Search

Background Evidence on body fat distribution shows opposing effects of waist circumference (WC) and hip circumference (HC) for coronary heart disease (CHD). We aimed to investigate the causality and the shape of such associations. Methods UK Biobank is a prospective cohort study of 0.5 million adults aged 40–69 years recruited between 2006 and 2010. Adjusted hazard ratios (HRs) for the associations of measured and genetically predicted body mass index (BMI), WC, HC and waist-to-hip ratio with incident CHD were obtained from Cox models. Mendelian randomization (MR) was used to assess causality. The analysis included 456 495 participants (26 225 first-ever CHD events) without prior CHD. Results All measures of adiposity demonstrated strong, positive and approximately log-linear associations with CHD risk over a median follow-up of 12.7 years. For HC, however, the association became inverse given the BMI and WC (HR per usual SD 0.95, 95% CI 0.93–0.97). Associations for BMI and WC remained independently positive after adjustment for other adiposity measures and were similar (1.14, 1.13–1.16 and 1.18, 1.15–1.20, respectively), with WC displaying stronger associations among women. Blood pressure, plasma lipids and dysglycaemia accounted for much of the observed excess risk. MR results were generally consistent with the observational, implying causality. Conclusions Body fat distribution measures displayed similar associations with CHD risk as BMI except for HC, which was inversely associated with CHD risk (given WC and BMI). These findings suggest that different measures of body fat distribution likely influence CHD risk through both overlapping and independent mechanisms. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) has a higher prevalence in men than in women and is associated with measures of adiposity and lean mass (LM). However, it remains uncertain whether the risks of AF associated with these measures vary by sex.Methods: Among 477 904 UK Biobank participants aged 40-69 without prior AF, 23 134 incident AF cases were identified (14 400 men, 8734 women; median follow-up 11.1 years). Cox proportional hazards models were used to estimate the covariate adjusted hazard ratios (HRs) describing the association of AF with weight, measures of adiposity [fat mass (FM), waist circumference (WC)] and LM, and their independent relevance, by sex.Results: Weight and WC were independently associated with risk of AF [HR: 1.25 (1.23-1.27) per 10 kg, HR: 1.11 (1.09-1.14) per 10 cm, respectively], with comparable effects in both sexes. The association with weight was principally driven by LM, which, per 5 kg, conferred double the risk of AF compared with FM when mutually adjusted [HR: 1.20 (1.19-1.21), HR: 1.10 (1.09-1.11), respectively]; however, the effect of LM was weaker in men than in women (p-interaction = 4.3 x 10-9). Comparing the relative effects of LM, FM and WC identified different patterns within each sex; LM was the strongest predictor for both, whereas WC was stronger than FM in men but not in women.Conclusions: LM and FM (as constituents of weight) and WC are risk factors for AF. However, the independent relevance of general adiposity for AF was more limited in men than in women. The relevance of both WC and LM suggests a potentially important role for visceral adiposity and muscle mass in AF development. [ABSTRACT FROM AUTHOR]

Aims  Altered left atrial (LA) blood flow characteristics account for an increase in cardioembolic stroke risk in atrial fibrillation (AF). Here, we aimed to assess whether exposure to stroke risk factors is sufficient to alter LA blood flow even in the presence of sinus rhythm (SR). Methods and results  We investigated 95 individuals: 37 patients with persistent AF, who were studied before and after cardioversion [Group 1; median CHA2DS2-VASc = 2.0 (1.5–3.5)]; 35 individuals with no history of AF but similar stroke risk to Group 1 [Group 2; median CHA2DS2-VASc = 3.0 (2.0–4.0)]; and 23 low-risk individuals in SR [Group 3; median CHA2DS2-VASc = 0.0 (0.0–0.0)]. Cardiac function and LA flow characteristics were evaluated using cardiac magnetic resonance. Before cardioversion, Group 1 displayed impaired left ventricular (LV) and LA function, reduced LA flow velocities and vorticity, and a higher normalized vortex volume (all P  < 0.001 vs. Groups 2 and 3). After restoration of SR at ≥4-week post-cardioversion, LV systolic function and LA flow parameters improved significantly (all P  < 0.001 vs. pre-cardioversion) and were no longer different from those in Group 2. However, in the presence of SR, LA flow peak and mean velocity, and vorticity were lower in Groups 1 and 2 vs. Group 3 (all P  < 0.01), and were associated with impaired LA emptying fraction (LAEF) and LV diastolic dysfunction. Conclusion  Patients at moderate-to-high stroke risk display altered LA flow characteristics in SR in association with an LA myopathic phenotype and LV diastolic dysfunction, regardless of a history of AF. [ABSTRACT FROM AUTHOR]

Aims Statins are widely used to prevent cardiovascular events, but little is known about the impact of different risk factors for statin-related myopathy or their relevance to reports of other types of muscle symptom. Methods and results An observational analysis was undertaken of 171 clinically adjudicated cases of myopathy (defined as unexplained muscle pain or weakness with creatine kinase >10× upper limit of normal) and, separately, of 15 208 cases of other muscle symptoms among 58 390 individuals with vascular disease treated with simvastatin for a mean of 3.4 years. Cox proportional hazards models were used to identify independent predictors of myopathy. The rate of myopathy was low: 9 per 10 000 person-years of simvastatin therapy. Independent risk factors for myopathy included: simvastatin dose, ethnicity, sex, age, body mass index, medically treated diabetes, concomitant use of niacin-laropiprant, verapamil, beta-blockers, diltiazem and diuretics. In combination, these risk factors predicted more than a 30-fold risk difference between the top and bottom thirds of a myopathy risk score (hazard ratio : 34.35, 95% CI: 12.73–92.69, P across thirds = 9·1 × 10−48). However, despite the strong association with myopathy, this score was not associated with the other reported muscle symptoms (P across thirds = 0.93). Likewise, although SLCO1B1 genotype was associated with myopathy, it was not associated with other muscle symptoms. Conclusions The absolute risk of simvastatin-related myopathy is low, but individuals at higher risk can be identified to help guide patient management. The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial. [ABSTRACT FROM AUTHOR]

Motivation Common small-effect genetic variants that contribute to human complex traits and disease are typically identified using traditional fixed-effect (FE) meta-analysis methods. However, the power to detect genetic associations under FE models deteriorates with increasing heterogeneity, so that some small-effect heterogeneous loci might go undetected. A modified random-effects meta-analysis approach (RE2) was previously developed that is more powerful than traditional fixed and random-effects methods at detecting small-effect heterogeneous genetic associations, the method was updated (RE2C) to identify small-effect heterogeneous variants overlooked by traditional fixed-effect meta-analysis. Here, we re-appraise a large-scale meta-analysis of coronary disease with RE2C to search for small-effect genetic signals potentially masked by heterogeneity in a FE meta-analysis. Results Our application of RE2C suggests a high sensitivity but low specificity of this approach for discovering small-effect heterogeneous genetic associations. We recommend that reports of small-effect heterogeneous loci discovered with RE2C are accompanied by forest plots and standardized predicted random-effects statistics to reveal the distribution of genetic effect estimates across component studies of meta-analyses, highlighting overly influential outlier studies with the potential to inflate genetic signals. Availability and implementation Scripts to calculate standardized predicted random-effects statistics and generate forest plots are available in the getspres R package entitled from https://magosil86.github.io/getspres/. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Aims PCSK9 genetic variants that have large effects on low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD) have prompted the development of therapeutic PCSK9-inhibition. However, there is limited evidence that PCSK9 variants are associated with ischaemic stroke (IS). Methods and results Associations of the loss-of-function PCSK9 genetic variant (rs11591147; R46L), and five additional PCSK9 variants, with IS and IS subtypes (cardioembolic, large vessel, and small vessel) were estimated in a meta-analysis involving 10 307 IS cases and 19 326 controls of European ancestry. They were then compared with the associations of these variants with LDL-C levels (in up to 172 970 individuals) and CHD (in up to 60 801 CHD cases and 123 504 controls). The rs11591147 T allele was associated with 0.5 mmol/L lower LDL-C level (P=9Γ10-143) and 23% lower CHD risk [odds ratio (OR): 0.77, 95% confidence interval (CI): 0.69-0.87, P=7Γ10-6]. However, it was not associated with risk of IS (OR: 1.04, 95% CI: 0.84-1.28, P=0.74) or IS subtypes. Information from additional PCSK9 variants also indicated consistently weaker effects on IS than on CHD. Conclusion PCSK9 genetic variants that confer life-long lower PCSK9 and LDL-C levels appear to have significantly weaker, if any, associations with risk of IS than with risk of CHD. By contrast, similar proportional reductions in risks of IS and CHD have been observed in randomized trials of therapeutic PCSK9-inhibition. These findings have implications for our understanding of when Mendelian randomization can be relied upon to predict the effects of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Aims Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response. Methods and results A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1, and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE, and SLCO1B1. The largest and most significant effects were with LPA and APOE, but were only 2–3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response. Conclusions Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited. [ABSTRACT FROM PUBLISHER]