Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

6-6-20, Mme Gouraud-Morris et [Raoul] Paoli [démonstration de lancer de javelot, stade Elisabeth] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 59568

Mme [Violette] Gouraud-Morris [nageuse, 1er août 1920, Bassin Niclausse à Paris, La Villette] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 60309

Morris Norman collection, 1863-1971, n.d.

Morris Norman is a chartered accountant and partner at Norman, Goldberg & Co. LLP, an accounting firm in Toronto. He is an avid collector of Canadiana and generously donates much of the material he acquires to various Archives.

Architecture at the service of ideology : William Morris, the Anglican Church and the destruction, restoration and protection of medieval architecture in victorian England

Résumé Cet ouvrage examine les fondements du mouvement de conservation architecturale moderne. Dans ce contexte, la création de la « Society for the Protection of Ancient Buildings » par William Morris est considéré comme le point culminant d’un processus historique qui mena à l’apparition du mouvement. Sa genèse est présentée comme ayant été le résultat d’une confrontation entre deux visions utopiques du moyen-âge; celle de l’Église Anglicane et celle de William Morris. Un survol détaillé des origines, des résultats et des effets de la « Renaissance Gothique » ouvre tout grand sur les sources littéraires, idéologiques et religieuses qui y donnèrent sa force. Les grands programmes de restaurations qui ont vu le jour en Angleterre à l’ère victorienne sont examinés en relation avec l’Église Anglicane et caractérisés par les motivations idéologiques de celle-ci. Bien que ce memoire ne réussit pas à démontré de manière sans équivoque que la création du mouvement de conservation architectural moderne par Morris fut essentiellement en reaction au programme idéologique de l’Église Anglicane au dix-neuvième siècle, nous y retrouvons néanmoins une réévaluation des causes et de l’impact de la « Renaissance Gothique » qui, de manière significative, allaient à l’encontre des croyances et des principes les plus chers à Morris. Il existe une quantité admirable d’ouvrages examinant les travaux et l’impact de William Morris en littérature et en arts, ainsi que son activisme socialiste. Cependant, il serait juste de constater qu’en comparaison, la grande contribution qu’il apporta à la protection de l’architecture patrimoniale a certainement été négligée dans les publications à son sujet. Ce projet de recherche examine les éléments et les conditions qui ont motivé Morris à créer un mouvement qui encore aujourd’hui continue de croitre en importance et en influence.

Earl of Aylesford v Morris (1873)

A Characteristic of a landmark case is that it stands for a proposition of law. In Earl of Aylesford v Morris,1 Lord Selborne held that where there existed an inequality between contracting parties, with weakness on one side and an extortionate advantage taken of that weakness on the other, the contract could not stand unless the party claiming the benefit of the contract could rebut the presumption by establishing that the transaction was ‘fair, just and reasonable’. This chapter examines the historical circumstances behind the formulation of this proposition.