Inhibition of Lipoprotein-Associated Phospholipase A2 Ameliorates Inflammation and Decreases Atherosclerotic Plaque Formation in ApoE-Deficient Mice

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is thought to play modulatory roles in the development of atherosclerosis. Here we evaluated the effects of a specific lp-PLA2 inhibitor on atherosclerosis in ApoE-deficient mice and its associated mechanisms.ApoE-deficient mice fed an atherogenic high-fat diet for 17 weeks were divided into two groups. One group was administered the specific lp-PLA2 inhibitor, darapladib (50 mg/kg/day; p.o.) daily for 6 weeks, while the control group was administered saline. We observed no differences in body weight and serum lipids levels between the two groups at the end of the dietary period. Notably, serum lp-PLA2 activity as well as hs-CRP (C-reactive protein) and IL-6 (Interleukin-6) levels were significantly reduced in the darapladib group, compared with the vehicle group, while the serum PAF (platelet-activating factor) levels were similar between the two groups. Furthermore, the plaque area through the arch to the abdominal aorta was reduced in the darapladib group. Another finding of interest was that the macrophage content was decreased while collagen content was increased in atherosclerotic lesions at the aortic sinus in the darapladib group, compared with the vehicle group. Finally, quantitative RT-PCR performed to determine the expression patterns of specific inflammatory genes at atherosclerotic aortas revealed lower expression of MCP-1, VCAM-1 and TNF-α in the darapladib group. inflammation and decreased plaque formation in ApoE-deficient mice, supporting an anti-atherogenic role during the progression of atherosclerosis

Apolipoprotein E gene polymorphism modifies fasting total cholesterol concentrations in response to replacement of dietary saturated with monounsaturated fatty acids in adults at moderate cardiovascular disease risk

Consumption of ≤10% total energy from fat as saturated fatty acids (SFA) is recommended for cardiovascular disease risk reduction in the UK; however there is no clear guidance on the optimum replacement nutrient. Lipid-associated single-nucleotide polymorphisms (SNPs) have been shown to modify the lipid responses to dietary fat interventions. Hence, we performed a retrospective analysis in 120 participants from the Dietary Intervention and VAScular function (DIVAS) study to investigate whether lipoprotein lipase (LPL) and apolipoprotein E (APOE) SNPs modify the fasting lipid response to replacement of SFA with monounsaturated (MUFA) or n-6 polyunsaturated (PUFA) fatty acids. The DIVAS study was a randomized, single-blinded, parallel dietary intervention study performed in adults with a moderate cardiovascular risk who received one of three isoenergetic diets rich in SFA, MUFA or n-6 PUFA for 16 weeks. After the 16-week intervention, a significant diet-gene interaction was observed for changes in fasting total cholesterol (P = 0.001). For the APOE SNP rs1064725, only TT homozygotes showed a significant reduction in total cholesterol after the MUFA diet (n = 33; -0.71 ± 1.88 mmol/l) compared to the SFA (n = 38; 0.34 ± 0.55 mmol/l) or n-6 PUFA diets (n = 37; -0.08 ± 0.73 mmol/l) (P = 0.004). None of the interactions were statistically significant for the other SNPs. In summary, our findings have demonstrated a greater sensitivity of the APOE SNP rs1064725 to dietary fat composition, with a total cholesterol lowering effect observed following substitution of SFA with MUFA but not n-6 PUFA. Further large intervention studies incorporating prospective genotyping are required to confirm or refute our findings. The trial was registered at www.clinicaltrials.gov as NCT01478958

Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed similar to 250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.Peer reviewe

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention

Discard mitigation increases skate survival in the Bristol Channel

The survival of fish discarded after being caught can be improved by simple gear-based technical measures aimed at reducing discards. We look at the effects of three different codends on the initial health and short-term survival of trawl-caught skate (Rajidae), using a control codend (80 mm diamond mesh used as standard in the fishery) and two experimental codends (100 mm diamond mesh and 100 mm diamond mesh turned on the square). Both experimental nets reduced discarded numbers of fish by ~70%, with no commercial loss. This reduction in discards had an effect in reducing the total weight of the experimental codends by as much as 80%. We also placed 278 skate in onboard holding tanks for 48 h and evaluated the survival rates of fish caught in the different codends. Visual inspection of "health" at time zero was a good indicator of survival, because 86% of skate with a good health score survived (p < 0.01). From a further 1539 skate assessed for health, we show that fish caught in the control codend have the lowest proportional good health score (25%), followed by the 100 mm diamond mesh codend (34%) and the 100 mm square mesh codend (47%). The health of the fish caught is related to codend weight (p = 0.01). We conclude that technical measures aimed at reducing discards have an additional benefit; they indirectly increase discard survival, and the benefits of mitigating discards through by-catch reduction devices may be a more powerful tool in fisheries management than previously thought

Physical activity, dietary intake and metabolic risk factors in non-diabetic daughters of patients with type II diabetes

Background. It has been reported that the offspring of patients with type II diabetes have an adverse metabolic risk profile. This study aimed to investigate the impact of habitual physical activity and diet on metabolic risk factors in the daughters of patients with type II diabetes and control subjects.&lt;p&gt;&lt;/p&gt; Methods. Thirty-nine offspring and 39 age- and sex-matched controls completed physical activity and food intake diaries, during the week preceding a fasting blood sample.&lt;p&gt;&lt;/p&gt; Results. The offspring had higher body mass index, percentage body fat, and waist circumference than the control subjects (all P &#60; 0.01). Fasting glucose and insulin, and insulin sensitivity estimated by the homeostasis model assessment (HOMAIR) method, were also higher in the offspring group (all P &#60; 0.01). Daily energy expenditure was lower (P &#60; 0.0001) in the offspring than control group. Dietary profile was not different between the groups. Daily energy expenditure was significantly correlated with waist circumference, fasting insulin, and HOMAIR (all P &#60; 0.05) in offspring but not controls.&lt;p&gt;&lt;/p&gt; Conclusions. Offspring had a less favourable physical and metabolic profile and were less physically active than control subjects. In offspring, central adiposity and metabolic risk factors were influenced by habitual physical activity to a greater degree than in control subjects.&lt;p&gt;&lt;/p&gt