Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms

Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

Shared common variants in prostate cancer and blood lipids

BACKGROUND: Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors.

METHODS: We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n=50 000) and CVD risk factors (n=200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR.

RESULTS: We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR <0.01). For T2D, we detected one locus adjacent to HNF1B.

CONCLUSIONS: We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.

Spitzer infrared spectrograph point source classification in the Small Magellanic Cloud

The Magellanic Clouds are uniquely placed to study the stellar contribution to dust emission. Individual stars can be resolved in these systems even in the mid-infrared, and they are close enough to allow detection of infrared excess caused by dust. We have searched the Spitzer Space Telescope data archive for all Infrared Spectrograph (IRS) staring-mode observations of the Small Magellanic Cloud (SMC) and found that 209 Infrared Array Camera (IRAC) point sources within the footprint of the Surveying the Agents of Galaxy Evolution in the Small Magellanic Cloud (SAGE-SMC) Spitzer Legacy programme were targeted, within a total of 311 staring-mode observations. We classify these point sources using a decision tree method of object classification, based on infrared spectral features, continuum and spectral energy distribution shape, bolometric luminosity, cluster membership and variability information. We find 58 asymptotic giant branch (AGB) stars, 51 young stellar objects, 4 post-AGB objects, 22 red supergiants, 27 stars (of which 23 are dusty OB stars), 24 planetary nebulae (PNe), 10 Wolf-Rayet stars, 3 H II regions, 3 R Coronae Borealis stars, 1 Blue Supergiant and 6 other objects, including 2 foreground AGB stars. We use these classifications to evaluate the success of photometric classification methods reported in the literature.

Development of polymeric–cationic peptide composite nanoparticles, a nanoparticle-in-nanoparticle system for controlled gene delivery

We report the formulation of novel composite nanoparticles that combine the high transfection efficiency of cationic peptide-DNA nanoparticles with the biocompatibility and prolonged delivery of polylactic acid–polyethylene glycol (PLA-PEG). The cationic cell-penetrating peptide RALA was used to condense DNA into nanoparticles that were encapsulated within a range of PLA-PEG copolymers. The composite nanoparticles produced exhibited excellent physicochemical properties including size <200 nm and encapsulation efficiency >80%. Images of the composite nanoparticles obtained with a new transmission electron microscopy staining method revealed the peptide-DNA nanoparticles within the PLA-PEG matrix. Varying the copolymers modulated the DNA release rate >6 weeks in vitro. The best formulation was selected and was able to transfect cells while maintaining viability. The effect of transferrin-appended composite nanoparticles was also studied. Thus, we have demonstrated the manufacture of composite nanoparticles for the controlled delivery of DNA.

Debating Darwin at the Cape

This paper focuses attention on the fortunes of Darwin's theory among the English-speaking community in Cape Colony during the latter part of the nineteenth century. The paper begins with a review of early encounters with Darwin dwelling particularly on the response of figures like Roderick Noble - professor and editor of the Cape Monthly Magazine, the geologist John Shaw, and Sir Henry Barkly, governor of the colony. Besides these more theoretical responses, Darwin's ideas were also mobilised in a range of scientific inquiries on such subjects as birds and butterflies. But most conspicuous was the use of evolutionary thought-forms in the work of the eminent philologist Wilhelm Bleek, cousin of Darwin's leading German apologist, Ernst Haeckel. The prevailing sense is of a liberal intelligentsia calmly interacting with a novel theory with all due deference. During the 1870s, an address by Langham Dale at the South African Public Library injected new energy into the Darwin discussion. Dale expressed disquiet over some of the anthropological implications of evolution as well as its apparent reductionism, and this stimulated a range of reactions. Several anonymous commentators responded but the most sustained evaluation of Dale's position emanated from the Queenstown physician and later politician, Sir William Bisset Berry. Then, in 1874, copious extracts from John Tyndall's infamous 'Belfast Address' were printed in the Cape Monthly and this added yet further impetus to the debate. Tyndall's seeming materialism bothered a number of readers, not least Hon William Porter, former attorney-general of Cape Colony. To figures like these the materialist extrapolations of radical Darwinians such as Haeckel were deeply disturbing, not just for religious reasons, but because they seemed to destabilise the moral and pedagogic progressivism that lay at the heart of their civilising credo. While reservations about Darwin's proposals were certainly audible, taken in the round Darwinian conversations among the English-speaking literati at the Cape were conducted with liberal sentiments, not least when evolutionary science approached questions of race. For Darwin's writings were seen to confirm a monogenetic account of the origin and unity of the human race, and could readily be called upon to justify the paternalistic ideology that governed colonial affairs.

Does mothers' postnatal depression influence the development of imitation?

Background: Links between mothers' postnatal depression (PND) and children's cognition have been identified in several samples, but the evidence is inconsistent. We hypothesized that PND may specifically interfere with infants' imitation, an early learning ability that features in early mother-infant interaction and is linked to memory, causal understanding and joint attention. 

Methods: A randomly controlled experiment on imitation was embedded into a longitudinal study of a representative sample of firstborn British infants, whose mothers were assessed for depression using the SCAN interview during pregnancy and at 6 months postpartum. At a mean of 12.8 months, 253 infants were presented with two imitation tasks that varied in difficulty, in counterbalanced order. 

Results: The infants of mothers who experienced PND were significantly less likely than other infants in the sample to imitate the modelled actions, showing a 72% reduction in the likelihood of imitation. The association with PND was not explained by sociodemographic adversity, or a history of depression during pregnancy or prior to conception. Mothers' references to infants' internal states during mother-infant interaction at 6 months facilitated imitation at 12 months, but did not explain the link with PND. 

Conclusions: The findings support the hypothesis that associations between PND and later cognitive outcomes may partly derive from effects of the mother's illness on infants' early learning abilities. Support for infants' learning should be considered as an age-appropriate, child-focused component of interventions designed to ameliorate the effects of PND.

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

Introducing the CTA concept

The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project. © 2013 Elsevier B.V. All rights reserved.

Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study.

Introduction The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of ‘isotoxic’ radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable.

Methods and analysis Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years.

Ethics and dissemination The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West—Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally.

Trial registration number NCT01836692; Pre-results.

Addiction to Runx1 is partially attenuated by loss of p53 in the Eµ-Myc lymphoma model

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt's lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ-Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status.