Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

The MR-Base platform supports systematic causal inference across the human phenome.

Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (http://www.mrbase.org): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.Supported by Cancer Research UK grant C18281/A19169 (the Integrative Cancer Epidemiology Programme) and the Roy Castle Lung Cancer Foundation (2013/18/Relton). The Medical Research Council Integrative Epidemiology Unit is supported by grants MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8. PCH is supported by a Cancer Research UK Population Research Postdoctoral Fellowship (C52724/A20138). Jack Bowden is supported by a MRC Methodology Research Fellowship (grant MR/N501906/1). DME supported by the NHMRC APP1125200, APP1137714. GH is supported by Wellcome (208806/Z/17/Z)

Measurements of elliptic and triangular flow in high-multiplicity 3^{3}He++Au collisions at sNN=200\sqrt{s_{_{NN}}}=200 GeV

We present the first measurement of elliptic ($v_2$) and triangular ($v_3$) flow in high-multiplicity $^{3}$He$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV. Two-particle correlations, where the particles have a large separation in pseudorapidity, are compared in $^{3}$He$+$Au and in $p$$+$$p$ collisions and indicate that collective effects dominate the second and third Fourier components for the correlations observed in the $^{3}$He$+$Au system. The collective behavior is quantified in terms of elliptic $v_2$ and triangular $v_3$ anisotropy coefficients measured with respect to their corresponding event planes. The $v_2$ values are comparable to those previously measured in $d$$+$Au collisions at the same nucleon-nucleon center-of-mass energy. Comparison with various theoretical predictions are made, including to models where the hot spots created by the impact of the three $^{3}$He nucleons on the Au nucleus expand hydrodynamically to generate the triangular flow. The agreement of these models with data may indicate the formation of low-viscosity quark-gluon plasma even in these small collision systems.Comment: 630 authors, 9 pages, 4 figures, 2 tables. v2 is the version accepted for publication by Physical Review Letters. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Transverse energy production and charged-particle multiplicity at midrapidity in various systems from sNN=7.7\sqrt{s_{NN}}=7.7 to 200 GeV

Measurements of midrapidity charged particle multiplicity distributions, $dN_{\rm ch}/d\eta$, and midrapidity transverse-energy distributions, $dE_T/d\eta$, are presented for a variety of collision systems and energies. Included are distributions for Au$+$Au collisions at $\sqrt{s_{_{NN}}}=200$, 130, 62.4, 39, 27, 19.6, 14.5, and 7.7 GeV, Cu$+$Cu collisions at $\sqrt{s_{_{NN}}}=200$ and 62.4 GeV, Cu$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV, U$+$U collisions at $\sqrt{s_{_{NN}}}=193$ GeV, $d$$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV, $^{3}$He$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV, and $p$$+$$p$ collisions at $\sqrt{s_{_{NN}}}=200$ GeV. Centrality-dependent distributions at midrapidity are presented in terms of the number of nucleon participants, $N_{\rm part}$, and the number of constituent quark participants, $N_{q{\rm p}}$. For all $A$$+$$A$ collisions down to $\sqrt{s_{_{NN}}}=7.7$ GeV, it is observed that the midrapidity data are better described by scaling with $N_{q{\rm p}}$ than scaling with $N_{\rm part}$. Also presented are estimates of the Bjorken energy density, $\varepsilon_{\rm BJ}$, and the ratio of $dE_T/d\eta$ to $dN_{\rm ch}/d\eta$, the latter of which is seen to be constant as a function of centrality for all systems.Comment: 706 authors, 32 pages, 20 figures, 34 tables, 2004, 2005, 2008, 2010, 2011, and 2012 data. v2 is version accepted for publication in Phys. Rev.

Anticipated impact of the 2009 Four Corners raid and arrests

Archaeological looting on United States federal land has been illegal for over a century. Regardless, the activity has continued in the Four Corners region. This paper discusses how the 1979 Archaeological Resources Protection Act (ARPA) can be viewed as sumptuary law, and within a sumptuary context, subversion can be anticipated. An analysis of 1986 and June 2009 federal raids in the Four Corners will exemplify this point by identifying local discourses found in newspapers both before and after each raid, which demonstrate a sumptuary effect. Ultimately, this paper concludes that looting just adapted, rather than halted, after each federal raid and that understanding this social context of continued local justification and validation of illegal digging is a potential asset for cultural resource protection

Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis

Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND