Changfeng Study Research Articles

A metabolome-derived score predicts metabolic dysfunction-associated steatohepatitis and mortality from liver disease

BackgroundMetabolic dysfunction-associated steatohepatitis (MASH) is associated with more than a 10-fold increase in liver-related mortality. However, biomarkers predicting both MASH and mortality are missing. We developed a metabolome-derived prediction score for MASH and examined whether it predicts mortality in Chinese and European cohorts. MethodsThe MASH prediction score was developed using a multi-step machine learning strategy, based on 44 clinical parameters and 250 plasma metabolites measured by proton nuclear magnetic resonance (1H-NMR) in 311 Chinese adults undergoing a liver biopsy. External validation was conducted in a Finnish liver biopsy cohort (n=305). We investigated association of the score with all-cause and cause-specific mortality in the population-based Shanghai Changfeng Study (n=5,893) and the UK Biobank (n=111,673). ResultsA total of 24 clinical parameters and 194 1H-NMR metabolites were significantly associated with MASH in the Chinese liver biopsy cohort. The final MASH score included body mass index, aspartate transaminase, tyrosine, and the phospholipids-to-total lipids ratio in very-low density lipoprotein. The score identified patients with MASH with AUROCs of 0.87 (95% CI, 0.83-0.91) and 0.81 (95% CI, 0.75-0.87) in the Chinese and Finnish cohorts, with high negative predictive values. Participants with a high or intermediate risk of MASH based on the score had a markedly higher risk of MASLD-related mortality than those with a low risk in Chinese (HR, 23.19; 95%CI, 4.80-111.97) and European individuals (HR, 27.80; 95%CI, 15.08-51.26) after 7.4 and 12.6 years of follow-up. The MASH prediction score was superior to the FIB-4 index and the NAFLD Fibrosis Score in predicting MASLD-related mortality. ConclusionThe metabolome-derived MASH prediction score accurately predicts risk of MASH and MASLD-related mortality in both Chinese and European individuals. Impact and implicationsMetabolic dysfunction-associated steatohepatitis (MASH) is associated with more than a 10-fold increase in liver-related death. However, biomarkers predicting not only MASH, but also death due to liver disease, are missing. We established a MASH prediction score based on 44 clinical parameters and 250 plasma metabolites using a machine learning strategy. This metabolome-derived MASH prediction score could accurately identify patients with MASH among both Chinese and Finnish individuals, and it was superior to the FIB-4 index and the NAFLD Fibrosis Score in predicting MASLD-related death in the general population. Thus, the new MASH prediction score is a useful tool for identifying individuals with a markedly increased risk of serious liver-related outcomes among at-risk and general populations.

Longitudinal association of peripheral blood DNA methylation with liver fat content: distinguishing between predictors and biomarkers

BackgroundAlterations in DNA methylation (DNAm) have been observed in patients with fatty liver, but whether they are cause or consequence remains unknown. The study aimed to investigate longitudinal association of epigenome-wide DNAm with liver fat content (LFC) in Chinese participants, and explore their temporal relationships.MethodsData were obtained from 2 waves over a four-year time period of the Shanghai Changfeng Study (discovery, n = 407 and replication, n = 126). LFC and peripheral blood DNAm were repeatedly measured using quantitative hepatic ultrasonography and the 850 K Illumina EPIC BeadChip, respectively. Longitudinal and cross-sectional epigenome-wide association studies (EWASs) were conducted with linear mixed model and linear regression model, respectively. Meta-analysis was performed using METAL. Cross-lagged panel analysis (CLPA) was carried out to infer temporal relationships between the significant CpGs and LFC.ResultsLongitudinal EWAS identified cg11024682 (SREBF1), cg06500161 (ABCG1), cg16740586 (ABCG1), cg15659943 (ABCA1) and cg00163198 (SNX19) significantly associated with LFC with P < 1e-7. Another 6 of the 22 previously reported CpGs were replicated in the present longitudinal EWAS. CLPA showed longitudinal effects of cg11024682 (SREBF1) (β = 0.14 [0.06, 0.23]), cg16740586 (ABCG1) (β = 0.17 [0.08, 0.25]), cg06500161 (ABCG1) (β = 0.12 [0.03, 0.20]), cg17901584 (DHCR24) (β = -0.10 [-0.18, -0.02]), cg00574958 (CPT1A) (β = -0.09 [-0.17, -0.01]), cg08309687 (LINC00649) (β = -0.11 [-0.19, -0.03]), and cg27243685 (ABCG1) (β = 0.09 [0.01, 0.18]) on subsequent LFC. The effects were attenuated when further adjusting for body mass index. High levels of LFC led to alterations in DNAm of cg15659943 (ABCA1) (β = 0.13 [0.04, 0.21]), cg07162647 (β = -0.11 [-0.19, -0.03]), cg06500161 (ABCG1) (β = 0.10 [0.02, 0.18]), and cg27243685 (ABCG1) (β = 0.10 [0.02, 0.18]).ConclusionsBlood DNAm at SREBF1, ABCG1, DHCR24, CPT1A, and LINC00649 may be predictors of subsequent LFC change. The effects of DNAm at SREBF1 and ABCG1 on LFC were partially influenced by obesity. The findings have potential implications in understanding disease pathogenesis and highlight the potential of DNAm for early detection or intervention of fatty liver.

DNA methylation age acceleration contributes to the development and prediction of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is prevalent in the aging society. Despite body weight reduction, the prevalence of NAFLD has been increasing with aging for unknown reasons. Here, we investigate the association of DNA methylation age acceleration, a hallmark of aging, with risk of NAFLD. Genome-wide DNA methylation profiles were measured in 95 participants who developed type 2 diabetes during 4-year follow-up, and 356 randomly sampled participants from Shanghai Changfeng Study. DNA methylation age was calculated using the Horvath’s method, and liver fat content (LFC) was measured using a quantitative ultrasound method. Subjects with highest tertile of DNA methylation age acceleration (≥ 9.5 years) had significantly higher LFC (7.2% vs 3.1%, P = 0.008) but lower body fat percentage (29.7% vs 33.0%, P = 0.032) than those with lowest tertile of DNA methylation age acceleration (< 4.0 years). After adjustment for age, sex, alcohol drinking, cigarette smoking, BMI, waist circumference, and different type blood cell counts, the risk of NAFLD was still significantly increased in the highest tertile group (OR, 4.55; 95% CI, 1.06–19.61). Even in subjects with similar LFC at baseline, DNA methylation age acceleration was associated with higher increase in LFC (4.0 ± 10.7% vs 0.9 ± 9.5%, P = 0.004) after a median of 4-year follow-up. Further analysis found that 6 CpGs of Horvath age predictors were associated with longitudinal changes in LFC after multivariate adjustment and located on genes that might lead to fat redistribution from peripheral adipose to liver. Combination of the key CpG methylation related to liver fat content with conventional risk factors improves the performance for NAFLD prediction.Graphical

Sex disparity of cerebral white matter hyperintensity in the hypertensive elderly: The Shanghai Changfeng study.

White matter hyperintensity (WMH) is associated with vascular hemodynamic alterations and reflects white matter injury. To date, the sex difference of tract-specific WMH and the relationship between high blood pressure (BP) and tract-specific WMH remain unclear. We recruited 515 subjects from the Shanghai Changfeng study (range 53-89 years, mean age 67.33 years). Systolic and diastolic blood pressure (SBP and DBP) were collected and used to calculate pulse pressure (PP). Magnetic resonance T1 and T2 FLAIR images were acquired to measure WMH and calculate WMH index. The ANCOVA test was performed to test the difference between sexes, and the linear regression model was used to examine the associations between BP and WMH index. Men showed higher WMH index than women in all white matter tracts (p < .001, respectively) except for the bilateral superior longitudinal fasciculus (SLF) and its left temporal part (tSLF). High SBP and PP was associated with a lower WMH index on the left corticospinal tract (CST), SLF, tSLF and right cingulum in hippocampus (p ≤ .001, respectively) in women, while high DBP was associated with a higher WMH index on the bilateral CST (left p < .001; right p=.001), left inferior longitudinal fasciculus (p < .001) and inferior fronto-occipital fasciculus (p=.002) in men. Men tend to have more WMH compared to women. A high SBP/PP relates to a lower WMH burden in women. This suggests that women could benefit from higher blood pressure in older age.

Presence of sarcopenia identifies a special group of lean NAFLD in middle-aged and older people.

Sarcopenia, the age-related loss of muscle mass and function, is closely associated and frequently concomitant with non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the clinical features of the sarcopenic NAFLD patients from middle-aged and older people. A total of 1305 patients with NAFLD from the Shanghai Changfeng Study were included for analysis. Sarcopenia was diagnosed based on the height-adjusted appendicular skeletal muscle mass (ASM/height2). We comprehensively analyzed the metabolic phenotype, carotid artery condition, liver fibrosis score, and serum metabolomic profile of each participant. Among the middle-aged and older population, 68.1% of patients with sarcopenia and NAFLD were lean. Sarcopenia was independently associated with increased risk of carotid plaque (OR, 2.22; 95%CI 1.23-4.02) and liver fibrosis (OR, 2.07; 95%CI 1.24-3.44), and the sarcopenic lean NAFLD patients were characterized by a higher risk of carotid plaque (p = 0.008) and liver fibrosis (p = 0.001) than the non-sarcopenic lean NAFLD patients, despite their lower BMI and similar prevalence of metabolic syndrome and diabetes. Further serum metabolomic examination indicated that the sarcopenic lean NAFLD patients presented a distinct metabolomic profile prone to carotid plaque and liver fibrosis, with upregulated serum valine, N-acetylneuraminyl-glycoproteins, lactic acid, small LDL triglycerides and VLDL5 components, and reduced components of HDL4. A sarcopenic characterization score based on above metabolites was established and could also predict increased risk of carotid plaque and liver fibrosis. The presence of sarcopenia identifies a special subgroup of lean NAFLD with increased risk of cardiovascular disease and liver fibrosis clinically.

Twelve Loci Associated With Bone Density in Middle-aged and Elderly Chinese: The Shanghai Changfeng Study.

Previous genome-wide association studies (GWASs) of bone mineral density (BMD) were mainly conducted in Europeans. To explore genetic variants that affect BMD and sex differences in a Chinese population. A total of 5428 middle-aged and elderly Chinese were included. Dual-energy X-ray absorptiometry was used to measure BMD at the lumbar spine, and total and specific sites of the hip. A mixed linear model was used to analyze the associations between BMD and autosomal genetic variants, adjusting for age, age squared, sex, and menopausal women (model 1); model 2 was further adjusted for height and weight. A GWAS of osteoporosis in the Biobank Japan (BBJ) project was used for replication. GWAMA software was used to detect the statistical significance of sex differences of estimated effects. Gene annotation and pathway enrichment analysis were performed. Women lost BMD at earlier ages and faster than men. The 2 models identified a total of 12 loci that were associated with BMD at any site. Single nucleotide polymorphisms rs72354346, rs2024219, rs1463093, rs10037512, and rs5880932 were successfully replicated in the BBJ. Variations of rs79262027 G>A (VKORC1L1) and rs4795209 A>G (DDX52) were associated with BMD only in men, and rs1239055408 G>GA (KCNJ2) was associated with BMD only in women. Gene enrichment analysis showed that BMD in a Chinese elderly population was mainly related to ossification, bone resorption, sex hormones, and kidney physiology. The present GWAS identified 12 loci that were significantly associated with BMD at any site in a Chinese population, and 3 of them showed sex differences in their effects.

Twelve loci associated with bone density in middle-aged and elderly Chinese: the Shanghai Changfeng Study

Twelve loci associated with bone density in middle-aged and elderly Chinese: the Shanghai Changfeng Study

Comparison of criteria for metabolically healthy overweight/obesity in Shanghai Changfeng study

Objective: To establish a more suitable and practicable criterion of metabolically healthy overweight/obesity (MHO/O) in Chinese, a comparison study on different criteria of MHO/O was conducted in subjects aged over 45-year-old in Shanghai Changfeng Community. Method: A total of 3 301 overweight/obese subjects over 45 years old (men 1 521, women 1 789) in Shanghai Changfeng Community was included in the study. According to the inclusion or exclusion of waist circumference (WC), homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.5, and numbers of abnormal metabolic components, the MHO/O criteria were divided into 7 types: Adult Treatment Panel Ⅲ (ATP-Ⅲ) (with WC)<1 component, ATP-Ⅲ (with WC)<2 components, ATP-Ⅲ (with WC)<3 components, ATP-Ⅲ (without WC)<1 component, ATP-Ⅲ (without WC)<2 components, adjusted metabolic associated fatty liver disease (MAFLD) criteria<1 component, and adjusted MAFLD criteria<2 components. The prevalence of MHO/O and its relationship with the changes of body mass index (BMI), and the differences of the characteristics of MHO/O among the 7 types of metabolic health standards were compared. Result: The prevalence of MHO/O according to the ATP-Ⅲ (with WC)<1, ATP-Ⅲ (with WC)<2, ATP-Ⅲ (with WC)<3, ATP-Ⅲ (without WC)<1, ATP-Ⅲ (without WC)<2, adjusted MAFLD criteria<1, and adjusted MAFLD criteria<2 was 2.85%, 15.48%, 39.87%, 8.00%, 33.66%, 2.33%, 12.24%, respectively. The prevalence of MHO/O decreased as BMI increased. When BMI ≥ 28 kg/m2, the prevalence of MHO/O by ATP-Ⅲ (with WC)<1 and adjusted MAFLD criteria<1 dropped to 0. Conclusion: The adjusted MAFLD criterion without abnormal metabolic components is the most practicable definition of MHO/O.

Cover Image

The cover image is based on the Original Article NAFLD-related gene polymorphisms and all-cause and cause-specific mortality in an Asian population: the Shanghai Changfeng Study by Mingfeng Xia et al., https://doi.org/10.1111/apt.16772.

Image enhancement of color fundus photographs for age-related macular degeneration: the Shanghai Changfeng Study.

To develop and evaluate a new fundus image optimization software based on red, green, blue channels (RGB) for the evaluation of age-related macular degeneration (AMD) in the Chinese population. Fundus images that were diagnosed as AMD from the Shanghai Changfeng Study database were analyzed to develop a standardized optimization procedure. Image brightness, contrast, and color balance were measured. Differences between central lesion area and normal retinal area under different image brightness, contrast, and color balance were observed. The optimal optimization parameters were determined based on the visual system to avoid image distortion. A paired-sample diagnostic test was used to evaluate the enhancement software. Fundus optical coherence tomography (OCT) was used as the gold standard. Diagnostic performances were compared between original images and optimized images using McNemar's test. A fundus image optimization procedure was developed using 86 fundus images of 74 subjects diagnosed with AMD. By observing gray-scale images, choroid can be best displayed in red channel and retina in green channel was found. There was limited information in blue channel. Totally 104 participants were included in the paired sample diagnostic test to assess the performance of the optimization software. After the image enhancement, sensitivity increased from 74% to 88% (P=0.008), specificity decreased slightly from 88% to 84% (P=0.500), and Youden index increased by 0.11. The standardized image optimization software increases diagnostic sensitivity and may help ophthalmologists in AMD diagnosis and screening.

NAFLD-related gene polymorphisms and all-cause and cause-specific mortality in an Asian population: the Shanghai Changfeng Study.

The PNPLA3 and TM6SF2 gene variants have been found to cause NAFLD with a favourable cardiovascular risk profile. To investigate the effects of the NAFLD risk alleles on the all-cause and cause-specific mortality in 5581 Chinese adults. The genome-wide genotypes were detected using a genotyping array and serum lipoprotein profiles were examined using 1H NMR platform. Liver fat content (LFC) was measured using a quantitative ultrasound method. The vital status was determined using official registration data. Genome-wide association analysis showed that a series of variants in PNPLA3 were associated with LFC, including rs738409 C>G variant (P=8.6×10-7 ). Further analyses validated the associations of TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants with NAFLD. During 29425.1 person-years of follow-up, the overall mortality was 816 per 100000 person-years, where 299 deaths were attributable to cardiovascular disease and 85 to liver disease. The PNPLA3 rs738409 C>G variant was independently associated with increased liver-specific mortality (P for trend=0.034) but reduced cardiovascular mortality (P for trend=0.047). A composite genetic-predisposition score of PNPLA3, TM6SF2, and MBOAT7 risk alleles presented similar opposite effects on liver-specific and cardiovascular mortality. Moreover, interactions of the NAFLD risk alleles with adiposity for liver-specific mortality were found (Pinteraction <0.05). The reduced serum VLDL1 concentration was responsible for the increased liver-specific mortality related to NAFLD risk alleles. The PNPLA3 rs738409 C>G variant and its combination with TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants increase liver-specific mortality but reduce cardiovascular mortality in overweight/obese Chinese.

Prediction of Metabolic Disorders Using NMR-Based Metabolomics: The Shanghai Changfeng Study.

A metabolically healthy status, whether obese or not, is a transient stage with the potential to develop into metabolic disorders during the course of life. We investigated the incidence of metabolic disorders in 1078 metabolically healthy Chinese adults from the Shanghai Changfeng Study and looked for metabolites that discriminated the participants who would develop metabolic disorders in the future. Participants were divided into metabolically healthy overweight/obesity (MHO) and metabolically healthy normal weight (MHNW) groups according to their body mass index (BMI) and metabolic status. Their serum metabolomic profile was measured using a 1H nuclear magnetic resonance spectrometer (1H-NMR). The prevalence of diabetes, hypertriglyceridemia, hypercholesterolemia and metabolic syndrome was similar between the MHNW and MHO participants at baseline. After a median of 4.2years of follow-up, more MHO participants became metabolically unhealthy than MHNW participants. However, a subgroup of MHO participants who remained metabolically healthy (MHO → MHO) had a similar prevalence of metabolic disorders as the MHNW participants at the follow-up examination, despite a significant reduction in their serum concentrations of high-density lipoprotein (HDL) and an elevation in valine, leucine, alanine and tyrosine. Further correlation analysis indicated that serum intermediate-density lipoprotein (IDL) and very low-density lipoprotein cholesterol (VLDL-CH) might be involved in the transition from metabolically healthy to unhealthy status and could be valuable to identify the MHNW and MHO with increased metabolic risks.

Incidental Brain Magnetic Resonance Imaging Findings and the Cognitive and Motor Performance in the Elderly: The Shanghai Changfeng Study

BackgroundThe frequently discovered incidental findings (IFs) from imaging observations are increasing. The IFs show the potential clues of structural abnormalities underlying cognitive decline in elders. Detecting brain IFs and their relationship with cognitive and behavioral functions helps provide the information for clinical strategies.MethodsFive hundred and seventy-nine participants were recruited in the Shanghai Changfeng Study. All participants performed the demographic, biochemical, and cognitive functions and gait speed assessment and underwent the high-resolution multimodal magnetic resonance imaging scans. We calculated the detection rate of brain IFs. The association between cardiovascular risk factors and IFs and the associations between IFs and cognitive and motor functions were assessed using regression models. The relationships among gray matter volume, cognitive function, and gait speed were assessed with/without adjusting the IFs to evaluate the effects of potential IFs confounders.ResultsIFs were found in a total of 578 subjects with a detection rate of 99.8%. Age and blood pressure were the most significant cardiovascular risk factors correlated with IFs. IFs were found to be negatively associated with Montreal Cognitive Assessment, Mini-Mental State Examination, and gait speed. The gray matter volume was found to be positively correlated with the cognitive function without adjusting the white matter hyperintensity but not if adjusted.ConclusionIFs are commonly found in the elderly population and related to brain functions. The adequate intervention of IFs related cardiovascular risk factors that may slow down the progression of brain function decline. We also suggest that IFs should be considered as confounding factors that may affect cognitive issues on the structural neuroimaging researches in aging or diseases.

Type 2 Diabetes Is Causally Associated With Reduced Serum Osteocalcin: A Genomewide Association and Mendelian Randomization Study.

Recent advances indicate that bone and energy metabolism are closely related. However, little direct evidence on causality has been provided in humans. We aimed to assess the association of three bone-related biomarkers-25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and osteocalcin (OCN)-with several metabolic phenotypes and investigate any causal relevance to the associations using a Mendelian randomization (MR) study. Serum 25OHD, PTH, and total OCN were measured at baseline in 5169 eligible Chinese participants in Changfeng study. Partial correlation and bivariate GREML analysis were used to estimate phenotypic and genetic correlations, respectively. Multiple linear regression and logistic regression were used to assess linear associations. Genomewide association analysis (GWAS) was performed. Bidirectional two-sample MR analyses were conducted to examine causal relationships between OCN and body mass index (BMI), diastolic blood pressure (DBP), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), glycated hemoglobin A1c (HbA1c), and type 2 diabetes (T2DM), using our GWAS result of OCN and GWAS statistics from Biobank Japan project (BBJ) and the largest meta-analysis of T2DM GWAS in East Asian population. Circulating OCN was significantly associated with higher DBP and HDL-C and decreased TG, blood glucose level, insulin resistance, liver fat content, bone mineral density, BMI, and a favorable body fat distribution pattern. GWAS identified one novel serum PTH locus and two novel serum OCN loci, explaining 0.81% and 1.98% of variances of PTH and OCN levels, respectively. MR analysis suggested a causal effect of T2DM on lower circulating OCN concentration (causal effect: -0.03; -0.05 to -0.01; p=0.006 for T2DM_BBJ and -0.03; -0.05 to -0.01; p=0.001 for T2DM_EAS). These findings indicate that T2DM might impact bone remodeling and provide a resource for understanding complex relationships between osteocalcin and metabolic (and related) traits in humans. © 2021 American Society for Bone and Mineral Research (ASBMR).

Osteocalcin and Non-Alcoholic Fatty Liver Disease: Lessons From Two Population-Based Cohorts and Animal Models.

Osteocalcin regulates energy metabolism in an active undercarboxylated/uncarboxylated form. However, its role on the development of non-alcoholic fatty liver disease (NAFLD) is still controversial. In the current study, we investigated the causal relationship of circulating osteocalcin with NAFLD in two human cohorts and studied the effect of uncarboxylated osteocalcin on liver lipid metabolism through animal models. We analyzed the correlations of serum total/uncarboxylated osteocalcin with liver steatosis/fibrosis in a liver biopsy cohort of 196 participants, and the causal relationship between serum osteocalcin and the incidence/remission of NAFLD in a prospective community cohort of 2055 subjects from Shanghai Changfeng Study. Serum total osteocalcin was positively correlated with uncarboxylated osteocalcin (r = 0.528, p < .001). Total and uncarboxylated osteocalcin quartiles were inversely associated with liver steatosis, inflammation, ballooning, and fibrosis grades in both male and female participants (all p for trend <.05). After adjustment for confounding glucose, lipid, and bone metabolism parameters, the male and female participants with lowest quartile of osteocalcin still had more severe liver steatosis, with multivariate-adjusted odds ratios (ORs) of 7.25 (1.07-49.30) and 4.44 (1.01-19.41), respectively. In the prospective community cohort, after a median of 4.2-year follow-up, the female but not male participants with lowest quartile of osteocalcin at baseline had higher risk to develop NAFLD (hazard ratio [HR] = 1.90; 95% confidence interval [CI] 1.14-3.16) and lower chance to achieve NAFLD remission (HR = 0.56; 95% CI 0.31-1.00). In wild-type mice fed a Western diet, osteocalcin treatment alleviated hepatic steatosis and reduced hepatic SREBP-1 and its downstream proteins expression. In mice treated with osteocalcin for a short term, hepatic SREBP-1 expression was decreased without changes of glucose level or insulin sensitivity. When SREBP-1c was stably expressed in a human SREBP-1c transgenic rat model, the reduction of lipogenesis induced by osteocalcin treatment was abolished. In conclusion, circulating osteocalcin was inversely associated with NAFLD. Osteocalcin reduces liver lipogenesis via decreasing SREBP-1c expression. © 2020 American Society for Bone and Mineral Research (ASBMR).

Sarcopenia, sarcopenic overweight/obesity and risk of cardiovascular disease and cardiac arrhythmia: A cross-sectional study.

Sarcopenia is an age-dependent skeletal muscle disorder that is common in patients with heart failure. The current study aimed to investigate the associations of sarcopenia with carotid atherosclerosis, cardiovascular disease and cardiac arrhythmia in a middle-aged and elderly population without clinical heart failure. A total of 2432 participants (992 men and 1440 women) from Shanghai Changfeng Study were included for analysis. The degree of sarcopenia was measured using height-adjusted appendicular skeletal muscle mass (ASM/height2). Carotid plaques were detected by carotid artery ultrasonography, and myocardial ischemia, infarction and cardiac arrhythmia were diagnosed based on electrocardiogram, past history and clinical manifestations. Sarcopenia was associated with higher prevalence of carotid atherosclerosis (26.4% vs 20.4%, P=0.027), myocardial infarction (4.0% vs 1.1%, P=0.001), and premature ventricular contraction (4.0% vs 2.0%, P=0.034) in the participants with normal body weight, and higher prevalence of carotid atherosclerosis (45.0% vs 31.2%, P=0.016), myocardial infarction (10.0% vs 4.3%, P=0.020) and atrial fibrillation (7.5% vs 1.3%, P<0.001) in those with overweight/obese status. After adjustment for age, gender, cigarette smoking, alcohol drinking, menopausal status in women and other metabolic and inflammatory confounding factors, sarcopenia was independently associated with the risk of myocardial infarction in the whole population, and the risk of atrial fibrillation in the overweight/obese participants (all P<0.05). Compared with nonsarcopenic lean participants, the risk of myocardial infarction was gradually increased in sarcopenic lean (OR 3.08 [1.28-7.45], P=0.012) and sarcopenic overweight/obese participants (OR 4.07 [1.31-12.62], P=0.015). For the atrial fibrillation, the participants with either sarcopenia or overweight/obesity alone showed no higher risk. However, concomitant sarcopenia and overweight/obesity was associated with approximately 5-fold risk of atrial fibrillation (OR 5.68 [1.34-24.12], P=0.019) after multiple adjustment. Sarcopenia is associated with myocardial infarction and atrial fibrillation in middle-aged and elderly adults without clinical heart failure.

The major causes and risk factors of total and cause-specific mortality during 5.4-year follow-up: the Shanghai Changfeng Study

To investigate the major causes and predictive factors of death in a middle-aged and elderly Chinese population. A total of 6591 residents aged ≥ 45 years from Shanghai Changfeng community were followed up for an average of 5.4 years. The causes of death were coded according to the 10th Revision of International Classification of Diseases. The mortality rate was calculated by person-years of follow up and age-standardized according to the 2010 Chinese census data. Multivariable-adjusted Cox proportional hazards model was performed to investigate the predictors of all-cause and cause-specific mortality. During the total follow-up of 35,739 person-years, 370 deaths were documented (157 from malignant neoplasms, 70 from heart diseases, 68 from cerebrovascular diseases, 75 from other causes). The age-standardized all-cause mortality rate was 798.2 per 100,000 person-years (927.9 among men and 716.7 among women). Results from multivariable analyses showed that aging, diabetes, and osteoporosis at baseline were independent predictors of all-cause mortality, with hazard ratios (HR) of 1.11 (95% CI 1.10–1.13), 1.91 (1.51–2.42), and 1.71 (1.24–2.35), respectively. The population attributable risk percent of diabetes and osteoporosis was 19.7% and 11.7%, respectively. Cigarette smoking was associated with a higher risk of all-cause mortality in men (HR and 95%CI 1.44, 1.01–2.06). In women, diabetes and osteoporosis were related to a higher risk of cardiovascular mortality (3.27, 1.82–5.88 and 1.89, 1.04–3.46, respectively). While in men, osteoporosis was related to a higher risk of malignant neoplasms mortality (2.39, 1.07–5.33). Malignant neoplasms, heart diseases, and cerebrovascular diseases are the leading causes of death. Aging, smoking, underweight, diabetes, and osteoporosis are independent predictors of premature death among middle-aged and elderly Chinese community population. Moreover, there may have been some differences in the causes and predictors of premature death between men and women.

The PNPLA3 rs738409 C>G variant influences the association between low skeletal muscle mass and NAFLD: the Shanghai Changfeng Study.

Age-related skeletal muscle loss and patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphisms are both associated with increased liver steatosis and fibrosis in the absence of obesity. To investigate the influence of PNPLA3 polymorphism on the relationship between skeletal muscle loss and non-alcoholic fatty liver disease (NAFLD). Liver fat content was measured using a quantitative ultrasound method, and liver fibrosis was assessed by NAFLD fibrosis, BARD and FIB-4 scores in 3969 Chinese adults. The degree of sarcopenia was measured by weight-adjusted appendicular skeletal muscle mass (ASM%=appendicular skeletal muscle mass(kg)/body weight(kg)100%). The NAFLD proportion increased from 19.9% to 41.2% in men and 26.3% to 42.3% in women with decreasing ASM% quartiles (P<0.001). Low ASM% was inversely associated with NAFLD in PNPLA3 CC (odds ratio [OR]: men, 0.735 [0.610-0.885] and women, 0.812 [0.718-0.918], both P=0.001) and CG (OR: men, 0.673 [0.573-0.790] and women, 0.798 [0.713-0.893], both P<0.001) but not GG genotype carriers. The association remained significant after adjustment for age, cigarette smoking, fat mass, interaction between fat mass and ASM%, obesity, diabetes and all components of metabolic syndrome. Subgroup analyses found that PNPLA3 GG gene variant did not increase the risk for NAFLD in individuals with low ASM% regardless of obesity status. Low ASM% also increased risk for liver fibrosis (all P<0.05), which became insignificant after multiple adjustments. Low ASM% is associated with NAFLD and liver fibrosis. Dissociation of sarcopenia and NAFLD was found in PNPLA3 GG genotype carriers. A stratification based on PNPLA3 genotypes might facilitate personalised treatment for NAFLD.

The PNPLA3 rs738409 C>G variant interacts with changes in body weight over time to aggravate liver steatosis, but reduces the risk of incident type 2 diabetes.

The rs738409 C>G variant of the patatin-like phospholipase domain containing 3 gene (PNPLA3) increases the risk of non-alcoholic fatty liver disease (NAFLD) with no predisposition for insulin resistance. In this study, we aimed to investigate the influence of PNPLA3 polymorphisms on liver fat content (LFC) and glucose metabolic variables, and the associations between these, during the natural course of body weight changes in a Chinese adult cohort. The LFC, measured using a quantitative ultrasound method, was prospectively monitored in 2189 middle-aged and elderly adults from the Shanghai Changfeng Study, together with changes in body weight and metabolic variables. General linear models were used to detect interactive effects between the PNPLA3 rs738409 genotype and 4year changes in body weight on liver steatosis and glucose metabolism. The PNPLA3 homozygous GG genotype dissociated the changes in the LFC and OGTT 2h post-load blood glucose (PBG) in relation to 4year changes in body weight. PNPLA3 GG genotype carriers showed greater increases in the LFC and serum alanine aminotransferase (ALT) but lower PBG elevation and incident diabetes than PNPLA3 wild-type (CC) genotype carriers exhibiting the same degree of body weight increase. The interactions between the PNPLA3 genotype and changes in body weight on the LFC (false discovery rate [FDR]-adjusted pinteraction = 0.044) and ALT (FDR-adjusted pinteraction = 0.044) were significant. Subgroup analyses showed that the effect of the PNPLA3 GG genotype on changes in the LFC and PBG was only observed in metabolically unhealthy participants with insulin resistance or abdominal obesity. The PNPLA3 GG genotype interacted with changes in body weight to aggravate liver steatosis but reduced the risk of incident type 2 diabetes in metabolically unhealthy participants.

Serum ferritin levels are associated with insulin resistance in Chinese men and post-menopausal women: the Shanghai Changfeng study.

Associations between ferritin and insulin sensitivity have been described in recent studies. The possible association showed conflicting results by sex and menopausal status. We aimed to investigate the cross-sectional association of ferritin levels with insulin resistance and β-cell function. A total of 2518 participants (1033 men, 235 pre-menopausal women and 1250 post-menopausal women) were enrolled from the Changfeng Study. A standard interview was conducted, as well as anthropometric measurements and laboratory analyses, for each participant. The serum ferritin level was measured using electrochemiluminescence immunoassay. Insulin resistance and β-cell function indices were derived from a homeostasis model assessment. The results showed that the serum ferritin levels were 250·4 (sd 165·2), 94·6 (sd 82·0) and 179·8 (sd 126·6) ng/ml in the men, pre-menopausal and post-menopausal women, respectively. In fully adjusted models (adjusting for age, current smoking, BMI, waist:hip ratio, systolic blood pressure, diastolic blood pressure, TAG, HDL-cholesterol, LDL-cholesterol, log urine albumin:creatinine ratio, leucocytes, alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transpeptidase), serum ferritin concentrations are significantly associated with insulin resistance in men and post-menopausal females, and the null association was observed in pre-menopausal females. Interestingly, an increased β-cell function associated with higher ferritin was observed in post-menopausal participants, but not in male participants. In conclusion, these results suggested that elevated serum ferritin levels were associated with surrogate measures of insulin resistance among the middle-aged and elderly male and post-menopausal women, but not in pre-menopausal women.