Effect of a PCSK9 Inhibitor and a Statin on Cholesterol Efflux Capacity: a Limitation of Current Cholesterol-Lowering Treatments?

Background: Cellular cholesterol efflux is a key step in reverse cholesterol transport that may impact on atherosclerotic cardiovascular risk. The process may be reliant on the availability of apolipoprotein (apo) B-100 containing lipoproteins to accept cholesterol from high-density lipoprotein. Evolocumab and atorvastatin are known to lower plasma apoB-100-containing lipoproteins which could impact on cholesterol efflux capacity (CEC). Methods: We conducted a 2-by-2 factorial trial of the effects of subcutaneous evolocumab (420mg every 2 weeks) and atorvastatin (80mg daily) for 8 weeks on CEC in 81 healthy, normolipidaemic men. The capacity of whole plasma and apoB-depleted plasma, including ATP binding cassette transporter A1 (ABCA1)-mediated and passive diffusion, to efflux cholesterol was measured. Results: Evolocumab and atorvastatin independently decreased whole plasma CEC (main effect P<0.01 for both). However, there were no significant effects of evolocumab and atorvastatin on apoB-depleted plasma, ABCA1-mediated and passive diffusion-mediated CEC (P>0.05 in all). In the three intervention groups combined, the reduction in whole plasma CEC was significantly correlated with the corresponding reduction in plasma apoB-100 concentration (r =0.339, P<0.01). In the evolocumab monotherapy group, the reduction in whole plasma CEC was also significantly correlated with the corresponding reduction in plasma lipoprotein(a) concentration (r =0.487, P<0.05). Conclusions: In normolipidaemic men, evolocumab and atorvastatin decrease the capacity of whole plasma to efflux cellular cholesterol. These effects may be chiefly owing to a fall in the availability of apoB-100 containing lipoproteins. Reduction in circulating lipoprotein(a) may also contribute to the decrease in whole plasma cholesterol efflux with evolocumab monotherapy

Sibling comparisons elucidate the associations between educational attainment polygenic scores and alcohol, nicotine and cannabis.

Background and aimsThe associations between low educational attainment and substance use disorders (SUDs) may be related to a common genetic vulnerability. We aimed to elucidate the associations between polygenic scores for educational attainment and clinical criterion counts for three SUDs (alcohol, nicotine and cannabis).DesignPolygenic association and sibling comparison methods. The latter strengthens inferences in observational research by controlling for confounding factors that differ between families.SettingSix sites in the United States.ParticipantsEuropean ancestry participants aged 25 years and older from the Collaborative Study on the Genetics of Alcoholism (COGA). Polygenic association analyses included 5582 (54% female) participants. Sibling comparisons included 3098 (52% female) participants from 1226 sibling groups nested within the overall sample.MeasurementsOutcomes included criterion counts for DSM-5 alcohol use disorder (AUDSX), Fagerström nicotine dependence (NDSX) and DSM-5 cannabis use disorder (CUDSX). We derived polygenic scores for educational attainment (EduYears-GPS) using summary statistics from a large (> 1 million) genome-wide association study of educational attainment.FindingsIn polygenic association analyses, higher EduYears-GPS predicted lower AUDSX, NDSX and CUDSX [P < 0.01, effect sizes (R2 ) ranging from 0.30 to 1.84%]. These effects were robust in sibling comparisons, where sibling differences in EduYears-GPS predicted all three SUDs (P < 0.05, R2 0.13-0.20%).ConclusionsIndividuals who carry more alleles associated with educational attainment tend to meet fewer clinical criteria for alcohol, nicotine and cannabis use disorders, and these effects are robust to rigorous controls for potentially confounding factors that differ between families (e.g. socio-economic status, urban-rural residency and parental education)

Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer-associated variants.

A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Effect of weight loss on HDL-apoA-II kinetics in the metabolic syndrome

Reduced HDL (high-density lipoprotein) concentration in the MetS (metabolic syndrome) is associated with increased risk of cardiovascular disease and is related to defects in HDL-apoA-II (apolipoprotein A-II) kinetics. Dietary restriction is the most commonly used weight loss strategy. In the present study, we examined the effect of weight loss on HDL-apoA-II kinetics in men with the MetS at the start and end of a 16-week intervention trial of a hypocaloric low-fat diet (n=20) compared with a weight maintenance diet (n=15), using a stable isotope technique and compartmental modelling. The low-fat diet achieved a significant reduction (P<0.01) in BMI (body mass index), abdominal fat compartments and HOMA (homoeostasis model assessment) score compared with weight maintenance. Weight loss also significantly (P<0.05) decreased both the production rate (−23%) and FCR (fractional catabolic rate) (−12%) of HDL-apoA-II, accounting for a net decrease in apoA-II concentration (−9%). Reductions in the HDL-apoA-II production rate were significantly associated with changes in body weight (r=0.683, P<0.01), plasma triacylglycerols (triglycerides) (r=0.607, P<0.01) and, to a lesser extent, plasma insulin (r=0.440, P=0.059) and HOMA-IR (HOMA of insulin resistance) (r=0.425, P=0.069). Changes in the apoA-II FCR were also significantly associated with reductions in visceral adipose tissue mass (r=0.561, P=0.010). In conclusion, in obese men with the MetS, short-term weight loss with a low-fat low-caloric diet lowers plasma apoA-II concentrations by decreasing both the production and catabolism of HDL-apoA-II. The cardiometabolic significance of this effect on HDL metabolism remains to be investigated further

Psychosocial moderation of polygenic risk for cannabis involvement: the role of trauma exposure and frequency of religious service attendance

Cannabis use and disorders (CUD) are influenced by multiple genetic variants of small effect and by the psychosocial environment. However, this information has not been effectively incorporated into studies of gene-environment interaction (GxE). Polygenic risk scores (PRS) that aggregate the effects of genetic variants can aid in identifying the links between genetic risk and psychosocial factors. Using data from the Pasman et al. GWAS of cannabis use (meta-analysis of data from the International Cannabis Consortium and UK Biobank), we constructed PRS in the Collaborative Study on the Genetics of Alcoholism (COGA) participants of European (N: 7591) and African (N: 3359) ancestry. The primary analyses included only individuals of European ancestry, reflecting the ancestral composition of the discovery GWAS from which the PRS was derived. Secondary analyses included the African ancestry sample. Associations of PRS with cannabis use and DSM-5 CUD symptom count (CUDsx) and interactions with trauma exposure and frequency of religious service attendance were examined. Models were adjusted for sex, birth cohort, genotype array, and ancestry. Robustness models were adjusted for cross-term interactions. Higher PRS were associated with a greater likelihood of cannabis use and with CUDsx among participants of European ancestry (p < 0.05 and p < 0.1 thresholds, respectively). PRS only influenced cannabis use among those exposed to trauma (R2: 0.011 among the trauma exposed vs. R2: 0.002 in unexposed). PRS less consistently influenced cannabis use among those who attend religious services less frequently; PRS × religious service attendance effects were attenuated when cross-term interactions with ancestry and sex were included in the model. Polygenic liability to cannabis use was related to cannabis use and, less robustly, progression to symptoms of CUD. This study provides the first evidence of PRS × trauma for cannabis use and demonstrates that ignoring important aspects of the psychosocial environment may mask genetic influences on polygenic traits

Dose-Dependent Effect of Rosuvastatin on VLDL-Apolipoprotein C-III Kinetics in the Metabolic Syndrome

OBJECTIVE - Dysregulated apolipoprotein (apo)C-III metabolism may account for hypertriglyceridemia and increased cardiovascular risk in the metabolic syndrome. This study investigated the dose-dependent effect of rosuvastatin on VLDL apoC-III transport in men with the metabolic syndrome. RESEARCH DESIGN AND METHODS - Twelve men with the metabolic syndrome were studied in a randomized double-blind crossover trial of 5-week intervention periods with placebo, 10 mg rosuvastatin, or 40 mg rosuvastatin, with 2-week placebo washouts between each period. VLDL apoC-III kinetics were examined using a stable isotope method and compartmental modeling at the end of each intervention period. RESULTS - Compared with placebo, there was a significant dose-dependent reduction with rosuvastatin in plasma triglyceride and VLDL apoC-III concentrations. Rosuvastatin significantly (P P P P CONCLUSIONS - In this study, rosuvastatin decreased the production and increased the catabolism of VLDL apoC-III, a mechanism that accounted for the significant reduction in VLDL apoC-III and triglyceride concentrations. This has implications for the management of cardiometabolic risk in obese subjects with the metabolic syndrome

Using polygenic scores for identifying individuals at increased risk of substance use disorders in clinical and population samples

Genome-wide, polygenic risk scores (PRS) have emerged as a useful way to characterize genetic liability. There is growing evidence that PRS may prove useful for early identification of those at increased risk for certain diseases. The current potential of PRS for alcohol use disorders (AUD) remains an open question. Using data from both a population-based sample [the FinnTwin12 (FT12) study] and a high-risk sample [the Collaborative Study on the Genetics of Alcoholism (COGA)], we examined the association between PRSs derived from genome-wide association studies (GWASs) of (1) alcohol dependence/alcohol problems, (2) alcohol consumption, and (3) risky behaviors with AUD and other substance use disorder (SUD) criteria. These PRSs explain similar to 2.5-3.5% of the variance in AUD (across FT12 and COGA) when all PRSs are included in the same model. Calculations of area under the curve (AUC) show PRS provide only a slight improvement over a model with age, sex, and ancestral principal components as covariates. While individuals in the top 20, 10, and 5% of the PRS distribution had greater odds of having an AUD compared to the lower end of the continuum in both COGA and FT12, the point estimates at each threshold were statistically indistinguishable. Those in the top 5% reported greater levels of licit (alcohol and nicotine) and illicit (cannabis and opioid) SUD criteria. PRSs are associated with risk for SUD in independent samples. However, usefulness for identifying those at increased risk in their current form is modest, at best. Improvement in predictive ability will likely be dependent on increasing the size of well-phenotyped discovery samples.Peer reviewe

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB

Associations with photoreceptor thickness measures in the UK Biobank.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness