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821.
822.
Evaluating potential for whole-genome studies in Kosrae, an isolated population in Micronesia 总被引:8,自引:0,他引:8
Bonnen PE Pe'er I Plenge RM Salit J Lowe JK Shapero MH Lifton RP Breslow JL Daly MJ Reich DE Jones KW Stoffel M Altshuler D Friedman JM 《Nature genetics》2006,38(2):214-217
Whole-genome association studies are predicted to be especially powerful in isolated populations owing to increased linkage disequilibrium (LD) and decreased allelic diversity, but this possibility has not been empirically tested. We compared genome-wide data on 113,240 SNPs typed on 30 trios from the Pacific island of Kosrae to the same markers typed in the 270 samples from the International HapMap Project. The extent of LD is longer and haplotype diversity is lower in Kosrae than in the HapMap populations. More than 98% of Kosraen haplotypes are present in HapMap populations, indicating that HapMap will be useful for genetic studies on Kosrae. The long-range LD around common alleles and limited diversity result in improved efficiency in genetic studies in this population and augments the power to detect association of 'hidden SNPs'. 相似文献
823.
Graham RR Kozyrev SV Baechler EC Reddy MV Plenge RM Bauer JW Ortmann WA Koeuth T González Escribano MF;Argentine Spanish Collaborative Groups Pons-Estel B Petri M Daly M Gregersen PK Martín J Altshuler D Behrens TW Alarcón-Riquelme ME 《Nature genetics》2006,38(5):550-555
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity. 相似文献
824.
Bender A Krishnan KJ Morris CM Taylor GA Reeve AK Perry RH Jaros E Hersheson JS Betts J Klopstock T Taylor RW Turnbull DM 《Nature genetics》2006,38(5):515-517
Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% +/- 9.3%; individuals with Parkinson disease, 52.3% +/- 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease. 相似文献
825.
CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer 总被引:19,自引:0,他引:19
Weisenberger DJ Siegmund KD Campan M Young J Long TI Faasse MA Kang GH Widschwendter M Weener D Buchanan D Koh H Simms L Barker M Leggett B Levine J Kim M French AJ Thibodeau SN Jass J Haile R Laird PW 《Nature genetics》2006,38(7):787-793
Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1 . We propose a robust new marker panel to classify CIMP+ tumors. 相似文献
826.
Löbel M Bauer S Meisel C Eisenreich A Kudernatsch R Tank J Rauch U Kühl U Schultheiss HP Volk HD Poller W Scheibenbogen C 《Cellular and molecular life sciences : CMLS》2012,69(18):3101-3113
In this study, we performed a comprehensive analysis of the effect of CCN1 on the migration of human immune cells. The molecule CCN1, produced by fibroblasts and endothelial cells, is considered as an important matrix protein promoting tissue repair and immune cell adhesion by binding various integrins. We recently reported that CCN1 therapy is able to suppress acute inflammation in vivo. Here, we show that CCN1 binds to various immune cells including T cells, B cells, NK cells, and monocytes. The addition of CCN1 in vitro enhances both actin polymerization and transwell migration. Prolonged incubation with CCN1, however, results in the inhibition of migration of immune cells by a mechanism that involves downregulation of PI3Kγ, p38, and Akt activation. Furthermore, we observed that immune cells themselves produce constitutively CCN1 and secretion is induced by pro-inflammatory stimuli. In line with this finding, patients suffering from acute inflammation had enhanced serum levels of CCN1. These findings extend the classical concept of CCN1 as a locally produced cell matrix adhesion molecule and suggest that CCN1 plays an important role in regulating immune cell trafficking by attracting and locally immobilizing immune cells. 相似文献
827.
RA Scott V Lagou RP Welch E Wheeler ME Montasser J Luan R Mägi RJ Strawbridge E Rehnberg S Gustafsson S Kanoni LJ Rasmussen-Torvik L Yengo C Lecoeur D Shungin S Sanna C Sidore PC Johnson JW Jukema T Johnson A Mahajan N Verweij G Thorleifsson JJ Hottenga S Shah AV Smith B Sennblad C Gieger P Salo M Perola NJ Timpson DM Evans BS Pourcain Y Wu JS Andrews J Hui LF Bielak W Zhao M Horikoshi P Navarro A Isaacs JR O'Connell K Stirrups V Vitart C Hayward T Esko E Mihailov RM Fraser T Fall BF Voight 《Nature genetics》2012,44(9):991-1005
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control. 相似文献
828.
Robert Haas 《Annals of science》2013,70(2):113-156
Thomas Urquhart (1611–1660), celebrated for his English translation of Rabelais’ Gargantua et Pantagruel, has earned some notoriety for his eccentric, putatively incomprehensible early book on trigonometry The Trissotetras (1645). The Trissotetras was too impractical to succeed in its own day as a textbook, since it lacked both trigonometric tables and sample calculations. But its current bad reputation is based on literary authors’ amplifications of the verdict prefaced to its 19th century reprinting by one mathematician, William Wallace, who lacked the background to appreciate the book’s historical context. Considering that context (including seventeenth century ‘copious’ prose, and medieval logic and ‘art of memory’), the bad reputation is undeserved: the book is mathematically clear, clever (e.g. in superimposing 16 problems into one diagram), and complete. The Trissotetras may thus be viewed as simply one more of Urquhart’s polymathic projects and involvements – which included education, rise of the middle class, religious and class conflicts, development of science and mathematics, search for patronage, universal language construction, and development of English prose – which serve to make him a lively and instructive intellectual Everyman for his time. 相似文献
829.
Kant’s transcendental method, as applied to natural philosophy, considers the laws of physics as conditions of the possibility of experience. A more modest transcendental project is to show how the laws of motion explicate the concepts of motion, force, and causal interaction, as conditions of the possibility of an objective account of nature. This paper argues that such a project is central to the natural philosophy of Newton, and explains some central aspects of the development of his thinking as he wrote the Principia. One guiding scientific aim was the dynamical analysis of any system of interacting bodies, and in particular our solar system; the transcendental question was, what are the conceptual prerequisites for such an analysis? More specifically, what are the conditions for determining “true motions” within such a system—for posing the question of “the frame of the system of the world” as an empirical question? A study of the development of Newton’s approach to these questions reveals surprising connections with his developing conceptions of force, causality, and the relativity of motion. It also illuminates the comparison between his use of the transcendental method and that of Euler and Kant. 相似文献
830.