Context:
The p.Leu167del mutation in the APOE gene has been associated with hyperlipidemia.
Objectives:
Our objective was to determine the frequency of p.Leu167del mutation in APOE gene in subjects ...with autosomal dominant hypercholesterolemia (ADH) in whom LDLR, APOB, and PCSK9 mutations had been excluded and to identify the mechanisms by which this mutant apo E causes hypercholesterolemia.
Design:
The APOE gene was analyzed in a case-control study.
Setting:
The study was conducted at a University Hospital Lipid Clinic.
Patients or Other Participants:
Two groups (ADH, 288 patients; control, 220 normolipidemic subjects) were included.
Intervention:
We performed sequencing of APOE gene and proteomic and cellular experiments.
Main Outcome Measure:
To determine the frequency of the p.Leu167del mutation and the mechanism by which it causes hypercholesterolemia.
Results:
In the ADH group, nine subjects (3.1%) were carriers of the APOE c.500_502delTCC, p.Leu167del mutation, cosegregating with hypercholesterolemia in studied families. Proteomic quantification of wild-type and mutant apo E in very low-density lipoprotein (VLDL) from carrier subjects revealed that apo E3 is almost a 5-fold increase compared to mutant apo E. Cultured cell studies revealed that VLDL from mutation carriers had a significantly higher uptake by HepG2 and THP-1 cells compared to VLDL from subjects with E3/E3 or E2/E2 genotypes. Transcriptional down-regulation of LDLR was also confirmed.
Conclusions:
p.Leu167del mutation in APOE gene is the cause of hypercholesterolemia in the 3.1% of our ADH subjects without LDLR, APOB, and PCSK9 mutations. The mechanism by which this mutation is associated to ADH is that VLDL carrying the mutant apo E produces LDLR down-regulation, thereby raising plasma low-density lipoprotein cholesterol levels.
p.Leu167del mutation in APOE is the cause of hypercholesterolemia in the 3.1% of our ADH subjects without LDLR, APOB, and PCSK9 mutations, because VLDL carrying this mutant apo E produces LDLR downregulation.
The association between APOE genotypes and cardiovascular disease (CVD) is partially mediated by LDL-cholesterol concentration but persists after adjusting for lipid levels and other cardiovascular ...risk factors. Data from the Aragon Workers Health Study (AWHS) (n = 4159) and the Lipid Unit at the Hospital Universitario Miguel Servet (HUMS) (n = 3705) were used to investigate the relationship between C-reactive protein (CRP) levels and APOE genotype. Lipoprotein particle and GlycA concentrations were analyzed in a subsample from AWHS. APOE genotyping was carried out by the Sanger method in both cohorts. APOE4 carriers had significantly lower levels of CRP than APOE3 carriers. Furthermore, APOE4 carriers had cholesterol-enriched LDL particles compared to APOE2 carriers. APOE4 carriers also had higher concentrations of small, medium, and large LDL particles. CRP levels were not associated with lipoprotein particle number, size, or composition. GlycA levels were not associated with APOE genotypes. However, GlycA levels were significantly associated with the size and the amount of cholesterol contained in HDL, VLDL, and LDL particles. APOE genotype influences CRP concentration regardless of lipid profile. APOE2 carriers showed the highest CRP levels, followed by APOE3 and APOE4. A more atherogenic lipid profile, but not inflammatory markers could partly explain the higher CVD risk observed in APOE4 carriers.
The aim of our study was to investigate a large cohort of overweight subjects consuming a homogeneous diet to identify the genetic factors associated with weight loss that could be used as predictive ...markers in weight loss interventions. We retrospectively recruited subjects (N = 788) aged over 18 years with a Body Mass Index (BMI) between 25 and 40 kg/m
who were treated at our lipid unit for at least one year from 2008 to 2016, and we also recruited a control group (168 patients) with normal BMIs. All participants received counselling from a nutritionist that included healthy diet and physical activity recommendations. We genotyped 25 single nucleotide variants (SNVs) in 25 genes that were previously associated with obesity and calculated genetic scores that were derived from 25 SNVs. The risk allele in CADM2 showed a higher frequency in overweight and obese subjects than in controls (p = 0.007). The mean follow-up duration was 5.58 ± 2.68 years. Subjects with lower genetic scores showed greater weight loss during the follow-up period. The genetic score was the variable that best explained the variations in weight from the baseline. The genetic score explained 2.4% of weight change variance at one year and 1.6% of weight change variance at the end of the follow-up period after adjusting for baseline weight, sex, age and years of follow-up.
The Feel4Diabetes intervention was a school and community-based intervention aiming to promote healthy lifestyle and tackle obesity and obesity-related metabolic risk factors for the prevention of ...type 2 diabetes (T2D) among families at risk of developing this disease. The current study aims to present the results on lifestyle behaviors obtained from parents during the first year of the Feel4Diabetes intervention. This multicomponent intervention had a cluster randomized design and was implemented in Belgium, Bulgaria, Finland, Greece, Hungary and Spain over two years (2016–2018). Standardized protocols and procedures were used by the participating centers in all countries to collect data on parents’ lifestyle behaviors (diet, physical activity, sedentary behavior). The Feel4Diabetes intervention was registered at clinicaltrials.gov (registration number: NCT02393872). In total, 2110 high-risk parents participated in the baseline and 12-month follow-up examination measurements. Participants allocated to the intervention group reduced their daily consumption of sugary drinks (p = 0.037) and sweets (p = 0.031) and their daily screen time (p = 0.032), compared with the control group. In addition, participants in the intervention group in Greece and Spain increased their consumption of breakfast (p = 0.034) and fruits (p = 0.029), while in Belgium and Finland they increased their water intake (p = 0.024). These findings indicate that the first year of the Feel4Diabetes intervention resulted in the improvement of certain lifestyle behaviors in parents from high-risk families.
Omega-3 poly-unsaturated fatty acids (ω-3 PUFAs) have demonstrated to be beneficial in the prevention of cardiovascular disease, however, the mechanisms by which they perform their cardiovascular ...protection have not been clarified. Intriguingly, some of these protective effects have also been linked to HDL. The hypothesis of this study was that ω-3 PUFAs could modify the protein cargo of HDL particle in a triglyceride non-dependent mode. The objective of the study was to compare the proteome of HDL before and after ω-3 PUFAs supplemented diet.
A comparative proteomic analysis in 6 smoker subjects HDL before and after a 5 weeks ω-3 PUFAs enriched diet has been performed.
Among the altered proteins, clusterin, paraoxonase, and apoAI were found to increase, while fibronectin, α-1-antitrypsin, complement C1r subcomponent and complement factor H decreased after diet supplementation with ω-3 PUFAs. Immunodetection assays confirmed these results. The up-regulated proteins are related to anti-oxidant, anti-inflammatory and anti-atherosclerotic properties of HDL, while the down-regulated proteins are related to regulation of complement activation and acute phase response.
Despite the low number of subjects included in the study, our findings demonstrate that ω-3 PUFAs supplementation modifies lipoprotein containing apoAI (LpAI) proteome and suggest that these protein changes improve the functionality of the particle.
Hypertriglyceridemia (HTG) is a common complex metabolic trait that results of the accumulation of relatively common genetic variants in combination with other modifier genes and environmental ...factors resulting in increased plasma triglyceride (TG) levels. The majority of severe primary hypertriglyceridemias is diagnosed in adulthood and their molecular bases have not been fully defined yet. The prevalence of HTG is highly variable among populations, possibly caused by differences in environmental factors and genetic background. However, the prevalence of very high TG and the frequency of rare mutations causing HTG in a whole non-selected population have not been previously studied.
The total of 23,310 subjects over 18 years from a primary care-district in a middle-class area of Zaragoza (Spain) with TG >500 mg/dL were selected to establish HTG prevalence. Those affected of primary HTG were considered for further genetic analysis. The promoters, coding regions and exon-intron boundaries of LPL, LMF1, APOC2, APOA5, APOE and GPIHBP1 genes were sequenced. The frequency of rare variants identified was studied in 90 controls.
One hundred ninety-four subjects (1.04%) had HTG and 90 subjects (46.4%) met the inclusion criteria for primary HTG. In this subgroup, nine patients (12.3%) were carriers of 7 rare variants in LPL, LMF1, APOA5, GPIHBP1 or APOE genes. Three of these mutations are described for the first time in this work. The presence of a rare pathogenic mutation did not confer a differential phenotype or a higher family history of HTG.
The prevalence of rare mutations in candidate genes in subjects with primary HTG is low. The low frequency of rare mutations, the absence of a more severe phenotype or the dominant transmission of the HTG would not suggest the use of genetic analysis in the clinical practice in this population.
The Mediterranean Diet (MedDiet) is the dietary pattern par excellence for managing and preventing metabolic diseases, such as Type 2 Diabetes (T2DM). The MedDiet incorporates spices and aromatic ...herbs, which are abundant sources of bioactive compounds. The aim of this study was to analyze the effect of all aromatic herbs and spices included in the MedDiet, such as black cumin, clove, parsley, saffron, thyme, ginger, black pepper, rosemary, turmeric, basil, oregano, and cinnamon, on the glycemic profile in T2DM subjects.
PubMed, Web of Science, and Scopus databases were searched for interventional studies investigating the effect of these aromatic herbs and spices on the glycemic profile in T2DM subjects.
This systematic review retrieved 6958 studies, of which 77 were included in the qualitative synthesis and 45 were included in the meta-analysis. Our results showed that cinnamon, turmeric, ginger, black cumin, and saffron significantly improved the fasting glucose levels in T2DM subjects. The most significant decreases in fasting glucose were achieved after supplementation with black cumin, followed by cinnamon and ginger, which achieved a decrease of between 27 and 17 mg/dL.
Only ginger and black cumin reported a significant improvement in glycated hemoglobin, and only cinnamon and ginger showed a significant decrease in insulin.
Background and Aims
Many addictive substances, such as tobacco and alcohol, influence atherosclerosis development. Whether or not tobacco's pro‐atherosclerotic effect is influenced by alcohol ...consumption is unknown. We aimed to estimate the impact of alcohol intake on the presence of subclinical atherosclerosis in femoral arteries in smoking and non‐smoking middle‐aged men.
Design, Setting and Participants
Cross‐sectional analysis of a subset of the Aragon Workers Health Study (AWHS), comprising 2099 men with mean age 50.9 years without previous cardiovascular disease.
Measurements
The presence of plaques in femoral arteries was assessed by high‐resolution sonography. Self‐reported alcohol consumption over the previous year was measured with a food frequency questionnaire. The sample was divided into four groups according to their daily grams of alcohol consumption ≤ 1 (abstainers), ≥ 2 to < 30, ≥ 30 to < 60 and ≥ 60 g/day. Participants were divided on ever‐smoking (current and former) versus never‐smoking strata in the main analysis.
Findings
We did not find a significant association between the different levels of alcohol intake and the likelihood of developing femoral artery atherosclerosis in never‐smokers. Ever‐smoking was positively associated with femoral atherosclerosis overall odds ratio (OR) = 3.00; 95% confidence interval (CI) = 2.40, 3.74; P < 0.001 and within each level of alcohol consumption. Atherosclerosis was lower in ever‐smokers who consumed 2 g/day or more but less than 30 g/day with respect to those ever‐smokers who were abstainers (OR = 0.70; 95% CI = 0.49, 0.99; P < 0.05). However, among these ever‐smokers, atherosclerosis prevalence was still higher than among never‐smokers who consumed alcohol in the same amount (2 g/day or more but less than 30 g/day) (OR = 2.73; 95% CI = 2.07, 3.61; P < 0.001).
Conclusions
Among middle‐aged men, moderate alcohol consumption appears to be associated with lower prevalence of femoral artery subclinical atherosclerosis compared with alcohol abstinence only in ever‐smokers.
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