Prevalence, characteristics and mortality outcomes of obese, nonobese and lean NAFLD in the United States, 1999-2016.

BACKGROUND: Updated prevalence and outcome data for nonobese NAFLD for the multi-ethnic US population is limited. OBJECTIVES: We aimed to investigate the prevalence, clinical characteristics and mortality of obese and nonobese individuals with NAFLD in the United Sates. METHODS: A retrospective study was conducted using the 1999-2016 NHANES databases. We determined hazard ratio stratified by obesity status in NAFLD individuals using Cox regression and log-rank test. RESULTS: Overall NAFLD prevalence was 32.3%: 22.7% were obese and 9.6% were nonobese, with increasing trend over time for obese NAFLD, but not nonobese NAFLD. Amongst those with NAFLD, 29.7% (95% CI: 27.8%-31.7%) were nonobese, of which 13.6% had lean NAFLD. Nonobese NAFLD was more common in older (40.9% if ≥ 65 vs. 24.2% if < 65 years), male (34.0% vs. 24.2%) and foreign-born Asian people (39.8% vs. 11.4%) and uncommon in black (11.5% vs 30-35% in other ethnicities, P < 0.001). Metabolic comorbidities were common in nonobese NAFLD individuals who also had more advanced fibrosis. Nonobese NAFLD individuals had higher 15-year cumulative all-cause mortality (51.7%) than obese NAFLD (27.2%) and non-NAFLD (20.7%) (P < 0.001). However, DM and fibrosis, but neither obese nor nonobese NAFLD compared to non-NAFLD was independently associated with higher mortality. CONCLUSION: Nonobese NAFLD makes up about one-third of the NAFLD in the United States (even higher in older, male and foreign-born individuals) and carries higher mortality than obese NAFLD. Screening for NAFLD should be considered in high-risk groups even in the absence of obesity.

Targeted proteomic analysis of habitual coffee consumption.

BACKGROUND: Coffee drinking has been implicated in mortality and a variety of diseases but potential mechanisms underlying these associations are unclear. Large-scale systems epidemiological approaches may offer novel insights to mechanisms underlying associations of coffee with health. OBJECTIVE: We performed an analysis of known and novel protein markers linked to cardiovascular disease and their association with habitual coffee intake in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS, n = 816) and followed up top proteins in the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 635) and EpiHealth (n = 2418). METHODS: In PIVUS and ULSAM, coffee intake was measured by 7-day dietary records whilst a computer-based food frequency questionnaire was used in EpiHealth. Levels of up to 80 proteins were assessed in plasma by a proximity extension assay. RESULTS: Four protein-coffee associations adjusted for age, sex, smoking and BMI, met statistical significance in PIVUS (FDR < 5%, P < 2.31 × 10-3 ): leptin (LEP), chitinase-3-like protein 1 (CHI3L), tumour necrosis factor (TNF) receptor 6 and TNF-related apoptosis-inducing ligand. The inverse association between coffee intake and LEP replicated in ULSAM (ß, -0.042 SD per cup of coffee, P = 0.028) and EpiHealth (ß, -0.025 SD per time of coffee, P = 0.004). The negative coffee-CHI3L association replicated in EpiHealth (ß, -0.07, P = 1.15 × 10-7 ), but not in ULSAM (ß, -0.034, P = 0.16). CONCLUSIONS: The current study supports an inverse association between coffee intake and plasma LEP and CHI3L1 levels. The coffee-CHI3L1 association is novel and warrants further investigation given links between CHI3L1 and health conditions that are also potentially influenced by coffee.

Big Data and medicine: a big deal?

Big Data promises huge benefits for medical research. Looking beyond superficial increases in the amount of data collected, we identify three key areas where Big Data differs from conventional analyses of data samples: (i) data are captured more comprehensively relative to the phenomenon under study; this reduces some bias but surfaces important trade-offs, such as between data quantity and data quality; (ii) data are often analysed using machine learning tools, such as neural networks rather than conventional statistical methods resulting in systems that over time capture insights implicit in data, but remain black boxes, rarely revealing causal connections; and (iii) the purpose of the analyses of data is no longer simply answering existing questions, but hinting at novel ones and generating promising new hypotheses. As a consequence, when performed right, Big Data analyses can accelerate research. Because Big Data approaches differ so fundamentally from small data ones, research structures, processes and mindsets need to adjust. The latent value of data is being reaped through repeated reuse of data, which runs counter to existing practices not only regarding data privacy, but data management more generally. Consequently, we suggest a number of adjustments such as boards reviewing responsible data use, and incentives to facilitate comprehensive data sharing. As data's role changes to a resource of insight, we also need to acknowledge the importance of collecting and making data available as a crucial part of our research endeavours, and reassess our formal processes from career advancement to treatment approval.

Serum selenium in relation to measures of glucose metabolism and incidence of Type 2 diabetes in an older Swedish population.

AIMS: The relation between selenium status and risk of Type 2 diabetes is controversial. We aimed to evaluate associations of serum selenium, a marker of dietary selenium, with measures of glucose metabolism and risk of diabetes. METHODS: We used data from a population-based, longitudinal cohort of 1925 Swedish men who were 50 years old and did not have diabetes at baseline in the 1970s. At baseline, an intravenous glucose tolerance test was performed and, at a follow-up examination after 20 years, an oral glucose tolerance test and a hyperinsulinaemic euglycaemic clamp for the assessment of insulin sensitivity were conducted. RESULTS: At baseline, the mean (standard deviation) selenium concentration was 75.6 (14.3) µg/l. During 20 years of follow-up, 88 incident cases of diabetes occurred in 1024 participants with follow-up data. Baseline serum selenium levels were not associated with risk of diabetes (odds ratio 1.06; 95% CI 0.83-1.38). Higher selenium levels were associated with lower early insulin response (standardized ß -0.08; 95% CI -0.14 to -0.03) at baseline after adjusting for potential confounders, but not with any other measures of ß-cell function or insulin sensitivity at baseline or follow-up. The association with early insulin response was non-significant after taking multiple testing into account. CONCLUSIONS: Our results do not support a role of dietary selenium in the development of disturbances in glucose metabolism or diabetes in older individuals.

Genetic factors may play a prominent role in the development of coronary heart disease dependent on important environmental factors.

OBJECTIVE: The aim of the study was to examine whether various lifestyle factors modify genetic influences on coronary heart disease (CHD). DESIGN: The effect of lifestyle factors [including smoking, sedentary lifestyle, alcohol intake and body mass index (BMI)] on risk of CHD was evaluated via Cox regression models in a twin study of gene-environment interaction. Using structure equation modelling, we estimated genetic variance of CHD dependent on lifestyle factors. SUBJECTS: In total, 51 065 same-sex twins from 25 715 twin pairs born before 1958 and registered in the Swedish Twin Registry were eligible for this study. During the 40-year follow-up, 7264 incident CHD events were recorded. RESULTS: Smoking, sedentary lifestyle and above average BMI were significantly associated with increased CHD incidence. The heritability of CHD decreased with increasing age, as well as with increasing levels of BMI, in both men and women. CONCLUSIONS: The difference in the genetic component of CHD as a function of BMI suggests that genetic factors may play a more prominent role for disease development in the absence of important environmental factors. Increased knowledge of gene-environment interactions will be important for a full understanding of the aetiology of CHD.

A common variant in the FTO locus is associated with waist-hip ratio in Indian adolescents.

BACKGROUND: Common variants in the FTO locus, and near MC4R locus, have been shown to have a robust association with obesity in children and adults among various ethnic groups. Associations with obesity traits among Indian adolescents have not been determined. OBJECTIVE: To study the association of rs9939609 (FTO) and rs17782313 (MC4R) to obesity related anthropometric traits in Indian adolescents. METHODS: Subjects for the current study were recruited from a cross-sectional cohort of 1,230 adolescents (age mean ± SD: 17.1 ± 1.9 years) from South India. RESULTS: The variant at the FTO locus was found to be associated with waist-hip ratio (WHR) but not with overall obesity in this population. No significant association was observed for obesity-traits and Mc4R variant rs17782313. CONCLUSION: The common variant of FTO (rs9939609) is associated with body fat distribution during early growth in Indian adolescents and may predispose to obesity and metabolic consequences in adulthood.

The role of obesity-related genetic loci in insulin sensitivity.

AIMS: Despite rapid advancements and many new diabetes susceptibility loci found in the past few years, few genetic variants associated with insulin sensitivity have been described, potentially attributable to the lack of larger cohorts examined with gold standard methods for insulin sensitivity assessment. There is a strong link between obesity and insulin sensitivity, and we hypothesized that known obesity susceptibility loci may act via effects on insulin sensitivity. METHODS: A cohort of 71-year-old men without diabetes (Uppsala Longitudinal Study of Adult Men) underwent a euglycaemic-hyperinsulinaemic clamp and genotyping for genetic variants representing 32 loci recently reported to be associated with BMI (n = 926). The effect of these loci on the insulin sensitivity index (M/I ratio) was examined using linear regression. An in silico replication was performed in publically available data for the three top single-nucleotide polymorphisms from the Meta-Analyses of Glucose and Insulin-related traits Consortium analyses of homeostasis model assessment of insulin resistance (n = 37,037). RESULTS: Three loci (SH2B1, MTCH2 and NEGR1) were associated with decreased insulin sensitivity at a nominal significance (P ≤ 0.05) after adjustment for BMI, but did not hold for multiple comparison correction. SH2B1 rs7359397 was also associated with homeostasis model assessment of insulin resistance in the Meta-Analyses of Glucose and Insulin-related traits Consortium data set (P = 3.9 × 10(-3)). CONCLUSIONS: Our study supports earlier reports of SH2B1 to be of importance in insulin sensitivity and, in addition, suggests potential roles of NEGR1 and MTCH2.

Plasma levels of glucagon like peptide-1 associate with diastolic function in elderly men.

AIMS: Congestive heart failure is a major cause of morbidity and mortality in diabetes. Besides the glycaemic effects of glucagon-like peptide 1 (GLP-1) mimetics, their effects on the heart are of interest. METHODS: We aimed to investigate longitudinal relationships between plasma levels of fasting GLP-1 (fGLP-1), 60-min oral glucose tolerance test-stimulated GLP-1 levels (60GLP-1), and the dynamic GLP-1 response after oral glucose tolerance test (ΔGLP-1 = 60GLP-1 - fGLP-1) and incidence of hospitalized congestive heart failure, during a follow-up time of a maximum of 9.8 years in 71-year-old men. We also investigated, cross-sectionally, the association between GLP-1 and left ventricular function as estimated by echocardiography. R: During the follow-up period, 16 of 290 participants with normal glucose tolerance experienced a congestive heart failure event (rate 0.7/100 person-years at risk), as did eight of 136 participants (rate 0.8/100 person-years at risk) with impaired glucose tolerance and nine of 72 participants (rate 1.7/100 person-years at risk) with Type 2 diabetes mellitus. Although GLP-1 concentrations did not predict congestive heart failure (fGLP-1: HR 0.98, 95% CI 0.4-2.4; 60GLP-1: HR 1.1, 95% CI 0.4-2.6; ΔGLP-1: HR 0.9, 95% CI 0.3-2.3), there was an association between left ventricular diastolic function (E/A ratio) and fGLP-1 (r = 0.19, P = 0.001), 60GLP-1 (r = 0.20, P < 0.001) and ΔGLP-1 (r = 0.18, P = 0.004). There was a lack of differences in plasma levels of GLP-1 between the groups with Type 2 diabetes and normal glucose tolerance. CONCLUSIONS: There were no longitudinal associations between GLP-1 levels and incidence of hospitalization for congestive heart failure. However, without any causality proven, GLP-1 levels did correlate, cross-sectionally, with left ventricular diastolic function in this cohort, suggesting that pathways including GLP-1 might be involved in the regulation of cardiac diastolic function.

Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.

BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.

Serum cathepsin S is associated with serum C-reactive protein and interleukin-6 independently of obesity in elderly men.

OBJECTIVE: Cathepsin S has been suggested provide a mechanistic link between obesity and atherosclerosis, possibly mediated via adipose tissue-derived inflammation. Previous data have shown an association between circulating cathepsin S and inflammatory markers in the obese, but to date, community-based reports are lacking. Accordingly, we aimed to investigate the association between serum levels of cathepsin S and markers of cytokine-mediated inflammation in a community-based sample, with prespecified subgroup analyses in nonobese participants. METHODS: Serum cathepsin S, C-reactive protein (CRP), and IL-6 were measured in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men; mean age 71 years, n = 991). CRP and IL-6 were also measured at a reexamination after 7 yr. RESULTS: After adjustment for age, body mass index, fasting plasma glucose, diabetes treatment, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum cholesterol, serum high-density lipoprotein cholesterol, prior cardiovascular disease, smoking, and leisure time physical activity, higher cathepsin S was associated with higher CRP (regression coefficient for 1 sd increase, 0.13; 95% confidence interval 0.07-0.19; P < 0.001) and higher serum IL-6 (regression coefficient for 1 sd increase, 0.08; 95% confidence interval 0.01-0.14; P = 0.02). These associations remained similar in normal-weight participants (body mass index <25 kg/m(2), n = 375). In longitudinal analyses, higher cathepsin S at baseline was associated with higher serum CRP and IL-6 after 7 yr. CONCLUSIONS: These results provide additional evidence for the interplay between cathepsin S and inflammatory activity and suggest that this association is present also in normal-weight individuals in the community.

Serum cystatin C and the risk of Alzheimer disease in elderly men.

BACKGROUND: Multiple lines of research suggest that increased cystatin C activity in the brain protects against the development of Alzheimer disease (AD). METHODS: Serum cystatin C levels were analyzed at two examinations of the Uppsala Longitudinal Study of Adult Men, a longitudinal, community-based study of elderly men (age 70 years, n = 1,153 and age 77 years, n = 761, a subset of the age 70 examination). Cox regressions were used to examine associations between serum cystatin C and incident AD. AD cases were identified by cognitive screening and comprehensive medical chart review in all subjects. RESULTS: On follow-up (median 11.3 years), 82 subjects developed AD. At age 70 years, lower cystatin C was associated with higher risk of AD independently of age, APOE4 genotype, glomerular filtration rate, diabetes, hypertension, stroke, cholesterol, body mass index, smoking, education level, and plasma amyloid-beta protein 40 and 42 levels (hazard ratio [HR] for lowest [<1.12 micromol/L] vs highest [>1.30 micromol/L] tertile = 2.67, 95% CI 1.22-5.83, p < 0.02). The results were similar at age 77 years (43 participants developed AD during follow-up). Furthermore, a 0.1-mumol/L decrease of cystatin C between ages 70 and 77 years was associated with a 29% higher risk of incident AD (HR 1.29, 95% CI 1.03-1.63, p < 0.03). CONCLUSIONS: Low levels of serum cystatin C precede clinically manifest Alzheimer disease (AD) in elderly men free of dementia at baseline and may be a marker of future risk of AD. These findings strengthen the evidence for a role for cystatin C in the development of clinical AD.

Inflammatory markers in relation to insulin resistance and the metabolic syndrome.

BACKGROUND: Inflammation has repeatedly been demonstrated to be associated with the metabolic syndrome (MetS) and insulin resistance, but the relative importance of different aspects of the inflammatory process is largely unexplored. DESIGN: We measured circulating interleukins (IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10); other cytokines (tumour necrosis factor-alpha, interferon gamma and monocyte chemotactic protein-1), cell adhesion molecules [vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, E-selectin, P-selectin, l-selectin], and systemic inflammation markers [C-reactive protein (CRP) and leukocyte count] in 943 70 year old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. We related these biomarkers to MetS and the homeostasis model assessment insulin resistance index (HOMA-IR). RESULTS: In a multivariable model including all inflammatory markers conjointly together with sex, log VCAM-1 [odds ratio (OR), 1.45; 95% confidence interval (CI), 1.22-1.72 per 1 SD increase; P < 0.0001], log E-selectin (OR, 1.33; 95% CI, 1.12-1.57 per 1SD increase; P = 0.001), and log CRP (OR, 1.41; 95% CI, 1.20-1.66 per 1-SD increase; P < 0.0001) were independently associated with MetS. These biomarkers were also independently associated with HOMA-IR. CONCLUSIONS: Among 17 inflammatory biomarkers, most of them previously not examined in relation to MetS and insulin resistance, VCAM-1, E-selectin and CRP demonstrated the strongest associations with MetS and insulin resistance in our community based sample of the elderly. The relative importance of these biomarkers in predicting the development of MetS, insulin resistance and cardiovascular disease needs to be further examined in a longitudinal setting.

Endothelium-dependent vasodilation in conduit and resistance vessels in relation to the endothelial nitric oxide synthase gene.

Single nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (NOS3) gene have been related to endothelium-dependent vasodilation in either conduit or resistance arteries with divergent results. In the Prospective Study of the Vasculature in Uppsala Seniors study, 959 participants aged 70 (51% men) were evaluated with brachial artery ultrasound to assess flow-mediated vasodilation (FMD; reflecting conduit arteries) and invasive forearm technique with intrabrachial infusion of acetylcholine (endothelium-dependent vasodilation (EDV); reflecting resistance arteries). The 23 SNPs analysed by minisequencing captured >90% of the common genetic variation in the NOS3 gene, using the HapMap population of European ancestry (CEU) as reference. One SNP (Glu298Asp) was related to FMD (nominal P=0.0018), but not to EDV (nominal P=0.76) after adjustment for sex, systolic blood pressure, diastolic blood pressure, pulse rate, antihypertensive treatment, total cholesterol, high-density cholesterol, lipid-lowering medication, fasting glucose, antidiabetic medication, body mass index, current smoking and prior diagnosis of cardiovascular disease. This relation was significant in both men and women in sex-specific analyses, and remained significant after adjusting for multiple testing (empirical P=0.029 from bootstrap resampling). None of the constructed haplotypes were related to vasodilation. The Glu298Asp SNP in the NOS3 gene was related to endothelium-dependent vasodilation in conduit, but not in resistance arteries. This SNP has previously been related to coronary heart disease, and our findings should stimulate to replication and exploration of the association of NOS3 variation with endothelial function in other settings.

Metabolic syndrome and risk for heart failure in middle-aged men.

OBJECTIVE: To explore metabolic syndrome as a possible risk factor for development of heart failure (HF). DESIGN: Community-based cohort study. SETTING: Uppsala, Sweden. PARTICIPANTS: 2314 50-year-old men free from HF, myocardial infarction and valvular disease at baseline were enrolled between 1970 and 1974 and were followed up until the age of 70. A modified National Cholesterol Education Program definition of metabolic syndrome was used with body mass index in the place of waist circumference. MAIN OUTCOME MEASURE: First hospitalisation for HF. RESULTS: In multivariable Cox proportional hazards models adjusted for established risk factors for HF (hypertension, diabetes, ECG left ventricular hypertrophy, smoking and body mass index), the presence at baseline of metabolic syndrome (hazard ratio 1.66, 95% confidence interval (CI) 1.02 to 2.70) was a predictor of subsequent HF. This relation was even stronger after adjustment for the presence of an acute myocardial infarction during follow up in addition to the other established risk factors for HF (hazard ratio 1.80, 95% CI 1.11 to 2.91). CONCLUSION: Metabolic syndrome was a significant predictor of HF, independent of established risk factors for HF including an interim myocardial infarction, during two decades of follow up in a community-based sample of middle-aged men. This implies that metabolic syndrome provides important risk information beyond that of established risk factors for HF.

Islet expression of perforin, Fas/Apo-1 and interleukin-1 converting enzyme (ICE) in non-obese diabetic (NOD) mice.

The aim of the present study was to correlate the islet expression of the apoptosis-associated factors Fas/Apo-1, FasL, ICE and perforin with the progression of beta-cell destruction in non-obese diabetic (NOD) mice. For this purpose, thymus and isolated pancreatic islets from male and female NOD mice of 5 and 15 weeks of age were subjected to immunoblot analysis. Islet expression of the Fas/Apo-1 receptor and ICE were increased in islets from female mice 15 weeks of age as compared to corresponding males. No Fas/Apo-1 or ICE signal was observed in the 5-week-old mice. The expression of perforin increased both in islets and in thymus with age and female gender. Islet expression of FasL could not be detected. Culture of isolated islets from NMRI mice in the presence of interleukin-1beta (IL-1beta) induced the expression of ICE. The present results support a direct role of the Fas/FasL and the perforin systems in the autoimmune destruction of insulin producing cells [corrected].