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Transcriptome-wide association studies (TWAS) have been increasingly applied to identify (putative) causal genes for complex traits and diseases. TWAS can be regarded as a two-sample two-stage least squares method for instrumental variable (IV) regression for causal inference. The standard TWAS (called TWAS-L) only considers a linear relationship between a gene's expression and a trait in stage 2, which may lose statistical power when not true. Recently, an extension of TWAS (called TWAS-LQ) considers both the linear and quadratic effects of a gene on a trait, which however is not flexible enough due to its parametric nature and may be low powered for nonquadratic nonlinear effects. On the other hand, a deep learning (DL) approach, called DeepIV, has been proposed to nonparametrically model a nonlinear effect in IV regression. However, it is both slow and unstable due to the ill-posed inverse problem of solving an integral equation with Monte Carlo approximations. Furthermore, in the original DeepIV approach, statistical inference, that is, hypothesis testing, was not studied. Here, we propose a novel DL approach, called DeLIVR, to overcome the major drawbacks of DeepIV, by estimating a related but different target function and including a hypothesis testing framework. We show through simulations that DeLIVR was both faster and more stable than DeepIV. We applied both parametric and DL approaches to the GTEx and UK Biobank data, showcasing that DeLIVR detected additional 8 and 7 genes nonlinearly associated with high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, respectively, all of which would be missed by TWAS-L, TWAS-LQ, and DeepIV; these genes include BUD13 associated with HDL, SLC44A2 and GMIP with LDL, all supported by previous studies. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibition is recognized for its evident renoprotective benefits in diabetic renal disease. Recent data suggest that SGLT2 inhibition also slows down kidney disease progression and reduces the risk of acute kidney injury, regardless of whether the patient has diabetes or not, but the mechanism behind these observed effects remains elusive. The objective of this study is to utilize a mendelian randomization (MR) methodology to comprehensively examine the influence of metabolites in circulation regarding the impact of SGLT2 inhibition on kidney function. Methods: We used a MR study to obtain associations between genetic proxies for SGLT2 inhibition and kidney function. We retrieved the most recent and comprehensive summary statistics from genome-wide association studies (GWAS) that have been previously published and involved kidney function parameters such as estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and albuminuria. Additionally, we included blood metabolite data from 249 biomarkers in the UK Biobank for a more comprehensive analysis. We performed MR analyses to explore the causal relationships between SGLT2 inhibition and kidney function and two-step MR to discover potential mediating metabolites. Results: The study found that a decrease in HbA1c levels by one standard deviation, which is genetically expected to result in SGLT2 inhibition, was linked to a decreased likelihood of developing type 2 diabetes mellitus (T2DM) (odds ratio [OR] = 0.55 [95% CI 0.35, 0.85], P = 0.007). Meanwhile, SGLT2 inhibition also protects eGFR (β = 0.05 [95% CI 0.03, 0.08], P = 2.45 × 10− 5) and decreased UACR (-0.18 [95% CI -0.33, -0.02], P = 0.025) and albuminuria (-1.07 [95% CI -1.58, -0.57], P = 3.60 × 10− 5). Furthermore, the study found that of the 249 metabolites present in the blood, only one metabolite, specifically the concentration of small high-density lipoprotein (HDL) particles, was significantly correlated with both SGLT2 inhibition and kidney function. This metabolite was found to play a crucial role in mediating the improvement of renal function through the use of SGLT2 inhibition (β = 0.01 [95% CI 0.005, 0.018], P = 0.001), with a mediated proportion of 13.33% (95% CI [5.71%, 26.67%], P = 0.020). Conclusions: The findings of this investigation provide evidence in favor of a genetically anticipated biological linkage between the inhibition of SGLT2, the presence of circulating metabolites, and renal function. The findings demonstrate that the protective effect of SGLT2 inhibition on renal function is mostly mediated by HDL particle concentrations in circulating metabolites. These results offer significant theoretical support for both the preservation of renal function and a better comprehension of the mechanisms underlying SGLT2 inhibition. [ABSTRACT FROM AUTHOR]

This document is a list of references and sources related to the topic of inferring causation from observational studies in the vision sciences. It includes articles and resources from various sources, such as scientific journals and research projects. The topics covered include genetic findings in the UK Biobank, Mendelian randomization, body composition measurement, and the relationship between muscle strength and various health factors. The document also includes information on cholesterol levels, lipoproteins, and their association with cardiovascular disease. It provides a comprehensive list of resources for library patrons conducting research on these topics. [Extracted from the article]

Background: Previous studies have yielded conflicting findings regarding the association between circulating lipids and lipid-lowering drugs with urinary stones, and the causal relationship between the two remains inconclusive. Objective: This study aimed to assess the causal relationship between circulating lipids (Triglycerides [TG], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], apolipoprotein A [APOA], apolipoprotein B [APOB] and Pure hypercholesterolaemia), lipid-lowering drugs (HMGCR [HMG-CoA reductase] inhibitors and PCSK9[Proprotein Convertase Subtilisin/Kexin Type 9] inhibitors) and the risk of urinary stones, using genetic data. Methods: Genetic instrumental variables (GIVs) for circulating lipids and lipid-lowering drugs were obtained from the UK Biobank and existing literature. Outcome data were extracted from a genetic association database with 3,625 urinary stone cases and 459,308 controls. Two-sample MR analysis, employing the TwoSampleMR software package in R 4.2.3, was conducted to assess the associations between multiple exposures. The primary outcome was determined using the inverse variance weighted (IVW) method for the causal relationship between exposure and outcome, while additional methods such as MR-Egger, weighted median, simple mode, and weighted mode were utilized as supplementary analyses. Robustness of the Mendelian Randomization (MR) analysis results was assessed through leave-one-out analysis and funnel plots. Results: The MR analysis revealed a significant association between elevated TG levels per 1 standard deviation and the occurrence of urinary stones (odds ratio [OR]: 1.002, 95% confidence interval [CI]: 1.000-1.003, P = 0.010). However, no significant association was observed between factors other than TG exposure and the risk of urinary stone occurrence across all methods(LDL-C: [OR], 1.001; 95% [CI], 1.000-1.003, P=0.132;HDL-C: [OR], 0.999; 95% [CI], 0.998-1.000, P=0.151;APOA:[OR] being 1.000 (95% [CI], 0.999-1.001, P=0.721;APOB: [OR] of 1.001 (95% [CI], 1.000-1.002, P=0.058;Pure hypercholesterolaemia: [OR] of 1.015 (95% [CI], 0.976-1.055, P=0.455) and lipid-lowering drugs (HMGCR inhibitors: [OR], 0.997; 95% [CI], 0.990-1.003, P=0.301 and PCSK9 inhibitors:[OR], 1.002; 95% [CI], 1.000-1.005, P=0.099). Conclusion: Our findings provide conclusive evidence supporting a causal relationship between an increased risk of urinary stones and elevated serum TG levels. However, we did not find a significant association between urinary stone occurrence and the levels of LDL-C, HDL-C, APOA, APOB, Pure hypercholesterolaemia and lipid-lowering drugs. [ABSTRACT FROM AUTHOR]

Background: Plasma cell neoplasms are a group of hematologic neoplasms that often develop in the elderly population. The relationship between cholesterol levels and hematologic malignancy has been identified in population studies. However, it is still unclear if there is a relationship between cholesterol levels and plasma cell neoplasm in European ancestry. Methods: Prospective cohorts included 502,507 individuals from the UK Biobank who were followed up to 2019 and assessed total cholesterol(TC) levels, low‐density lipoprotein (LDL) levels, high‐density lipoprotein (HDL) levels, apolipoprotein A (ApoA) and apolipoprotein B (ApoB) as risk factors for plasma cell neoplasms with Cox proportional hazard regression and restricted cubic spline model. We also used two‐sample Mendelian randomization to determine if the cholesterol level has a causal effect on developing plasma cell neoplasms. Results: We observed 1819 plasma cell neoplasm cases during 14.2 years of follow‐up in the UK Biobank. We found higher blood serum cholesterol levels at baseline were associated with a lower risk of plasma cell neoplasm in our study. All lipid profiles we analyzed in this study were inversely associated with plasma cell neoplasm risk (all ptrend <0.005) but triglycerides did not have such association. However, there was no suggestive association of genetically predicted serum LDL, HDL, and total cholesterol levels with multiple myeloma. Conclusion: Low serum total cholesterol, LDL, HDL, ApoA, and ApoB levels were all associated with increasing the risk of plasma cell neoplasm. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mendelian randomization (MR) is an increasingly popular approach to estimating causal effects. Although the assumptions underlying MR cannot be verified, they imply certain constraints, the instrumental inequalities, which can be used to falsify the MR conditions. However, the instrumental inequalities are rarely applied in MR. We aimed to explore whether the instrumental inequalities could detect violations of the MR conditions in case studies analyzing the effect of commonly studied exposures on coronary artery disease risk. Using 1077 single nucleotide polymorphisms (SNPs), we applied the instrumental inequalities to MR models for the effects of vitamin D concentration, alcohol consumption, C-reactive protein (CRP), triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol on coronary artery disease in the UK Biobank. For their relevant exposure, we applied the instrumental inequalities to MR models proposing each SNP as an instrument individually, and to MR models proposing unweighted allele scores as an instrument. We did not identify any violations of the MR assumptions when proposing each SNP as an instrument individually. When proposing allele scores as instruments, we detected violations of the MR assumptions for 5 of 6 exposures. Within our setting, this suggests the instrumental inequalities can be useful for identifying violations of the MR conditions when proposing multiple SNPs as instruments, but may be less useful in determining which SNPs are not instruments. This work demonstrates how incorporating the instrumental inequalities into MR analyses can help researchers to identify and mitigate potential bias. [ABSTRACT FROM AUTHOR]

Dried blood spot (DBS) sample collection has been suggested as a less invasive, cheaper and more convenient alternative to venepuncture, which requires trained personnel, making it a potentially viable approach for self-collection of blood on a large scale. We examine whether participants in a longitudinal survey were willing to provide a DBS sample in different interview settings, and how resulting cardiovascular risk biomarkers compared with those from venous blood to calculate clinical risk. Participants of the Understanding Society Innovation Panel, a representative sample of UK households, were randomly assigned to three modes of interview. Most participants (84%) were interviewed in their allocated mode. Participants (n = 2162) were interviewed by a nurse who collected both a blood sample by venepuncture and a DBS card ('nurse collection') or participants were seen by an interviewer or took part in the survey online to self-collect a DBS card ('self-collection'). All DBS cards were returned in the post after the sample had dried. Lipids (total cholesterol, HDL-cholesterol, triglycerides), HbA1c and C-reactive protein were measured in venous and DBS samples and equivalence was calculated. The resultant values were used to confirm equivalent prevalence of risk of cardiovascular disease in each type of blood sample by mode of participation. Of participants interviewed by a nurse 69% consented to venous blood sample and 74% to a DBS sample, while in the self-collection modes, 35% consented to DBS collection. Demographic characteristics of participants in self-collection mode was not different to those in nurse collection mode. The percentage of participants with clinically raised biomarkers did not significantly differ between type of blood collection (for example, 62% had high cholesterol (> 5 mmol/l) measured by venepuncture and 67% had high cholesterol within the self-collected DBS sample (p = 0.13)). While self-collected DBS sampling had a lower response rate to DBS collected by a nurse, participation did not vary by key demographic characteristics. This study demonstrates that DBS collection is a feasible method of sample collection that can provide acceptable measures of clinically relevant biomarkers, enabling the calculation of population levels of cardiovascular disease risk. [ABSTRACT FROM AUTHOR]

White matter hyperintensities (WMH) are the most compelling risk factors of stroke, dementia, and early mortality. We aimed to investigate the associations between WMH and circulating metabolites. We studied up to 8190 individuals from the UK Biobank, who have both measurements of 249 plasma metabolites and WMH volume. Linear regression models were applied in pooled samples, and age‐stratified and sex‐stratified subsamples to estimate the associations between WMH and metabolomic measures. We conducted three analytic models. In the basic model, we identified 45 metabolomic measures associated with WMH after multiple testing correction (p < 0.0022), 15 of which remained significant in additional adjustments, but no metabolites passed the full adjustment in pooled samples. The 15 WMH‐related metabolites were subfractions of various sizes of high‐density lipoprotein (HDL), fatty acids, and glycoprotein acetyls. Among them, one fatty acid metabolite and 12 HDL‐related traits showed significant negative associations with WMH. Higher glycoprotein acetyls were associated with large WMH. Strong age and sex specificities were observed indicating distinct metabolomic features accompany WMH in different samples. More metabolites were identified in males and adults under 50 years old. Circulating metabolites showed remarkably widespread associations with WMH. Population specificities may shed light on the different pertinent implications of WMH. [ABSTRACT FROM AUTHOR]

Objective: Liver fat associates with obesity‐related metabolic disturbances and may precede incident diseases. Metabolomic profiles of liver fat in the UK Biobank were investigated. Methods: Regression models assessed the associations between 180 metabolites and proton density liver fat fraction (PDFF) measured 5 years later through magnetic resonance imaging, as the difference (in SD units) of each log metabolite measure with 1‐SD higher PDFF among those without chronic disease and not taking statins, and by diabetes and cardiovascular diseases. Results: After accounting for confounders, multiple metabolites were associated positively with liver fat (p < 0.0001 for 152 traits), particularly extremely large and very large lipoprotein particle concentrations, very low‐density lipoprotein triglycerides, small high‐density lipoprotein particles, glycoprotein acetyls, monounsaturated and saturated fatty acids, and amino acids. Extremely large and large high‐density lipoprotein concentrations had strong inverse associations with liver fat. Associations were broadly comparable among those with versus without vascular metabolic conditions, although negative, rather than positive, associations were observed between intermediate‐density and large low‐density lipoprotein particles among those with BMI ≥25 kg/m2, diabetes, or cardiovascular diseases. Metabolite principal components showed a 15% significant improvement in risk prediction for PDFF relative to BMI, which was twice as great (but nonsignificant) compared with conventional high‐density lipoprotein cholesterol and triglycerides. Conclusions: Hazardous metabolomic profiles are associated with ectopic hepatic fat and are relevant to risk of vascular‐metabolic disease. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) risk prediction models for individuals with type 2 diabetes are important tools to guide intensification of interventions for CVD prevention. We aimed to assess the added value of incorporating risk factors variability in CVD risk prediction for people with type 2 diabetes.Methods: We used electronic health records (EHRs) data from 83 910 adults with type 2 diabetes but without pre-existing CVD from the UK Clinical Practice Research Datalink for 2004-2017. Using a landmark-modelling approach, we developed and validated sex-specific Cox models, incorporating conventional predictors and trajectories plus variability of systolic blood pressure (SBP), total and high-density lipoprotein (HDL) cholesterol, and glycated haemoglobin (HbA1c). Such models were compared against simpler models using single last observed values or means.Results: The standard deviations (SDs) of SBP, HDL cholesterol and HbA1c were associated with higher CVD risk (P < 0.05). Models incorporating trajectories and variability of continuous predictors demonstrated improvement in risk discrimination (C-index = 0.659, 95% CI: 0.654-0.663) as compared with using last observed values (C-index = 0.651, 95% CI: 0.646-0.656) or means (C-index = 0.650, 95% CI: 0.645-0.655). Inclusion of SDs of SBP yielded the greatest improvement in discrimination (C-index increase = 0.005, 95% CI: 0.004-0.007) in comparison to incorporating SDs of total cholesterol (C-index increase = 0.002, 95% CI: 0.000-0.003), HbA1c (C-index increase = 0.002, 95% CI: 0.000-0.003) or HDL cholesterol (C-index increase= 0.003, 95% CI: 0.002-0.005).Conclusion: Incorporating variability of predictors from EHRs provides a modest improvement in CVD risk discrimination for individuals with type 2 diabetes. Given that repeat measures are readily available in EHRs especially for regularly monitored patients with diabetes, this improvement could easily be achieved. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC), and particularly epithelial OC (EOC), is an increasing challenge for women. Circulating lipids play different roles in the occurrence and development of OC, but no causal relationship has been confirmed. We used two-sample Mendelian randomization (MR) to evaluate the genetic effects of circulating Apolipoprotein A1 (APOA1), Apolipoprotein B (APOB), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyc-erides (TG) on EOC risks based on summary data obtained from the UK Biobank and the Ovarian Cancer Association Consortium. We used the inverse-variance weight as the main statistical method and the MR-Egger, weighted median, and MR-PRESSO for sensitivity analysis. A 1-SD increment in HDL gave odds ratios (OR) and 95% confidence intervals (CI) of OR = 0.80 (95% CI: 0.69–0.93), OR = 0.77 (95% CI: 0.66–0.90), and OR = 0.76 (95% CI: 0.63–0.90) for low malignant potential OC (LMPOC), low-grade low malignant OC (LGLMSOC), and low malignant serous OC (LMSOC), respectively. Genetic liability due to TG was associated with an increased risk of LGLMSOC and LGSOC and a suggestive association with an increased risk of LMSOC (p = 0.001, p = 0.007, and p = 0.027, respectively). Circulating HDL was negatively associated with the risk of LMPOC, LGLMSOC, and LMSOC, while elevated circulating TG levels genetically predicted an increased risk of LGLMSOC and LGSOC. Further research is needed to investigate the causal effects of lipids on EOC and potential intervention and therapeutic targets. [ABSTRACT FROM AUTHOR]

The relevance between circulating metabolites and vascular events remains controversial and comprehensive studies are lacking. We sought to investigate the prospective associations of plasma metabolomics with risks of incident stroke, ischemic stroke (IS), hemorrhagic stroke (HS), and myocardial infarction (MI). Within the UK Biobank cohort, 249 circulating metabolites were measured in 90 438 participants without baseline vascular diseases. Cox proportional hazards regressions were applied to estimate adjusted hazard ratios (HRs) for per 1 standard deviation increment in metabolites. The least absolute shrinkage and selection operator algorithm was used for selecting metabolite subsets. During a median of 9.0 years of follow‐up, we documented 833 incident stroke and 1256 MI cases. Lipid constituents, comprising cholesterol, cholesteryl esters, free cholesterol, phospholipids, and total lipids, in very low‐ (VLDL), intermediate‐ (IDL), and low‐density lipoprotein (LDL) particles were positively associated with MI risk (HR = 1.12 to 1.36; 95% CI = 1.06 to 1.44), while in high‐density lipoprotein (HDL) particles showed inverse associations (HR = 0.68 to 0.81; 95% CI = 0.63 to 0.87). Similar association pattern with MI was also observed for VLDL, IDL, LDL, and HDL particles themselves. In contrast, triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI risk (HR = 1.14 to 1.28; 95% CI = 1.08 to 1.35) and, to a slightly lesser extent, with stroke and IS. Unsaturation of fatty acids and albumin were inversely associated with risks of stroke, IS, and MI. In contrast, the linear association for HS is absent. When combining multiple metabolites, the metabolite risk score captured a drastically elevated risk of all vascular events, about twice that of any single metabolite. Taken together, circulating metabolites showed remarkably widespread associations with incident MI, but substantially weakened associations with risks of stroke and its subtypes. Exhaustive metabolomics profiling may shed light on vascular risk prediction and, in turn, guide pertinent strategies of intervention and treatment. [ABSTRACT FROM AUTHOR]

The causation between lipids and renal cancer remains inconclusive. Our purpose is to explore the causal relationships between the three primary lipid metabolism‐related substances, namely triglycerides (TG), low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL) with the risk of renal cancer using Mendelian randomization (MR) methods. Genetic instruments for lipids were acquired from the UK Biobank. Outcome data were from the FinnGen study (1397 renal cancer cases and 204 070). Single‐variable MR (SVMR) and multi‐variable MR (MVMR) analyses were conducted with TwoSampleMR package based on R 4.0.3. The random‐effect inverse‐variance weighted (IVW), MR‐Egger, weighted‐median method, and weighted mode were the four main computing methods. We found that per 1 SD elevated LDL level was causally associated with renal cancer occurrence based on SVMR (OR, 1.31, 95% CI: 1.05‐1.64, P =.016). Similar significant associations were found in other methods. However, the results of SVMR did not support significant associations between TG, and HDL with renal cancer risk in all methods. The association between LDL and renal cancer was still significant in MVMR analysis (OR for IVW method: 1.22 per 1 SD higher trait (SD, 95% CI: 1.11‐1.34, P <.001; OR for MR‐Egger: 1.22 per 1 SD higher trait, 95% CI: 1.01‐1.47, P =.042) when taking TG and HDL into consideration. Our study supported that elevated serum LDL levels is causally associated with an increased risk of renal cancer independent of TG and HDL. [ABSTRACT FROM AUTHOR]

Background: In May 2021, the Scientific Advisory Committee on Nutrition (SACN) published a risk assessment on lower carbohydrate diets for adults with type 2 diabetes (T2D)(1). The purpose of the report was to review the evidence on 'low'-carbohydrate diets compared with the current UK government advice on carbohydrate intake for adults with T2D. However, since there is no agreed and widely utilised definition of a 'low'-carbohydrate diet, comparisons in the report were between lower and higher carbohydrate diets. SACN's remit is to assess the risks and benefits of nutrients, dietary patterns, food or food components for health by evaluating scientific evidence and to make dietary recommendations for the UK based on its assessment(2). SACN has a public health focus and only considers evidence in healthy populations unless specifically requested to do otherwise. Since the Committee does not usually make recommendations relating to clinical conditions, a joint working group (WG) was established in 2017 to consider this issue. The WG comprised members of SACN and members nominated by Diabetes UK, the British Dietetic Association, Royal College of Physicians and Royal College of General Practitioners. Representatives from NHS England and NHS Health Improvement, the National Institute for Health and Care Excellence and devolved health departments were also invited to observe the WG. The WG was jointly chaired by SACN and Diabetes UK. [ABSTRACT FROM AUTHOR]

Large-scale molecular profiling and genotyping provide a unique opportunity to systematically compare the genetically predicted effects of therapeutic targets on the human metabolome. We firstly constructed genetic risk scores for 8 drug targets on the basis that they primarily modify low-density lipoprotein (LDL) cholesterol (HMGCR, PCKS9, and NPC1L1), high-density lipoprotein (HDL) cholesterol (CETP), or triglycerides (APOC3, ANGPTL3, ANGPTL4, and LPL). Conducting mendelian randomisation (MR) provided strong evidence of an effect of drug-based genetic scores on coronary artery disease (CAD) risk with the exception of ANGPTL3. We then systematically estimated the effects of each score on 249 metabolic traits derived using blood samples from an unprecedented sample size of up to 115,082 UK Biobank participants. Genetically predicted effects were generally consistent among drug targets, which were intended to modify the same lipoprotein lipid trait. For example, the linear fit for the MR estimates on all 249 metabolic traits for genetically predicted inhibition of LDL cholesterol lowering targets HMGCR and PCSK9 was r2 = 0.91. In contrast, comparisons between drug classes that were designed to modify discrete lipoprotein traits typically had very different effects on metabolic signatures (for instance, HMGCR versus each of the 4 triglyceride targets all had r2 < 0.02). Furthermore, we highlight this discrepancy for specific metabolic traits, for example, finding that LDL cholesterol lowering therapies typically had a weak effect on glycoprotein acetyls, a marker of inflammation, whereas triglyceride modifying therapies assessed provided evidence of a strong effect on lowering levels of this inflammatory biomarker. Our findings indicate that genetically predicted perturbations of these drug targets on the blood metabolome can drastically differ, despite largely consistent effects on risk of CAD, with potential implications for biomarkers in clinical development and measuring treatment response. [ABSTRACT FROM AUTHOR]

Background: Numerous epidemiological studies have investigated the role of blood lipids in prostate cancer (PCa) risk, though findings remain inconclusive to date. The ongoing research has mainly involved observational studies, which are often prone to confounding. This study aimed to identify the relationship between genetically predicted blood lipid concentrations and PCa.Methods and Findings: Data for low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein A (apoA) and B (apoB), lipoprotein A (Lp(a)), and PCa were acquired from genome-wide association studies in UK Biobank and the PRACTICAL consortium, respectively. We used a two-sample summary-level Mendelian randomisation (MR) approach with both univariable and multivariable (MVMR) models and utilised a variety of robust methods and sensitivity analyses to assess the possibility of MR assumptions violation. No association was observed between genetically predicted concentrations of HDL, TG, apoA and apoB, and PCa risk. Genetically predicted LDL concentration was positively associated with total PCa in the univariable analysis, but adjustment for HDL, TG, and Lp(a) led to a null association. Genetically predicted concentration of Lp(a) was associated with higher total PCa risk in the univariable (ORweighted median per standard deviation (SD) = 1.091; 95% CI 1.028 to 1.157; P = 0.004) and MVMR analyses after adjustment for the other lipid traits (ORIVW per SD = 1.068; 95% CI 1.005 to 1.134; P = 0.034). Genetically predicted Lp(a) was also associated with advanced (MVMR ORIVW per SD = 1.078; 95% CI 0.999 to 1.163; P = 0.055) and early age onset PCa (MVMR ORIVW per SD = 1.150; 95% CI 1.015,1.303; P = 0.028). Although multiple estimation methods were utilised to minimise the effect of pleiotropy, the presence of any unmeasured pleiotropy cannot be excluded and may limit our findings.Conclusions: We observed that genetically predicted Lp(a) concentrations were associated with an increased PCa risk. Future studies are required to understand the underlying biological pathways of this finding, as it may inform PCa prevention through Lp(a)-lowering strategies. [ABSTRACT FROM AUTHOR]

Background: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization.Methods: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included.Results: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2.Conclusions: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD. [ABSTRACT FROM AUTHOR]

Background& Aims: Little is known on the gender-specific effect and potential role of non-linear associations between metabolic syndrome (MetS) components and liver cancer risk. We evaluated these associations based on the UK Biobank cohort.Methods: We included 474,929 individuals without previous cancer based on the UK Biobank cohort. Gender-specific hazard ratios (HRs) and 95% confidence interval (CIs) were calculated by Cox proportional hazards regression, adjusting for potential confounders. Non-linear associations for individual MetS components were assessed by the restricted cubic spline method.Results: Over a median follow-up of 6.6 years, we observed 276 cases of liver cancer (175 men, 101 women). MetS [HR 1.48, 95% CI 1.27-1.72] and central obesity [HR 1.65, 95% CI 1.18-2.31] were associated with higher risk of liver cancer in men but not in women. Participants with hyperglycaemia has higher risk of liver cancer. High waist circumference and blood glucose were dose-dependently associated with increased liver cancer risk in both genders. For high density lipoprotein (HDL) cholesterol (both genders) and blood pressure (women), U-shaped associations were observed. Low HDL cholesterol (< 1.35 mmol/L) in men and high HDL cholesterol in women (> 1.52 mmol/L) were associated with increased liver cancer risk.Conclusions: MetS components showed gender-specific linear or U- shaped associations with the risk of liver cancer. Our study might provide evidence for individualized management of MetS for preventing liver cancer. [ABSTRACT FROM AUTHOR]

Background: Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear.Methods: We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in ∼30 000 adults and 4000 children across 10 UK and Finnish cohort studies.Results: In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents) and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids.Conclusions: Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities. [ABSTRACT FROM AUTHOR]

Purpose: The impact of gluten intake on metabolic health in subjects without celiac disease is unclear. The present study aimed to assess the association between gluten intake and body fat percentage (primary objective), as well as a broad set of metabolic health markers. Methods: Gluten intake was estimated in 39,927 participants of the UK Biobank who completed a dietary questionnaire for assessment of previous 24-h dietary intakes. Multiple linear regression analyses were performed between gluten intake and markers of metabolic health with Holm adjustment for multiple comparisons. Results: Median gluten intake was 9.7 g/day (male: 11.7 g/day; female: 8.2 g/day; p < 0.0001). In multiple linear regression analysis, association between gluten intake and percentage body fat was negative in males (β = − 0.028, p = 0.0020) and positive in females (β = 0.025, p = 0.0028). Furthermore, gluten intake was a negative predictor of total cholesterol (male: β = − 0.031, p = 0.0154; female: β = − 0.050, p < 0.0001), high-density lipoprotein cholesterol (male: β = − 0.052, p < 0.0001; female: β = − 0.068, p < 0.0001), and glomerular filtration rate (sexes combined: β = − 0.031, p < 0.0001) in both sexes. In females only, gluten intake was positively associated with waist circumference (β = 0.041, p < 0.0001), waist-to-height ratio (β = 0.040, p < 0.0001), as well as body mass index (β = 0.043, p < 0.0001), and negatively related to low-density lipoprotein cholesterol (β = − 0.035, p = 0.0011). A positive association between gluten intake and triglycerides was observed in males only (β = 0.043, p = 0.0001). Conclusion: This study indicates that gluten intake is associated with markers of metabolic health. However, all associations are weak and not clinically meaningful. Limiting gluten intake is unlikely to provide metabolic health benefits for a population in total. [ABSTRACT FROM AUTHOR]

Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis.Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87).Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis. [ABSTRACT FROM AUTHOR]

Background: Age-related macular degeneration (AMD) is a leading cause of vision loss. Whereas lipids have been studied extensively to understand their effects on cardiovascular diseases, their relationship with AMD remains unclear.Methods: Two-sample Mendelian randomization (MR) analyses were performed to systematically evaluate the causal relationships between eight serum lipid biomarkers, consisting of apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], triglycerides (TG) and non-HDL cholesterol (non-HDL-C), and the risk of different AMD stages and subtypes. We derived 64-407 genetic instruments for eight serum lipid biomarkers in 419 649 participants of European descent from the UK Biobank cohort. We conducted genome-wide association studies (GWAS) for 12 711 advanced AMD cases [8544 choroidal neovascularization (CNV) and 2656 geographic atrophy (GA) specific AMD subtypes] and 5336 intermediate AMD cases with 14 590 controls of European descent from the International AMD Genomics Consortium.Results: Higher genetically predicted HDL-C and ApoA1 levels increased the risk of all AMD subtypes. LDL-C, ApoB, CHOL and non-HDL-C levels were associated with decreased risk of intermediate and GA AMD but not with CNV. Genetically predicted TG levels were associated with decreased risk of different AMD subtypes. Sensitivity analyses revealed no evidence for directional pleiotropy effects. In our multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results.Conclusion: These results suggest the role of lipid metabolism in drusen formation and particularly in AMD development at the early and intermediate stages. Mechanistic studies are warranted to investigate the utility of lipid pathways for therapeutic treatment in preventing AMD. [ABSTRACT FROM AUTHOR]

Objective: We conducted a Mendelian randomization (MR) study to disentangle the comparative effects of lipids and apolipoproteins on ischemic stroke. Methods: Single‐nucleotide polymorphisms associated with low‐ and high‐density lipoprotein (LDL and HDL) cholesterol, triglycerides, and apolipoprotein A‐I and B (apoA‐I and apoB) at the level of genomewide significance (p < 5 × 10−8) in the UK Biobank were used as instrumental variables. Summary‐level data for ischemic stroke and its subtypes were obtained from the MEGASTROKE consortium with 514,791 individuals (60,341 ischemic stroke cases, and 454,450 non‐cases). Results: Increased levels of apoB, LDL cholesterol, and triglycerides were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke in the main and sensitivity univariable MR analyses. In multivariable MR analysis including apoB, LDL cholesterol, and triglycerides in the same model, apoB retained a robust effect (p < 0.05), whereas the estimate for LDL cholesterol was reversed, and that for triglycerides largely attenuated. Decreased levels of apoA‐I and HDL cholesterol were robustly associated with increased risk of any ischemic stroke, large artery stroke, and small vessel stroke in all univariable MR analyses, but the association for apoA‐I was attenuated to the null after mutual adjustment. Interpretation: The present MR study reveals that apoB is the predominant trait that accounts for the etiological basis of apoB, LDL cholesterol, and triglycerides in relation to ischemic stroke, in particular large artery and small vessel stroke. Whether HDL cholesterol exerts a protective effect on ischemic stroke independent of apoA‐I needs further investigation. ANN NEUROL 2020;88:1229–1236 [ABSTRACT FROM AUTHOR]

Background: Despite a growing body of evidence suggesting that short sleep duration may be linked to adverse metabolic outcomes, how these associations differ between age groups remains unclear. We use eight years of data from the UK National Diet and Nutritional Survey (NDNS) (2008–2016) to analyse cross-sectional relationships between sleep duration and metabolic risk in participants aged 11–70 years. Methods: Participants (n = 2008) who provided both metabolic risk and sleep duration data were included. Self-reported sleep duration was standardised by age, to account for differences in age-related sleep requirements. A standardised metabolic risk score was constructed, comprising: waist circumference, blood pressure, serum triglycerides, serum high-density lipoprotein cholesterol, and fasting plasma glucose. Regression models were constructed across four age groups from adolescents to older adults. Results: Overall, decreased sleep duration (hrs) was associated with an increased metabolic risk (standard deviations) with significant quadratic (B:0.028 [95%CI: 0.007, 0.050]) and linear (B:-0.061 [95%CI: -0.111, -0.011]) sleep duration coefficients. When separated by age group, stronger associations were seen among mid-aged adults (36-50y) (quadratic coefficient: 0.038 [95%CI: 0.002, 0.074]) compared to other age groups (e.g. adolescents (11-18y), quadratic coefficient: -0.009 [95%CI: -0.042, 0.025]). An increased difference between weekend and weekday sleep was only associated with increased metabolic risk in adults aged 51–70 years (B:0.18 [95%CI: 0.005, 0.348]). Conclusions: Our results indicate that sleep duration is linked to adverse metabolic risk and suggest heterogeneity between age groups. Longitudinal studies with larger sample sizes are required to explore long-term effects of abnormal sleep and potential remedial benefits. [ABSTRACT FROM AUTHOR]

Objective: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH.Methods: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses.Results: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively.Interpretation: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66. [ABSTRACT FROM AUTHOR]

Background: High-density lipoprotein cholesterol (HDL-C) is a complex mixture of subclasses with heterogeneous atheroprotective activities. We analyzed HDL-C subclass in relation to cardiovascular risk and metabolic syndrome (MetS) in a population with high HDLC levels. Methods: A total of 300 Korean individuals with high HDL-C levels (=2.331 mmol/L) were enrolled following a comprehensive general medical examination including body composition analysis. HDL3-C levels were measured using the HDL3-EX SEIKEN kit (Randox Ltd., Crumlin, UK) and non-HDL3-C levels were calculated by subtracting HDL3-C levels from total HDL-C levels. Results: HDL3-C levels and HDL3-C proportion had a weak positive correlation with lowdensity lipoprotein cholesterol (LDL-C) and triglycerides (r=0.21, r=0.25; r=0.26, r=0.34, respectively, all P <0.001); in contrast, non-HDL3-C levels had a weak negative correlation with these parameters (r=-0.17 and r=-0.25, respectively, both P <0.005). HDL3-C levels and HDL3-C proportion were significantly higher in the MetS group (N=8) than in the non- MetS group (0.71 vs 0.63 mmol/L, P =0.001; 29.7 vs 25.8%, P =0.001, respectively); these were the only predictors of MetS among the lipid variables (areas under the curves [AUC]=0.84 and 0.83, respectively, both P =0.001). Conclusions: In populations with high HDL-C levels, HDL-C subclass may provide a greater amount of information on cardiovascular risk and MetS than HDL-C levels alone. [ABSTRACT FROM AUTHOR]

Background: Child maltreatment is associated with cardiovascular disease (CVD), but mediation pathways have not been fully elucidated. The aim of the current study was to determine and quantify the underlying pathways linking child maltreatment and CVD.Methods: We conducted a retrospective cohort study using the UK Biobank. The number and types of child maltreatment, including abuse and neglect, were recalled by the participants. Lifestyle, biological, physical, and mental health factors measured at baseline were explored as potential mediators. Incident CVD was ascertained through record linkage after baseline measurement. Age, sex, ethnicity, area-based deprivation, and education level were adjusted for as confounders. Cox proportional hazard models were conducted to test for associations between child maltreatment and incident CVD.Results: A total of 152,040 participants who completed the child maltreatment assessment were included in the analyses, and one third reported at least one type of child maltreatment. There was a dose-response relationship between the number of maltreatment types and incident CVD. On average, each additional type of child maltreatment was associated with an 11% (95% CI 8-14%, P < 0.0001) increased risk of CVD. The majority (56.2%) of the association was mediated through depressive symptoms, followed by smoking (14.7%), high-density lipoprotein cholesterol (8.7%), and sleep duration (2.4%).Conclusion: Child maltreatment is associated with incident CVD through a combination of mental health, lifestyle, and biological pathways. Therefore, in addition to interventions to reduce the occurrence of child maltreatment, attention should be targeted at promoting healthy lifestyles and preventing, identifying, and treating depression among children and adults who have previously been maltreated. [ABSTRACT FROM AUTHOR]

Background The consumption of some types of dairy products has been associated with lower cardiometabolic disease incidence. Knowledge remains limited about habitual dairy consumption and the pathways to cardiometabolic risk. Objective We aimed to investigate associations of habitual consumption of total and types of dairy products with markers of metabolic risk and adiposity among adults in the United Kingdom. Methods We examined associations of changes in dairy consumption (assessed with a food-frequency questionnaire) with parallel changes in cardiometabolic markers using multiple linear regression among 15,612 adults aged 40–78 y at baseline (1993–1997) and followed up over 1998–2000 (mean ± SD: 3.7±0.7 y) in the European Prospective Investigation into Cancer and Nutrition (EPIC)–Norfolk study. Results For adiposity, an increase in fermented dairy products [yogurt (total or low-fat) or low-fat cheese] consumption was associated with a lower increase in body weight and body mass index (BMI). For example, over 3.7 y, increasing yogurt consumption by 1 serving/d was associated with a smaller increase in body weight by 0.23 kg (95% CI: −0.46, −0.01 kg). An increase in full-fat milk, high-fat cheese, and total high-fat dairy was associated with greater increases in body weight and BMI [e.g., for high-fat dairy: β = 0.13 (0.05, 0.21) kg and 0.04 (0.01, 0.07) kg/m2, respectively]. For lipids, an increase in milk (total and low-fat) or yogurt consumption was positively associated with HDL cholesterol. An increase in total low-fat dairy was negatively associated with LDL cholesterol (−0.03 mmol/L; −0.05, −0.01 mmol/L), whereas high-fat dairy (total, butter, and high-fat cheese) consumption was positively associated [e.g., 0.04 (0.02, 0.06) mmol/L for total high-fat dairy]. For glycemia, increasing full-fat milk consumption was associated with a higher increase in glycated hemoglobin (P  = 0.027). Conclusions The habitual consumption of different dairy subtypes may differently influence cardiometabolic risk through adiposity and lipid pathways. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Purpose: This study aimed to investigate whether prospectively reallocating time away from sedentary behavior (SB) into different physical activity intensities is associated with 12-month change to cardiometabolic health in a cohort at high risk of type 2 diabetes (T2DM). Methods: Participants with known risk factors for T2DM were recruited from primary care (Leicestershire, United Kingdom) as part of the Walking Away from Type 2 Diabetes trial (n = 808). Participants were followed up at 12, 24, and 36 months. SB, light-intensity physical activity (LPA) and moderate-to-vigorous intensity physical activity (MVPA) were measured objectively by accelerometer. Postchallenge glucose, triglycerides, HDL cholesterol, systolic blood pressure, and waist circumference were analyzed individually and combined into a clustered cardiometabolic risk score (CMRS). Associations of changing SB over each consecutive 12-month period were analyzed taking account of repeated measures. Results: Reallocating 30 min from SB to LPA was associated with 0.21-cm (95% confidence interval, 0.03–0.38 cm) reduction in waist circumference, 0.09-mmol·L−1 (0.04–0.13 mmol·L−1) reduction in 2-h glucose, 0.02-mmol·L−1 (0.00–0.04 mmol·L−1) reduction in triglycerides, and 0.02 (0.01–0.03) reduction in CMRS. Every 30-min reallocation from SB to MVPA was associated with 1.23-cm (0.68–1.79 cm) reduction in waist circumference, 0.23-mmol·L−1 (0.10–0.36 mmol·L−1) reduction in 2-h glucose, 0.04-mmol·L−1 (0.00–0.09 mmol·L−1) reduction in triglycerides, and 0.07 (0.04–0.11) reduction in CMRS. Reallocating 30 min from LPA into MVPA was also associated with 1.02-cm (0.43–1.60 cm) reduction in waist circumference, 0.16-mmol·L−1 (0.02–0.30 mmol·L−1) reduction in 2-h glucose, and 0.05 (0.01–0.09) reduction in CMRS. Conclusion: Over 12 months, reallocating time away from SB into LPA or MVPA was associated with improved cardiometabolic health in a population at risk of T2DM, with the greatest benefits observed for MVPA. [ABSTRACT FROM AUTHOR]

The National Institute for Health and Care Excellence (NICE) has acknowledged the value of waist-to-height ratio (WHtR) as an indicator for 'early health risk'. We used recent UK data to explore whether classification based on WHtR identifies more adults at cardiometabolic risk than the 'matrix' based on BMI and waist circumference, currently used for screening. Data from the Health Survey for England (4112 adults aged 18+ years) were used to identify cardiometabolic risk, indicated by raised glycated Hb, dyslipidaemia and hypertension. HbA1c, total/HDL-cholesterol and systolic blood pressure (BP) were more strongly associated with WHtR than the 'matrix'. In logistic regression models for HbA1c ≥ 48 mmol/mol, total/HDL-cholesterol > 4 and hypertension (BP > 140/90 mmHg or on medication), WHtR had a higher predictive value than the 'matrix'. AUC was significantly greater for WHtR than the 'matrix' for raised HbA1c and hypertension. Of adults with raised HbA1c, 15 % would be judged as 'no increased risk' using the 'matrix' in contrast to 3 % using WHtR < 0·5. For hypertension, comparative values were 23 and 9 %, and for total/HDL-cholesterol > 4, 26 and 13 %. Nearly one-third of the 'no increased risk' group in the 'matrix' had WHtR ≥ 0·5 and hence could be underdiagnosed for cardiometabolic risk. WHtR has the potential to be a better indicator of cardiometabolic risks associated with central obesity than the current NICE 'matrix'. The cut-off WHtR 0·5 in early screening translates to a simple message, 'your waist should be less than half your height', that allows individuals to be aware of their health risks. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Purpose: To establish whether associations between sedentary behavior and cardiometabolic health differ when assessed by thigh-worn and waist-worn accelerometry. Methods: Participants were recruited from several areas in the United Kingdom. Sedentary behavior was assessed using the activPAL worn on the thigh and ActiGraph worn on the waist. Average total (TST), prolonged (bouts ≥30 min; PST) and breaks (BST) in sedentary time were calculated. Cardiometabolic health markers included: adiposity (body fat) and surrogate markers of adiposity ((waist circumference, body mass index [BMI]), lipids (total, low density lipoprotein, and high-density lipoprotein [HDL] cholesterol, triglycerides), blood pressure, and glucose (fasting, 2 h and glycated hemoglobin A1c). A clustered cardiometabolic risk score was calculated. Linear regression analysis examined the associations with cardiometabolic health. Results: There were 1457 participants (mean age [± standard deviation], 59.38 ± 11.85 yr; 51.7% male; mean BMI, 30.19 ± 5.59 kg·m−2) included in the analyses. ActivPAL and ActiGraph sedentary variables were moderately correlated (0.416–0.511, P < 0.01); however, all variables were significantly different from each other (P < 0.05). Consistency was observed across devices in the direction and magnitude of associations of TST and PST with adiposity, surrogate markers of adiposity, HDL, triglycerides, and cardiometabolic risk score and for BST with adiposity, surrogate markers of adiposity, and cardiometabolic risk. Differences across devices were observed in associations of TST and PST with diastolic blood pressure, for TST with 2-h glucose and for BST with HDL. No other associations were observed for any other health marker for either device. Conclusions: Results suggest that associations with cardiometabolic health are largely comparable across the two common assessments of sedentary behavior but some small differences may exist for certain health markers. [ABSTRACT FROM AUTHOR]

Background: The intrauterine environment is critical for fetal growth and development. However, observational associations between maternal gestational lipid concentrations and offspring birth weight (BW) have been inconsistent and ascertaining causality is challenging.Methods: We used a novel two-sample Mendelian randomization (MR) approach to estimate the causal effect of maternal gestational high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride concentrations on offspring BW. Single nucleotide polymorphisms (SNPs) associated with serum HDL-C, LDL-C and triglyceride concentrations identified in the Global Lipids Genetics Consortium genome-wide association study meta-analysis (n = 188 577 European-ancestry individuals; sample 1) were selected as instrumental variables. The effects of these SNPs on offspring BW were estimated using a structural equation model in the UK Biobank and Early Growth Genetics consortium (n = 230 069 European-ancestry individuals; sample 2) that enabled partitioning of the genetic associations into maternal- (intrauterine) and fetal-specific effects.Results: We found no evidence for a causal effect of maternal gestational HDL-C, LDL-C or triglyceride concentrations on offspring BW [standard deviation change in BW per standard deviation higher in HDL-C = -0.005 (95% confidence interval: -0.039, 0.029), LDL-C = 0.014 (-0.017, 0.045), and triglycerides = 0.014 (-0.025, 0.052)].Conclusions: Our findings suggest that maternal gestational HDL-C, LDL-C and triglyceride concentrations play a limited role in determining offspring BW. However, we cannot comment on the impact of these and other lipid fractions on fetal development more generally. Our study illustrates the power and flexibility of two-sample MR in assessing the causal effect of maternal environmental exposures on offspring outcomes. [ABSTRACT FROM AUTHOR]

The lipid profile is consistently associated with coronary artery disease (CAD) and ischemic stroke (IS). However, the lipoprotein subfractions have not been deeply explored in stroke subtypes, especially in IS outcome. We performed two-sample Mendelian randomization (MR) analysis using 92 lipid traits measured by nuclear magnetic resonance in 115,000 subjects from the UK Biobank. Data for genetic associations with IS, its subtypes, and long-term outcome (LTO) were obtained from three cohorts of European ancestry: GIGASTROKE (73,652 cases, 1,234,808 controls), GODS (n = 1791) and GISCOME (n = 6165). Results obtained using CARDIoGRAMPlusC4D were used to identify differences with CAD. Genetically determined low concentration of medium high-density lipoprotein (HDL) particles (odds ratio (OR) = 0.92, 95% CI 0.88–0.96; p = 3.6 × 10−4) and its cholesterol content (OR = 0.92, 95% CI 0.88–0.96; p = 1.9 × 10−4) showed causal associations with an increased risk of stroke. Genetic predisposition to high apolipoprotein (apo)B to apoA-I ratio was causally associated with an increased risk of IS (OR = 1.12, 95% CI 1.06–1.18, p = 1.1 × 10−4), and a highly suggestive association was found between non-esterified cholesterol in low-density lipoprotein (LDL) and increased risk of atherothrombotic stroke (LAS) (OR = 1.35, 95% CI 1.10–1.66; p = 4.0 × 10−3). Low cholesterol in small and medium LDL was suggestively associated with poor LTO. Our results support that low medium HDL concentration was causally associated with an increased stroke risk, while high levels of non-esterified cholesterol in LDL were suggestively associated with an increased risk of LAS and with a better LTO. [Display omitted] • Causal association of low HDL-C with stroke risk is due to the medium subfraction. • Free cholesterol content is implicated in the association of high LDL with stroke risk. • The association of triglyceride-rich lipoproteins with stroke remains inconclusive. • ApoB-lipoproteins play a more important role in CAD risk than in stroke risk. • The association of low LDL-C with a poor long-term outcome needs further studies. [ABSTRACT FROM AUTHOR]

Individuals with a higher abdominal adipose tissue accumulation are at higher risk of developing cardiometabolic diseases. For a given body mass index (BMI), women typically present lower abdominal adipose tissue accumulation compared to men. Whether abdominal adiposity is a causal driver of cardiometabolic risk, or a mere marker of ectopic fat deposition is debated. We investigated the sex-specific and sex-combined impact of height and BMI-adjusted gluteofemoral adipose tissue (GFATadj) adjusted abdominal subcutaneous adipose tissue (ASATadj) and adjusted visceral adipose tissue (VATadj) on cardiometabolic traits and diseases using Mendelian randomization. Leveraging genome-wide summary statistics on GFATadj, ASATadj and VATadj from 39,076 UK Biobank participants with full-body magnetic resonance imaging available, we found that GFATadj is associated with a more favourable cardiometabolic risk profile including lower low density lipoprotein (LDL) cholesterol, triglycerides, fasting glucose, fasting insulin, liver enzyme levels and blood pressure as well as higher high density lipoprotein (HDL) cholesterol levels. GFATadj also is negatively associated with ischemic stroke, coronary artery disease, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). ASATadj is not associated with cardiometabolic traits and diseases, whereas VATadj is associated with liver fat accumulation but not with NAFLD or other cardiometabolic traits or diseases. Although the absolute effect sizes of GFATadj on LDL cholesterol were more pronounced in women compared to men, most associations did not differ by sex. The inability of subcutaneous fat depots to efficiently store energy substrates could be the causal factor underlying the association of visceral lipid deposition with cardiometabolic health. [Display omitted] • For a given body mass index, body fat distribution influences metabolic risk. • Gluteofemoral adipose tissue accumulation may protect against metabolic risk. • Subcutaneous abdominal adipose tissue accumulation may not influence metabolic risk. • Visceral adipose tissue accumulation may increase liver fat. [ABSTRACT FROM AUTHOR]

Objective: To investigate the causal role of cardiometabolic risk factors in osteoarthritis (OA) using associated genetic variants. Methods: We studied 27,691 adults from the Malmö Diet and Cancer Study (MDCS) and replicated novel findings among 376,435 adults from the UK Biobank. Trait‐specific polygenic risk scores for low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL) cholesterol levels, triglyceride levels, body mass index (BMI), fasting plasma glucose (FPG) levels, and systolic blood pressure (BP) were used to test the associations of genetically predicted elevations in each trait with incident OA diagnosis (n = 3,559), OA joint replacement (n = 2,780), or both (total OA; n = 4,226) in Mendelian randomization (MR) analyses in the MDCS, and with self‐reported and/or hospital‐diagnosed OA (n = 65,213) in the UK Biobank. Multivariable MR, MR‐Egger, and weighted median MR were used to adjust for potential pleiotropic biases. Results: In the MDCS, genetically predicted elevation in LDL cholesterol level was associated with a lower risk of OA diagnosis (odds ratio [OR] 0.83 [95% confidence interval (95% CI) 0.73–0.95] per 1SD increase) and total OA (OR 0.87 [95% CI 0.78–0.98]), which was supported by multivariable MR for OA diagnosis (OR 0.84 [95% CI 0.75–0.95]) and total OA (0.87 [95% CI 0.78–0.97]), and by conventional 2‐sample MR for OA diagnosis (OR 0.86 [95% CI 0.75–0.98]). MR‐Egger indicated no pleiotropic bias. Genetically predicted elevation in BMI was associated with an increased risk of OA diagnosis (OR 1.65 [95% CI 1.14–2.41]), while MR‐Egger indicated pleiotropic bias and a larger association with OA diagnosis (OR 3.25 [1.26–8.39]), OA joint replacement (OR 3.81 [95% CI 1.39–10.4]), and total OA (OR 3.41 [95% CI 1.43–8.15]). No associations were observed between genetically predicted HDL cholesterol level, triglyceride level, FPG level, or systolic BP and OA outcomes. The associations with LDL cholesterol levels were replicated in the UK Biobank (OR 0.95 [95% CI 0.93–0.98]). Conclusion: Our MR study provides evidence of a causal role of lower LDL cholesterol level and higher BMI in OA. [ABSTRACT FROM AUTHOR]

This study used cross-sectional UK Biobank data to estimate the influence of active and passive commuting modes and commuting distance on cardiovascular disease (CVD) -related biomarkers as measures of health outcomes. The analysis applied logistic regression to assess the risk of exhibiting individual biomarker values outside a predefined reference interval and standard linear regression to estimate the relation between commuting practices and a composite CVD index. The study sample comprised 208,893 UK Biobank baseline survey participants aged 40 to 69 who use various modes of transport to commute to work at least once a week. Participants were recruited and interviewed between 2006 and 2010 at 22 centers geographically dispersed across England, Scotland, and Wales. The data set included these participants' sociodemographic and health-related information, including lifestyle indicators and biological measures. The primary outcome was a shift from low to high-risk blood serum levels in eight cardiovascular biomarkers: total cholesterol, low density lipoprotein, high density lipoprotein, triglycerides, apolipoprotein A and B, C-reactive protein, and lipoprotein (a). Our results indicated a small negative association between the composite risk index for CVD biomarkers and weekly commuting distance. Although estimates for active commuting modes (cycling, walking) may admittedly be sensitive to different covariate adjustments, our specifications show them to be positively associated with select CVD biomarkers. Commuting long distances by car is negatively associated with CVD-related biomarkers, while cycling and walking might be positively associated. This biomarker-based evidence, although limited, is less susceptible to residual confounding than that from distant outcomes like CVD mortality. • Active commuting modes have positive associations with CVD biomarkers. • Cycling is significantly linked to five biomarkers. • Walking is significantly related to two biomarkers. • Commuting by car is associated with low composite CVD biomarkers. [ABSTRACT FROM AUTHOR]

Background: The relationship between physical fitness and risk markers for type 2 diabetes (T2D) in children and the contribution to ethnic differences in these risk markers have been little studied. We examined associations between physical fitness and early risk markers for T2D and cardiovascular disease in 9‐ to 10‐year‐old UK children. Methods: Cross‐sectional study of 1445 9‐ to 10‐year‐old UK children of South Asian, black African‐Caribbean and white European origin. A fasting blood sample was used for measurement of insulin, glucose (from which homeostasis model assessment [HOMA]‐insulin resistance [IR] was derived), glycated hemoglobin (HbA1c), urate, C‐reactive protein (CRP), and lipids. Measurements of blood pressure (BP) and fat mass index (FMI) were made; physical activity was measured by accelerometry. Estimated VO2 max was derived from a submaximal fitness step test. Associations were estimated using multilevel linear regression. Results: Higher VO2 max was associated with lower FMI, insulin, HOMA‐IR, HbA1c, glucose, urate, CRP, triglycerides, LDL‐cholesterol, BP and higher HDL‐cholesterol. Associations were reduced by adjustment for FMI, but those for insulin, HOMA‐IR, glucose, urate, CRP, triglycerides and BP remained statistically significant. Higher levels of insulin and HOMA‐IR in South Asian children were partially explained by lower levels of VO2max compared to white Europeans, accounting for 11% of the difference. Conclusions: Physical fitness is associated with risk markers for T2D and CVD in children, which persist after adjustment for adiposity. Higher levels of IR in South Asians are partially explained by lower physical fitness levels compared to white Europeans. Improving physical fitness may provide scope for reducing risks of T2D. [ABSTRACT FROM AUTHOR]

Summary Objective To examine the utility of Body Mass Index (BMI), Waist-to-Height-Ratio (WHtR) and cardiorespiratory fitness thresholds to identify cardiometabolic risk in youth. Methods Cross-sectional cardiometabolic risk factor variables on 534 children aged 10.4–17.6 years of age (52% boys) from the United Kingdom were used. Binary logistic regression and receiver operating characteristic curves were used to examine the utility of established age and gender specific thresholds for BMI, WHtR and cardiorespiratory fitness to identify individuals with increased cardiometabolic risk (increased clustered triglycerides, HDL-cholesterol, systolic blood pressure and glucose). Results A WHtR ≥ 0.5 increased the odds by 11.4 (95% confidence interval 4.7, 27.4, P < 0.001) of having increased cardiometabolic risk in boys and by 2.5 (1.2, 5.3, P = 0.020) for girls. Similar associations were observed for BMI and cardiorespiratory fitness in both boys and girls with increased cardiometabolic risk. BMI-z, WHtR and cardiorespiratory fitness all showed a significant ability in identifying individuals for increased cardiometabolic risk in boys and girls ( P < 0.05) despite poor area under the curve (AUC) values (<0.70). Combining anthropometrical variables did improve the diagnostic accuracy for identifying cardiometabolic risk in boys, evidenced by an increased AUC of 0.74 (0.64, 0.85, P < 0.001), but not in girls. Conclusion The magnitude of associations was broadly similar for BMI, WHtR and cardiorespiratory fitness in identifying individuals at increased cardiometabolic risk. Yet, combining BMI with WHtR in boys may provide a more accurate method for identifying those at increased cardiometabolic risk. [ABSTRACT FROM AUTHOR]

Background: Diabetes, obesity and metabolic syndrome are highly prevalent in patients with severe mental illness and can impose a major physical health burden. Objective: To determine how anthropometric and metabolic features changed over time in a retrospective cohort of people with Severe Mental Illness living in Cheshire, UK. Methods: In all, 1307 individuals on the severe mental illness Register were followed up between 2002 and 2012 in UK general practice. Subjects were identified through a pseudanonymised search of general practice registers. Results: Baseline body mass index was 28.6 kg/m2 increasing to 31.0 at 10-year follow-up (r² = 0.84; p = 0.0002). There was a significant increase in fasting blood glucose from 5.72 to 6.79 mmol/L (r² = 0.48; p = 0.026). Correspondingly, there was a strong positive univariate relation between increase in body mass index and fasting blood glucose (r² = 0.54; p < 0.0001) taking into account all measurements. Fasting blood glucose also increased slightly with age (p = 0.028). With increasing use of statins, total cholesterol fell from 4.5 to 3.9 mmol/L (r² = 0.88; p = 0.0001), as did low-density lipoprotein cholesterol from 3.43 to 2.35 mmol/L (r² = 0.94; p = 0.0001). In multivariate models, adjusting for age, gender, smoking and blood pressure, each unit increase in body mass index (odds ratio = 1.07 [1.01, 1.13]; p = 0.031) and triglycerides (odds ratio = 1.28 (1.06, 1.55); p = 0.009) was independently associated with an increased risk of having type 2 diabetes. Conclusion: Increasing body mass index relates to increasing rates of dysglycaemia over time. Measures to encourage weight reduction should be key strategies to reduce dysglycaemia rates in severe mental illness. Prescribing statins may have been effective in improving the lipid profile in this group. [ABSTRACT FROM AUTHOR]

Context: There is a need to identify biomarkers capable of predicting risk of mortality and cardiovascular events in people with rheumatoid arthritis (RA). Ideally, such biomarkers should be simple, easy to measure and readily available in a clinical care setting to minimise burdens on patients and healthcare providers. Objective: Investigate associations, if any, between selected prognostic biomarkers, which are potentially readily available in a clinical care setting, and the risk of all-cause mortality and major adverse cardiovascular events (MACE; myocardial infarction/stroke) in a population-based RA cohort. Study Design and Analysis: Prospective analysis of cohort data. Cox proportional hazards models were used to analyse associations between selected biomarkers and all-cause mortality/MACE. Biomarkers included: body mass index (BMI), body fat percentage, waist circumference, waist-to-hip ratio, hand grip strength, usual walking pace, number of chronic pain sites, systolic blood pressure (BP), total cholesterol, high density lipoprotein (HDL)-cholesterol, glycated haemoglobin (HbA1c), C-reactive protein (CRP) and rheumatoid factor. All biomarkers listed were included in multivariable models for both outcomes which were also adjusted for age, sex, socioeconomic status and number of additional long-term conditions. Setting or Dataset: UK Biobank (population-based cohort of 502,414 participants, aged 37-73 years). Population Studied: 5,658 (1.1%) participants with self-reported RA (mean age 59 [standard deviation 7.13]; 69.8% female). Intervention/Instrument: None. Outcomes Measures: Allcause mortality and MACE. Results: 670 deaths and 370 MACE were recorded during available follow-up (median 11.3 and 8.9 years, respectively). Biomarkers associated with higher risk of all-cause mortality: underweight BMI (<18.50kg/m2) (hazard ratio 3.87 [95% confidence interval 1.94-7.72]), CRP 3-10mg/L (1.45 [1.16-1.83]) and CRP >10mg/L (1.76 [1.34-2.32]). Biomarkers associated with higher risk of MACE: underweight BMI (3.85 [1.18-12.49]), low hand grip strength (1.46 [1.10-1.95]), slow usual walking pace (1.62 [1.20-2.21]), raised systolic BP (=140mmHg) (1.61 [1.22-2.12]) and CRP >10mg/L (1.55 [1.09-2.22]). Conclusions: A multidimensional approach to risk assessment, combining simple, readily available measures, may provide important prognostic information for RA populations at primary/secondary care level, while minimising the extent/impact of testing on patients. [ABSTRACT FROM AUTHOR]

Background Novel epidemiology models are required to link correlated variables over time, especially haemoglobin A1c (HbA1c) and body mass index (BMI) for diabetes prevention policy analysis. This article develops an epidemiology model to correlate metabolic risk factor trajectories. Method BMI, fasting plasma glucose, 2-h glucose, HbA1c, systolic blood pressure, total cholesterol and high density lipoprotein (HDL) cholesterol were analysed over 16 years from 8150 participants of the Whitehall II prospective cohort study. Latent growth curve modelling was employed to simultaneously estimate trajectories for multiple metabolic risk factors allowing for variation between individuals. A simulation model compared simulated outcomes with the observed data. Results The model identified that the change in BMI was associated with changes in glycaemia, total cholesterol and systolic blood pressure. The statistical analysis quantified associations among the longitudinal risk factor trajectories. Growth in latent glycaemia was positively correlated with systolic blood pressure and negatively correlated with HDL cholesterol. The goodness-of-fit analysis indicates reasonable fit to the data. Conclusions This is the first statistical model that estimates trajectories of metabolic risk factors simultaneously for diabetes to predict joint correlated risk factor trajectories. This can inform comparisons of the effectiveness and cost-effectiveness of preventive interventions, which aim to modify metabolic risk factors. [ABSTRACT FROM AUTHOR]

Aim To investigate the association between pulse pressure and risk of hospitalization for cardiovascular events among people with Type 2 diabetes. Methods A population-based case-control study was carried out using data from medical databases. A total of 588 people with Type 2 diabetes from 18 general practices in Cambridgeshire recorded a first hospitalization for a cardiovascular event between 2009 and 2011, and a total of 2920 age-matched, gender-matched and practice-matched control subjects with Type 2 diabetes were selected based on risk-set sampling. Pulse pressure was assessed before admission in 2008-2009. Further dose-response relationships between pulse pressure and risks were explored using spline models. Results There was a non-linear relationship between pulse pressure and the risk of hospitalization for a cardiovascular event ( P < 0.001 for linearity test). The pulse pressure associated with the lowest risk of hospitalization for a cardiovascular event was 61 (95% CI 57-63) mmHg. Conclusion In people with Type 2 diabetes, pulse pressure is a good predictor of risk of hospitalization for cardiovascular events. The risk is lowest with a pulse pressure of 57-63 mmHg. [ABSTRACT FROM AUTHOR]

Aim To examine the feasibility and potential health impact of a diabetes self-management education and support intervention involving peer support on glycaemic control and diabetes distress. Methods A total of 41 South-Asian adults with Type 2 diabetes were recruited for a 24-week diabetes self-management education and support pilot intervention involving peer support. The intervention consisted of six weekly education sessions co-facilitated by a certified diabetes educator and two peer leaders, followed by 18 weekly support sessions facilitated by two peer leaders. Education sessions were guided entirely by participants' self-management questions and also emphasized goal setting and action planning. Support sessions were based on empowerment principles and participants discussed self-management challenges, shared emotions, asked self-management questions, problem-solved in a group, set goals, and developed and evaluated action plans. Feasibility outcomes included recruitment and retention. Primary health-related outcomes included HbA1c levels and diabetes distress (measured at baseline, 6 and 24 weeks). Programme satisfaction was also assessed. Results Pre-established criteria for recruitment and retention were met. Paired t-tests showed no changes in HbA1c and diabetes distress at 6 weeks. At 24 weeks, HbA1c levels deteriorated [54 mmol/mol (7.1%) vs 61 mmol/mol (7.7%)] while diabetes distress scores improved (2.0 vs 1.7). Conclusions Although feasible, findings suggest this peer-support model may have a positive impact on diabetes distress, but not on HbA1c levels. Culturally responsive modifications (e.g. intervention location) to the pilot model are needed and could lead to more favourable health outcomes for this community. Such a re-designed peer-support model will require further investigation. [ABSTRACT FROM AUTHOR]

Background: Public health strategies to lower cardiovascular disease (CVD) risk involve reducing dietary saturated fatty acid (SFA) intake to ≤10% of total energy (%TE). However, the optimal type of replacement fat is unclear. Objective: We investigated the substitution of 9.5-9.6%TE dietary SFAs with either monounsaturated fatty acids (MUFAs) or n-6 (v-6) polyunsaturated fatty acids (PUFAs) on vascular function and other CVD risk factors. Design: In a randomized, controlled, single-blind, parallel-group dietary intervention, 195 men and women aged 21-60 y from the United Kingdom with moderate CVD risk (≥50% above the population mean) followed one of three 16-wk isoenergetic diets (%TE target compositions, total fat:SFA:MUFA:n-6 PUFA) that were rich in SFAs (36:17:11:4, n = 65), MUFAs (36:9:19:4, n = 64), or n-6 PUFAs (36:9:13:10, n = 66). The primary outcome measure was flow-mediated dilatation; secondary outcome measures included fasting serum lipids, microvascular reactivity, arterial stiffness, ambulatory blood pressure, and markers of insulin resistance, inflammation, and endothelial activation. Results: Replacing SFAs with MUFAs or n-6 PUFAs did not affect the percentage of flow-mediated dilatation (primary endpoint) or other measures of vascular reactivity. Of the secondary outcome measures, substitution of SFAs with MUFAs attenuated the increase in night systolic blood pressure (-4.9 mm Hg, P = 0.019) and reduced E-selectin (-7.8%, P = 0.012). Replacement with MUFAs or n-6 PUFAs lowered fasting serum total cholesterol (-8.4% and -9.2%, respectively), low-density lipoprotein cholesterol (-11.3% and -13.6%), and total cholesterol to high-density lipoprotein cholesterol ratio (-5.6% and -8.5%) (P ≤ 0.001). These changes in low-density lipoprotein cholesterol equate to an estimated 17-20% reduction in CVD mortality. Conclusions: Substitution of 9.5-9.6%TE dietary SFAs with either MUFAs or n-6 PUFAs did not significantly affect the percentage of flow-mediated dilatation or other measures of vascular function. However, the beneficial effects on serum lipid biomarkers, blood pressure, and E-selectin offer a potential public health strategy for CVD risk reduction. This trial was registered at www.clinicaltrials.gov as NCT01478958. [ABSTRACT FROM AUTHOR]

BACKGROUND: Controversy surrounds the effectiveness of dietary guidelines for cardiovascular disease (CVD) prevention in healthy middle-aged and older men and women. OBJECTIVE: The objective was to compare effects on vascular and lipid CVD risk factors of following the United Kingdom dietary guidelines with a traditional British diet (control). DESIGN: With the use of a parallel-designed randomized controlled trial in 165 healthy nonsmoking men and women (aged 40-70 y), we measured ambulatory blood pressure (BP) on 5 occasions, vascular function, and CVD risk factors at baseline and during 12 wk after random assignment to treatment. The primary outcomes were differences between treatments in daytime ambulatory systolic BP, flow-mediated dilation, and total cholesterol/HDL cholesterol. Secondary outcomes were differences between treatment in carotid-to-femoral pulse wave velocity, high-sensitivity C-reactive protein, and a measure of insulin sensitivity (Revised Quantitative Insulin Sensitivity Check Index). RESULTS: Data were available on 162 participants, and adherence to the dietary advice was confirmed from dietary records and biomarkers of compliance. In the dietary guidelines group (n = 80) compared with control (n = 82), daytime systolic BP was 4.2 mm Hg (95% CI: 1.7, 6.6 mm Hg; P < 0.001) lower, the treatment effect on flow-mediated dilation [-0.62% (95% CI: -1.48%, 0.24%)] was not significant, the total cholesterol:HDL cholesterol ratio was 0.13 (95% CI: 0, 0.26; P = 0.044) lower, pulse wave velocity was 0.29 m/s (95% CI: 0.07, 0.52 m/s; P = 0.011) lower, high-sensitivity C-reactive protein was 36% (95% CI: 7%, 48%; P = 0.017) lower, the treatment effect on the Revised Quantitative Insulin Sensitivity Check Index [2% (95% CI: -2%, 5%)] was not significant, and body weight was 1.9 kg (95% CI: 1.3, 2.5 kg; P < 0.001) lower. Causal mediated effects analysis based on urinary sodium excretion indicated that sodium reduction explained 2.4 mm Hg (95% CI: 1.0, 3.9 mm Hg) of the fall in blood pressure. CONCLUSION: Selecting a diet consistent with current dietary guidelines lowers BP and lipids, which would be expected to reduce the risk of CVD by one-third in healthy middle-aged and older men and women. This study is registered at www.isrctn.com as 92382106. [ABSTRACT FROM AUTHOR]