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A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Introduction The function of arterial baroreflex (ABR), also expressed by baroreflex sensitivity (BRS), contributes importantly to the regulation of cardiovascular activities. The dysfunction of ABR has been linked to increased [...], The present study was designed to test the hypothesis that a small dose of ketanserin, which enhances baroreflex activity, prevents the early lesions of atherosclerosis. In experiment 1, baroreflex sensitivity (BRS) was measured in 31 spontaneously hypertensive rats (SHRs) in a conscious state using a computerized blood pressure monitoring system. Four weeks later, the rats were administered vitamin [D.sub.3] and fed a high-cholesterol diet for 8 weeks to induce atherosclerosis. Then their hearts and aortae were removed for pathological examination. A negative correlation was found between BRS and the scores of coronary (r = -0.460, P < 0.01) and aortic atherosclerosis (r = -0.448, P < 0.05) in SHR. In experiment 2, SHRs were divided into 3 groups (n = 10 in each group) and received a dose of ketanserin of 0.3, 1.0, and 3.0 mg/kg (i.g.), respectively. At the smallest dose (0.3 mg/kg), ketanserin did not lower blood pressure but enhanced BRS. In experiment 3, SHRs were administered vitamin [D.sub.3], fed a high-cholesterol diet, and simultaneously treated with low-dose ketanserin. The atherosclerosis scores of the treatment group were significantly lower than those of the control group (coronary score: 0.90 ± 0.14 vs. 1.76 ± 0.27, P < 0.05; aortic scores: 1.00 ± 0.39 vs. 2.18 ± 0.41, P < 0.05). In experiment 4, male New Zealand White rabbits were fed a high-cholesterol diet and treated with low-dose ketanserin at the same time. The atherosclerosis scores of the treatment group were significantly lower than those of the control group (aortic scores: 0.26 ± 0.20 vs. 0.60 ± 0.31, P < 0.05). In conclusion, the present study demonstrated, for the first time, that low-dose ketanserin prevented the development of atherosclerosis independent of its blood pressure lowering action in SHRs and New Zealand White rabbits at least in part via enhancement of arterial baroreflex function. Key words: atherosclerosis, baroreflex, spontaneously hypertensive rats, rabbit, ketanserin. La presente etude a eu pour objectif de verifier l'hypothese qu'une faible dose de ketanserine, qui stimule l'activite du baroreflexe, a pre;venu les lesions precoces de l'atherosclerose. Dans l'experience 1, on a mesure; la sensibilite du baroreflexe (SBR) chez 31 rats spontaneement hypertendus (RSH) eveillees, en utilisant un systeme informatise: de surveillance de la pression arterielle. Quatre semaines plus tard, on a administre de la vitamine [D.sub.3] aux rats, et on les a soumis a une diete riche en cholesterol pendant 8 semaines pour induire l'atherosclerose. On a ensuite preleve les coeurs et les aortes pour les soumettre a un examen pathologique. On a trouve une correlation negative entre la SBR et les scores coronaire (r =0,460, P < 0,01) et aortique (r = -0,448,P 0< 0,05) de l'atherosclerose. Dans l'experience 2, on a divise les RSH en trois groupes (n =10 dans chaque groupe) et on leur a administre une dose de ketanserine de 0,3, 1,0 et 3,0 mg/kg (i.g.) respectivement. A la plus faible dose (0,3 mg/kg), la ketanserine n'a pas abaisse la PA, mais a augmente la SBR. Dans l'expeerience 3, on a administer de la vitamine D3 aux RSH et on les a soumis a la diete riche en cholesterol, en plus de les traiter avec la faible dose de ketanserine. Les scores d'atheerosclerose du groupe traite ont etee significativement plus faibles que ceux du groupe teemoin (scores coronaires : 0,90 ± 0,14 par rapport a 1,76 ± 0,27, P < 0,05 ; scores aortiques 1,00 ± 0,39 par rapport a 2,18 ± 0,41, P < 0,05). Dans l'experience 4, on a soumis des lapins neo-zeelandais blancs males (NZB) a la diete riche en cholesterol et on les a traites simultanement avec la faible dose de ketanserine. Les scores de l'atherosclerose du groupe traite ont ete significativement plus faibles que ceux du groupe temoin (scores aortiques : 0,26 ± 0,20 contre 0,60 ± 0,31, P < 0,05). En conclusion, cette etude est la premiere a demontrer qu'une faible dose de ketanserine a prevenu le developpement de l'atherosclerose, independamment de son action d'abaissement de la PA, chez les RSH et les lapins NZB, en partie du moins, en stimulant la fonction du baroreflexe arteriel. Mots-cles: atherosclerose, baroreflexe, rats spontanement hypertendus, lapin, ketanserine. [Traduit par la Redaction]

Introduction Hypertension is a major risk factor for cardiovascular mortality and morbidity through its effects on target organs like the brain, heart, and kidney (Karpha and Lip 2006). End-organ damage [...], Sirt1 is a human homologue of the silent information regulator factor 2 (Sir2) and has an [NAD.sup.+]-dependent histone deacetylase activity. This protein is reported to have a pathogenetic role in muscle differentiation, diabetic nephropathy, and heart failure. In this study, we investigated the expression of sirt1 in spontaneously hypertensive rat (SHR) to obtain insight into the function of sirt1 in hypertensive cardiovascular hypertrophy. The gene and protein expression of sirt1 was increased in the heart in SHR compared with normotensive WKY rats. Sirt1 mRNA was not different in the aorta between SHR and WKY rats. Sirt1 mRNA expression in heart and aorta was not related to hemodynamic parameters in SHR. Hypertensive left ventricular hypertrophy was significantly and positively related to the expression of heart tissue sirt1 mRNA in SHR. Aortic hypertrophy, however, was not related to sirt1 mRNA in the aorta. The increased sirt1 protein expression was accompanied by severe cardiac hypertrophy in older SHR. These results suggest that the increase of sirt1 gene and protein expression in the heart was associated with cardiac hypertrophy. Key words: hypertension, sirt1, left ventricular hypertrophy, spontaneously hypertensive rat. Sir 1 est un homologue humain du regulateur de l'information silencieuse 2 (Sir2) et a une activite histone desacetylase dependante du NAD+. Il semble que cette proteine ait un role pathogene dans la differenciation cellulaire, la nephropathie diabetique et l'insuffisance cardiaque. Dans la presente etude, nous avons examine l'expression de sirtl chez des RSH pour avoir un apercu de la fonction de sirtl dans l'hypertrophie cardiovasculaire hypertensive. L'expression genique et proteique de sirtl a augmente dans le coeur des rats RSH par rapport a celle observee dans le coeur des WKY. L'ARNm de sirtl dans l'aorte n'a pas differe entre les deux souches de rats. L'expression de l'ARNm de sirtl dans le coeur et l'aorte n'a pas ete reliee au parametre hemodynamique chez les RSH. L'hypertrophie ventriculaire gauche hypertensive a ete correlee positivement avec l'expression de l'ARNm de sirtl dans le tissu cardiaque des RSH. Toutefois, l'hypertrophie aortique n'a pas ete associee a l'ARNm de sirtl dans l'aorte. L'augmentation de l'expression proteique de sirtl a ete accompagnee d'une hypertrophie cardiaque severe chez les RSH plus ages. Ces resultats donnent a penser que l'augmentation de l'expression genique et proteique de sirtl dans le coeur est liee a l'hypertrophie cardiaque. Mots-cles : hypertension, sirtl, hypertrophie cardiaque, rat spontanement hypertendu. [Traduit par la Redaction]