Non-alcoholic fatty liver disease is an increasing health issue that develops rather unnoticed with obesity, type 2 diabetes mellitus and metabolic syndrome. We investigated prevalence, determinants ...and associated metabolic abnormalities of non-alcoholic fatty liver disease in the largest population-based cohort to date.
Biochemical characteristics, type 2 diabetes mellitus and metabolic syndrome were determined in the Lifelines Cohort Study (N = 167,729), a population-based cohort in the North of the Netherlands. Non-alcoholic fatty liver disease was defined as Fatty Liver Index (FLI)≥60. Exclusion criteria were age <18 years, immigrants, missing data to assess FLI and metabolic syndrome, excessive alcohol use, previous-diagnosed hepatitis or cirrhosis and non-fasting blood sampling.
Out of 37,496 included participants (median age 44 years, 62.1% female), 8,259 (22.0%) had a FLI≥60. Individuals with a FLI≥60 were more often male, older, obese, had higher levels of hemoglobinA1c, fasting glucose, liver enzymes, total cholesterol, low-density lipoprotein cholesterol, triglycerides, c-reactive protein and leucocytes and lower high-density lipoprotein cholesterol (all P<0.0001). Participants with a FLI≥60 showed higher prevalence of type 2 diabetes mellitus (9.3% vs. 1.4%), metabolic syndrome (54.2% vs. 6.2%), impaired renal function (20.1% vs. 8.7%) and cardiovascular disease (4.6% vs. 1.6%) (all P<0.0001). Multivariable logistic analysis showed that smoking, hemoglobin, leucocytes, c-reactive protein, platelets, alanine aminotransferase, alkaline phosphatase, albumin, impaired renal function (OR 1.27, 95%CI 1.15-1.41), metabolic syndrome (OR 11.89, 95%CI 11.03-12.82) and its individual components hyperglycemia (OR 2.53, 95%CI 2.34-2.72), hypertension (OR 1.89, 95%CI 1.77-2.01) and reduced high-density lipoprotein cholesterol (OR 3.44, 95%CI 3.22-3.68) were independently associated with suspected non-alcoholic fatty liver disease (all P<0.0001).
Twenty-two percent (22.0%) of the population in the North of the Netherlands is suspected to suffer from non-alcoholic fatty liver disease, coinciding with a significant increased risk of type 2 diabetes mellitus, metabolic syndrome, cardiovascular disease and impaired renal function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CONTEXT The importance of the cholesteryl ester transfer protein (CETP) pathway in coronary disease is uncertain. Study of CETP genotypes can help better understand the relevance of this pathway to ...lipid metabolism and disease risk. OBJECTIVE To assess associations of CETP genotypes with CETP phenotypes, lipid levels, and coronary risk. DATA SOURCES Studies published between January 1970 and January 2008 were identified through computer-based and manual searches using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database. Previously unreported studies were sought through correspondence with investigators. STUDY SELECTION Relevant studies related principally to 3 common (TaqIB rs708272, I405V rs5882, and −629C>A rs1800775) and 3 uncommon (D442G rs2303790, −631C>A rs1800776, and R451Q rs1800777) CETP polymorphisms. DATA EXTRACTION Information on CETP genotypes, CETP phenotypes, lipid levels, coronary disease, and study characteristics was abstracted from publications, supplied by investigators, or both. RESULTS Ninety-two studies had data on CETP phenotypes, lipid levels, or both in 113 833 healthy participants, and 46 studies had data on 27 196 coronary cases and 55 338 controls. For each A allele inherited, individuals with the TaqIB polymorphism had lower mean CETP mass (−9.7%; 95% confidence interval CI, −11.7% to −7.8%), lower mean CETP activity (−8.6%; 95% CI, −13.0% to −4.1%), higher mean high-density lipoprotein cholesterol (HDL-C) concentrations (4.5%; 95% CI, 3.8%-5.2%), and higher mean apolipoprotein A-I concentrations (2.4%; 95% CI, 1.6%-3.2%). The pattern of findings was very similar with the I405V and −629C>A polymorphisms. The combined per-allele odds ratios (ORs) for coronary disease were 0.95 (95% CI, 0.92-0.99) for TaqIB, 0.94 (95% CI, 0.89-1.00) for I405V, and 0.95 (95% CI, 0.91-1.00) for −629C>A. CONCLUSIONS Three CETP genotypes that are associated with moderate inhibition of CETP activity (and, therefore, modestly higher HDL-C levels) show weakly inverse associations with coronary risk. The ORs for coronary disease were compatible with the expected reductions in risk for equivalent increases in HDL-C concentration in available prospective studies.
Since the discovery in 2003 that gain-of-function mutations in the gene encoding proprotein convertase subtilisin–kexin type 9 (PCSK9) cause autosomal dominant hypercholesterolemia, which was ...followed by the identification in 2005 of loss-of-function mutations in
PCSK9
as a cause of lower low-density lipoprotein (LDL) cholesterol levels, interest in the PCSK9 pathway has exploded. PCSK9 is a secreted serine protease that binds to the extracellular domain of the LDL receptor and targets the LDL receptor to the lysosomal compartment for degradation.
1
Consequently, PCSK9 prevents recycling of the LDL receptor to the cell surface, thereby attenuating LDL clearance. PCSK9 is present in human . . .
Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of ...vitamin A's functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true "vitamin A deficiency", but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.
The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is ...prospectively associated with first cardiovascular events in the general population.
HDL anti-inflammatory capacity was determined as its ability to suppress TNFα (tumor necrosis factor α)-induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNFα effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls.
HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% 15.7-44.2 versus 27.0% 7.4-36.1;
<0.001) and was inversely associated with incident CVD in a fully adjusted model (odds ratio OR per 1 SD, 0.74 CI, 0.61-0.90;
=0.002). Furthermore, this association was approximately similar with all individual components of the cardiovascular disease end point. The HDL anti-inflammatory was not correlated with cholesterol efflux capacity (
=-0.02;
>0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74;
=0.002; anti-inflammatory capacity: OR per 1 SD, 0.66;
<0.001). Adding HDL anti-inflammatory capacity improved risk prediction by the Framingham risk score, with a model likelihood-ratio statistic increase from 10.50 to 20.40 (
=0.002).
The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction.
The potential role of branched-chain amino acids (BCAAs) in the pathogenesis of cardiometabolic diseases is increasingly recognized, but the association of BCAAs with incident hypertension remains ...unknown. The aim of the present study was to explore the association of BCAAs with incident hypertension in a prospective population-based cohort study. We measured plasma concentrations of BCAAs by means of nuclear magnetic resonance spectroscopy in 4169 participants from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study. We estimated the risk of incident hypertension using multivariable-adjusted Cox regression models. After a median follow-up of 8.6 years, incident hypertension was ascertained in 924 subjects. Cox regression analyses revealed a significant association between BCAAs and incident hypertension. The hazard ratio per one SD of BCAAs was 1.11 (95% CI, 1.02–1.20; P=0.01) after full adjustment for multiple clinical variables. Likewise, the fully adjusted association remained significant when evaluated as categorical variable (hazard ratio for upper quartile with lowest quartile as reference category, 1.36; 95% CI, 1.11–1.68; P=0.003). Furthermore, the net reclassification improvement assessment improved after addition of BCAAs to a traditional risk model (P<0.001). This prospective study revealed that high plasma concentrations of BCAAs are associated with an increased risk of newly developed hypertension. The association remained after adjusting for age, sex, body mass index, and lipid profile.
GlycA is a novel nuclear magnetic resonance spectroscopy-measured biomarker of systemic inflammation. We determined whether GlycA is associated with incident cardiovascular disease (CVD) in men and ...women, examined whether this association with CVD is modified by renal function, and compared this association with high sensitivity C-reactive protein (hsCRP).
A prospective cohort study was performed among 4,759 subjects (PREVEND study) without a history of CVD and cancer. Incident CVD was defined as the combined endpoint of cardiovascular morbidity and mortality. Cox regression analyses were used to examine associations of baseline GlycA and hsCRP with CVD.
298 first CVD events occurred during a median follow-up of 8.5 years. After adjustment for clinical and lipid measures the hazard ratio (HR) for CVD risk in the highest GlycA quartile was 1.58 (95% CI, 1.05-2.37, P for trend = 0.004). This association was similar after further adjustment for renal function (estimated glomerular filtration rate and urinary albumin excretion). After additional adjustment for hsCRP, GlycA was still associated with incident CVD (HR: 1.16 per SD change (95% CI, 1.01-1.33), P = 0.04). Similar results were obtained for hsCRP (HR per SD change after adjustment for GlycA: 1.17 (95% CI 1.17 (95% CI, 1.01-3.60), P = 0.04). CVD risk was highest in subjects with simultaneously higher GlycA and hsCRP (fully adjusted HR: 1.79 (95% CI, 1.31-2.46), P<0.001).
GlycA is associated with CVD risk in men and women, independent of renal function. The association of GlycA with incident CVD is as strong as that of hsCRP.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE—To assess the association of circulating total bilirubin and cardiovascular disease (CVD) risk in a new prospective study and to determine whether adding information on total bilirubin ...values to established cardiovascular risk factors is associated with improvement in prediction of CVD risk.
APPROACH AND RESULTS—Circulating total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End-stage Disease) prospective study of 7222 participants and 773 incident CVD events. Total bilirubin was log-linearly associated with CVD risk. Age- and sex-adjusted hazard ratio (95% confidence interval) for CVD per 1-SD increase in loge total bilirubin was 0.82 (0.76 to 0.88; P<0.001), which was minimally attenuated to 0.89 (0.82 to 0.96; P=0.003) after further adjustment for established risk factors. In a meta-analysis of 12 population-based prospective studies involving 9378 incident CVD cases, the pooled multivariate-adjusted relative risk (95% confidence interval) for CVD was 0.93 (0.90 to 0.97; P<0.001) per 1-SD increase in total bilirubin levels. The corresponding pooled risks for coronary heart disease and stroke were 0.95 (0.92 to 0.99; P=0.018) and 0.93 (0.88 to 0.98; P=0.006), respectively. Addition of information on total bilirubin to a CVD risk prediction model containing established risk factors was associated with a C-index change of 0.0013 (−0.0004 to 0.0029; P=0.13).
CONCLUSIONS—There is a log-linear inverse association between circulating total bilirubin level and CVD risk, which is independent of established risk factors. Nonetheless, inclusion of total bilirubin in the standard established risk factors panel provides no significant improvement in CVD risk prediction.
Abstract Background Paraoxonase-1 (PON-1) has been suggested to be associated with cardiovascular disease (CVD) risk, however, aspects of the association, such as shape and independence from ...conventional risk factors are still uncertain. We aimed to assess the association of PON-1 with CVD risk and determine its potential utility for CVD risk prediction. Methods PON-1 was measured as its arylesterase activity at baseline in the PREVEND prospective study of 6902 participants. Results During a mean follow-up of 9.3 years, 730 CVD events were recorded. Serum PON-1 was weakly correlated with several cardiovascular risk markers including high-density lipoprotein cholesterol (HDL-C) (r = 0.18; P < 0.001) and was approximately log-linearly associated with CVD risk. In analyses adjusted for conventional risk factors, the hazard ratio (95% CI) for CVD per 1 standard deviation (SD) increase in loge PON-1 was 0.92 (0.85–0.99; P = 0.020), which remained persistent after additional adjustment for potential confounders 0.93 (0.86–0.99; P = 0.037). The association was attenuated on further adjustment for HDL-C 0.95 (0.88–1.02; P = 0.153). In a meta-analysis of 6 population-based prospective studies involving 15 064 participants and 2958 incident CVD outcomes, the pooled multivariable adjusted (including HDL-C) relative risk (95% CI) for CVD was 0.95 (0.90–1.02; P = 0.138) per 1 SD increase in PON-1 values. Adding PON-1 to a CVD risk prediction model containing conventional risk factors did not improve the C-index or net reclassification. Conclusions There is an approximately log-linear inverse association between PON-1 activity and CVD risk, which is partly dependent on HDL-C levels. In addition, serum PON-1 activity provides no significant improvement in CVD risk assessment beyond conventional CVD risk factors.
BACKGROUND:High-density lipoprotein (HDL) cholesterol concentration (HDL-C) is an established atheroprotective marker, in particular for coronary artery disease; however, HDL particle concentration ...(HDL-P) may better predict risk. The associations of HDL-C and HDL-P with ischemic stroke and myocardial infarction (MI) among women and Blacks have not been well studied. We hypothesized that HDL-P would consistently be associated with MI and stroke among women and Blacks compared with HDL-C.
METHODS:We analyzed individual-level participant data in a pooled cohort of 4 large population studies without baseline atherosclerotic cardiovascular diseaseDHS (Dallas Heart Study; n=2535), ARIC (Atherosclerosis Risk in Communities; n=1595), MESA (Multi-Ethnic Study of Atherosclerosis; n=6632), and PREVEND (Prevention of Renal and Vascular Endstage Disease; n=5022). HDL markers were analyzed in adjusted Cox proportional hazard models for MI and ischemic stroke.
RESULTS:In the overall population (n=15 784), HDL-P was inversely associated with the combined outcome of MI and ischemic stroke, adjusted for cardiometabolic risk factors (hazard ratio HR for quartile 4 Q4 versus quartile 1 Q1, 0.64 95% CI, 0.52–0.78), as was HDL-C (HR for Q4 versus Q1, 0.76 95% CI, 0.61–0.94). Adjustment for HDL-C did not attenuate the inverse relationship between HDL-P and atherosclerotic cardiovascular disease, whereas adjustment for HDL-P attenuated all associations between HDL-C and events. HDL-P was inversely associated with the individual end points of MI and ischemic stroke in the overall population, including in women. HDL-P was inversely associated with MI among White participants but not among Black participants (HR for Q4 versus Q1 for Whites, 0.49 95% CI, 0.35–0.69; for Blacks, 1.22 95% CI, 0.76–1.98; Pinteraction=0.001). Similarly, HDL-C was inversely associated with MI among White participants (HR for Q4 versus Q1, 0.53 95% CI, 0.36–0.78) but had a weak direct association with MI among Black participants (HR for Q4 versus Q1, 1.75 95% CI, 1.08–2.83; Pinteraction<0.0001).
CONCLUSIONS:Compared with HDL-C, HDL-P was consistently associated with MI and ischemic stroke in the overall population. Differential associations of both HDL-C and HDL-P for MI by Black ethnicity suggest that atherosclerotic cardiovascular disease risk may differ by vascular domain and ethnicity. Future studies should examine individual outcomes separately.
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