantly associated with an increased risk of ESKD compared to nondrinkers among those with diabetes (HR 2.00; 95% CI, 1.14-3.53) but not among those without diabetes (HR 0.91; 95% CI, 0.53-1.56; Pinteraction = .01). The risk of ESKD among those with diabetes and who also consumed ≥2 drinks per day was increased by nearly 12-fold compared to nondrinkers without diabetes (HR 11.6; 95% CI, 6.73-19.9). CONCLUSION: Low-dose drinking is associated with a reduced risk of ESKD among individuals without diabetes. However, joint exposure to heavy drinking and diabetes is associated with a substantially higher risk of ESKD.

Pulse Pressure and the Risk of End-Stage Renal Disease Among Chinese Adults in Singapore: The Singapore Chinese Health Study.

Background Although hypertension is an established risk factor for chronic kidney disease, less is known about the relationship of pulse pressure (PP), a measure of arterial stiffness, with chronic kidney disease. We investigated the association of systolic blood pressure (BP), diastolic BP, PP, and mean arterial pressure with the risk of end-stage renal disease (ESRD) in the prospective population-based Singapore Chinese Health Study. Methods and Results We used data from 30 636 participants who had BP measured at ages 46 to 85 years during follow-up I interviews between 1999 and 2004. Information on lifestyle factors was collected at recruitment from 1993 to 1998, and selected factors were updated at follow-up I. We identified 463 ESRD cases over an average 11.3 years of follow-up I by linkage with the nationwide Singapore Renal Registry. Cox proportional hazards regression models were used to assess the relations between different BP indexes and ESRD risk. Each BP index was positively associated with ESRD when studied individually. However, when PP was included as a covariate, systolic and diastolic BP and mean arterial pressure were no longer associated with ESRD. Conversely, PP remained significantly associated with ESRD risk in a dose-dependent manner (Ptrend<0.001) after adjusting for systolic or diastolic BP. Compared with the lowest group (<45 mm Hg) of PP, the hazard ratio was 5.25 (95% CI, 3.52-7.84) for the highest group (≥85 mm Hg). The association between hypertension and ESRD risk was attenuated and no longer significant after adjusting for PP. Conclusions Our findings provide a basis for targeting reduction of arterial stiffness to decrease ESRD risk.

Sleep duration and risk of end-stage renal disease: the Singapore Chinese Health Study.

OBJECTIVES: Although epidemiological evidence suggests that short sleep duration may affect renal function, the influence of long sleep and risk of end-stage renal disease (ESRD) is unclear. We examined the association between sleep duration and risk of ESRD. METHODS: We investigated sleep duration and ESRD risk in the Singapore Chinese Health Study, a prospective population-based cohort of 63,257 Chinese in Singapore, who were aged 45-74 years at recruitment (1993-1998). Information on daily sleep duration (including naps), diet, medical history and other lifestyle factors was collected at recruitment from in-person interviews. ESRD cases were identified via linkage with the nationwide Singapore Renal Registry through year 2014. We used the Cox proportional hazards regression method to estimate hazard ratio (HR) and 95% confidence interval (CI) of ESRD in relation to sleep duration. RESULTS: After an average 16.8 years of follow-up, 1143 (1.81%) ESRD cases were documented. Sleep duration had a U-shaped association with risk of ESRD (P for quadratic trend < 0.001). Compared with participants with 7 h/day of sleep, the multivariable adjusted HR (95% CI) of ESRD was 1.43 (1.18-1.74) for short sleep (≤5 h/day) and 1.28 (1.03-1.60) for long sleep duration (≥9 h/day). The increased risk was stronger in participants with more than 10 years of follow-up compared to those with shorter follow-up time, especially for long sleep (P for interaction = 0.003). CONCLUSIONS: Our findings demonstrated that both short and long sleep durations were associated with a higher risk of ESRD in this Asian population.