462 research outputs found
LowâDensity Lipoprotein Cholesterol Attributable Cardiovascular Disease Risk Is Sex Specific
Background:
Epidemiological studies show that women are generally at lower risk for cardiovascular disease than men. Here, we investigated the sexâspecific differential effect of genetically increased lowâdensity lipoprotein cholesterol (LDLâC) on cardiovascular disease (CVD) and other lipidâassociated diseases.
Methods and Results:
This is a 2âsample Mendelian randomization study that uses individual participant data from 425 043 participants from the UK Biobank, including 229 279 female participants. An 80âvariant LDLâC weighted genetic score was generated. Linear and logistic regression models with interactions were used to identify differences between sexâspecific LDLâC effects on lipids, carotidâintima media thickness, and multiple cardiovascular outcomes such as CVD, ischemic heart disease, peripheral artery disease, heart failure, aortic valve disease, type 2 diabetes, atrial fibrillation, and aortic aneurysm and dissection. After correction for multiple testing, we observed that the genetically increased LDLâC effect on CVD events was sex specific: per SD genetically increased LDLâC, female participants had a higher LDLâC increase but an attenuated CVD risk increase compared with male participants (LDLâC: female participants 0.71 mmol/L, 95% CI, 0.70â0.72 and male participants 0.57 mmol/L, 95% CI, 0.56â0.59. P for interaction: 5.03Ă10â60; CVD: female participants: odds ratio [OR], 1.32; 95% CI 1.24â1.40 and male participants: OR, 1.52; 95% CI, 1.46â1.58. P for interaction: 9.88Ă10â5). We also observed attenuated risks for ischemic heart disease and (nominally for) heart failure in female participants, and genetically increased LDLâC results in higher risk for aortic valve disease in female participants compared with male participants. Genetically increased LDLâC was also associated with an attenuated carotidâintima media thickness increase in female participants. We did not observe other significant attenuations. Sensitivity analyses with an unweighted genetic score and sexâspecific weighted genetic scores showed similar results.
Conclusions:
We found that genetically increased LDLâC has a sexâspecific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. Our observations provide evidence that LDLâC might be a less important determinant of CVD in women compared with men, suggesting that male patients might benefit more from LDLâC targeted therapies for CVD management than female patients and warranting investigations into the sexâspecific relative contribution of risk factors for CVD
Genetically Predicted Neutrophil-to-Lymphocyte Ratio and Coronary Artery Disease: Evidence From Mendelian Randomization.
Inflammation contributes to atherosclerosis and coronary artery disease (CAD). In order to
help identify therapeutic targets, it is important to ascertain whether biomarkers associated
with CAD risk are causal. In a recent meta-analysis of clinical trials, neutrophil-to lymphocyte ratio (NLR) was associated with increased cardiovascular risk 1
. We investigate a
potential causal nature of this relationship by performing Mendelian randomization (MR)
analyse
Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R
Aims: Chronic inflammation is a risk factor for cardiovascular disease (CVD). IL-6 signalling perturbation through IL-6 or IL-6R blockade may have potential benefit on cardiovascular risk. It is unknown whether targeting either IL-6 or IL-6 receptor may result in similar effects on CVD and adverse events. We compared the anticipated effects of targeting IL-6 and IL-6 receptor on cardiometabolic risk and potential side effects. // Methods: We constructed four instruments: two main instruments with genetic variants in the IL6 and IL6R loci weighted for their association with CRP, and two after firstly filtering variants for their association with IL-6 or IL-6R expression. Analyses were performed for coronary artery disease (CAD), ischemic stroke, atrial fibrillation (AF), heart failure, type 2 diabetes (T2D), rheumatoid arthritis (RA), infection endpoints, and quantitative haematological, metabolic and anthropometric parameters. // Results: A 1 mg/L lower CRP by the IL6 instrument was associated with lower CAD (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.77;0.96), AF and T2D risk. A 1 mg/L lower CRP by the IL6R instrument was associated with lower CAD (OR 0.90, 95% CI 0.86;0.95), any stroke and ischemic stroke, AF, RA risk and higher pneumonia risk. The eQTL-filtered results were in concordance with the main results, but with wider confidence intervals. // Conclusions: IL-6 signalling perturbation by either IL6 or IL6R genetic instruments is associated with a similar risk reduction for multiple cardiometabolic diseases, suggesting that both IL-6 and IL-6R are potential therapeutic targets to lower CVD. Moreover, IL-6 rather than IL-6R inhibition might have a more favourable pneumonia risk
Lysosomal acid lipase deficiency – An under-recognized cause of dyslipidaemia and liver dysfunction
Lysosomal acid lipase deficiency â An under-recognized cause of dyslipidaemia and liver dysfunction
AbstractLysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme
Taking One Step Back in Familial Hypercholesterolemia:STAP1 Does Not Alter Plasma LDL (Low-Density Lipoprotein) Cholesterol in Mice and Humans
International audienceSTAP1, encoding for STAP1 (signal transducing adaptor family member 1), has been reported as a candidate gene associated with familial hypercholesterolemia. Unlike established familial hypercholesterolemia genes, expression of STAP1 is absent in liver but mainly observed in immune cells. In this study, we set out to validate STAP1 as a familial hypercholesterolemia gene. Approach and Results: A whole-body Stap1 knockout mouse model (Stap1 -/ - ) was generated and characterized, without showing changes in plasma lipid levels compared with controls. In follow-up studies, bone marrow from Stap1 -/ - mice was transplanted to Ldlr -/ - mice, which did not show significant changes in plasma lipid levels or atherosclerotic lesions. To functionally assess whether STAP1 expression in B cells can affect hepatic function, HepG2 cells were cocultured with peripheral blood mononuclear cells isolated from heterozygotes carriers of STAP1 variants and controls. The peripheral blood mononuclear cells from STAP1 variant carriers and controls showed similar LDLR mRNA and protein levels. Also, LDL (low-density lipoprotein) uptake by HepG2 cells did not differ upon coculturing with peripheral blood mononuclear cells isolated from either STAP1 variant carriers or controls. In addition, plasma lipid profiles of 39 carriers and 71 family controls showed no differences in plasma LDL cholesterol, HDL (high-density lipoprotein) cholesterol, triglycerides, and lipoprotein(a) levels. Similarly, B-cell populations did not differ in a group of 10 STAP1 variant carriers and 10 age- and sex-matched controls. Furthermore, recent data from UK Biobank do not show association between STAP1 rare gene variants and LDL cholesterol
Relationship between moderate-to-vigorous physical activity, abdominal fat and immunometabolic markers in postmenopausal women
AbstractObjectsTo assess the burden of levels of physical activity, non-esterified fatty acids (NEFA), triacylglycerol and abdominal fat on the immunometabolic profile of postmenopausal women.Study designForty-nine postmenopausal women [mean age 59.43 (standard deviation 5.61) years] who did not undertake regular physical exercise participated in this study. Body composition was assessed using dual-energy X-ray absorptiometry, and levels of NEFA, tumour necrosis factor-α, adiponectin, insulin and triacylglycerol were assessed using fasting blood samples. The level of physical activity was assessed using an accelerometer (Actigraph GTX3x), and reported as counts/min, time spent undertaking sedentary activities and time spent undertaking moderate-to-vigorous physical activity (MVPA). The following conditions were considered to be risk factors: (i) sedentary lifestyle (<150min of MVPA per week); (ii) high level (above median) of abdominal fat; and (iii) hypertriacylglycerolaemia (<150mg/dl of triacylglycerol).ResultsIn comparison with active women, sedentary women had higher levels of body fat (%) (p=0.041) and NEFA (p=0.064). Women with higher levels of abdominal fat had impaired insulin resistance (HOMA-IR) (p=0.016) and spent more time undertaking sedentary activities (p=0.043). Moreover, the women with two risk factors or more had high levels of NEFA and HOMA-IR (p<0.05), as well as an eight-fold higher risk of a high level of NEFA, independent of age (p<0.05). No significant relationship was found between levels of physical activity, abdominal fat, tumour necrosis factor-α and adiponectin (p>0.05).ConclusionPostmenopausal women with a combination of hypertriacylglycerolaemia, a high level of abdominal fat and a sedentary lifestyle are more likely to have metabolic disturbances
Identification and Management of Statin-Associated Symptoms in Clinical Practice : Extension of a Clinician Survey to 12 Further Countries
Statins are the first-choice pharmacological treatment for patients with hypercholesterolemia and at risk for cardiovascular disease; however, a minority of patients experience statin-associated symptoms (SAS) and are considered to have reduced statin tolerance. The objective of this study was to establish how patients with SAS are identified and managed in clinical practice in Austria, Belgium, Colombia, Croatia, the Czech Republic, Denmark, Portugal, Switzerland, Russia, Saudi Arabia, Turkey, and the United Arab Emirates.
A cross-sectional survey was conducted (2015-2016) among clinicians (n = 60 per country; Croatia: n = 30) who are specialized/experienced in the treatment of hypercholesterolemia. Participants were asked about their experience of patients presenting with potential SAS and how such patients were identified and treated.
Muscle-related symptoms were the most common presentation of potential SAS (average: 51%; range across countries [RAC] 17-74%); other signs/symptoms included persistent elevation in transaminases. To establish whether symptoms are due to statins, clinicians required rechallenge after discontinuation of statin treatment (average: 77%; RAC 40-90%); other requirements included trying at least one alternative statin. Clinicians reported that half of high-risk patients with confirmed SAS receive a lower-dose statin (average: 53%; RAC 43-72%), and that most receive another non-statin lipid-lowering therapy with or without a concomitant statin (average: 65%; RAC 52-83%).
The specialists and GPs surveyed use stringent criteria to establish causality between statin use and signs or symptoms, and persevere with statin treatment where possible
Low-Cost High-Throughput Genotyping for Diagnosing Familial Hypercholesterolemia
BACKGROUND: Familial hypercholesterolemia (FH) is a common but underdiagnosed genetic disorder characterized by high low-density lipoprotein cholesterol levels and premature cardiovascular disease. Current sequencing methods to diagnose FH are expensive and time-consuming. In this study, we evaluated the accuracy of a low-cost, high-throughput genotyping array for diagnosing FH. METHODS: An Illumina Global Screening Array was customized to include probes for 636 variants, previously classified as FH-causing variants. First, its theoretical coverage was assessed in all FH variant carriers diagnosed through next-generation sequencing between 2016 and 2022 in the Netherlands (n=1772). Next, the performance of the array was validated in another sample of FH variant carriers previously identified in the Dutch FH cascade screening program (n=1268). RESULTS: The theoretical coverage of the array for FH-causing variants was 91.3%. Validation of the array was assessed in a sample of 1268 carriers of whom 1015 carried a variant in LDLR, 250 in APOB, and 3 in PCSK9. The overall sensitivity was 94.7% and increased to 98.2% after excluding participants with variants not included in the array design. Copy number variation analysis yielded a 89.4% sensitivity. In 18 carriers, the array identified a total of 19 additional FH-causing variants. Subsequent DNA analysis confirmed 5 of the additionally identified variants, yielding a false-positive result in 16 subjects (1.3%).CONCLUSIONS: The FH genotyping array is a promising tool for genetically diagnosing FH at low costs and has the potential to greatly increase accessibility to genetic testing for FH. Continuous customization of the array will further improve its performance.</p
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