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A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21 总被引:14,自引:0,他引:14
van Heel DA Franke L Hunt KA Gwilliam R Zhernakova A Inouye M Wapenaar MC Barnardo MC Bethel G Holmes GK Feighery C Jewell D Kelleher D Kumar P Travis S Walters JR Sanders DS Howdle P Swift J Playford RJ McLaren WM Mearin ML Mulder CJ McManus R McGinnis R Cardon LR Deloukas P Wijmenga C 《Nature genetics》2007,39(7):827-829
We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease. 相似文献
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Alterations of the hprt gene in human in vivo-derived 6-thioguanine-resistant T lymphocytes 总被引:1,自引:0,他引:1
Investigations into the extent and significance of somatic gene mutations occurring in vivo in humans have been hampered by the lack of a means of unambiguously defining the mutational origin of in vivo-derived variant cells. Several years ago we proposed that 6-thioguanine-resistant T lymphocytes, present at low frequencies in human peripheral blood, might be useful markers of in vivo somatic mutation. We and others have since described methods for the isolation and study of these unusual cells. The thioguanine-resistant T cell stably lack hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity, suggesting that they are somatic equivalents in normal individuals to cells from individuals with the X-chromosomal hprt Lesch-Nyhan germinal mutation. We now report that in vivo-derived thioguanine-resistant T-cell colonies from a single normal individual show a variety of hprt structural alterations, as determined by Southern blot analysis. This finding demonstrates unequivocally that these cells are genetic mutants and validates their use for fundamental and applied mutational studies in humans. 相似文献
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The lakes of Titan 总被引:1,自引:0,他引:1
Stofan ER Elachi C Lunine JI Lorenz RD Stiles B Mitchell KL Ostro S Soderblom L Wood C Zebker H Wall S Janssen M Kirk R Lopes R Paganelli F Radebaugh J Wye L Anderson Y Allison M Boehmer R Callahan P Encrenaz P Flamini E Francescetti G Gim Y Hamilton G Hensley S Johnson WT Kelleher K Muhleman D Paillou P Picardi G Posa F Roth L Seu R Shaffer S Vetrella S West R 《Nature》2007,445(7123):61-64
The surface of Saturn's haze-shrouded moon Titan has long been proposed to have oceans or lakes, on the basis of the stability of liquid methane at the surface. Initial visible and radar imaging failed to find any evidence of an ocean, although abundant evidence was found that flowing liquids have existed on the surface. Here we provide definitive evidence for the presence of lakes on the surface of Titan, obtained during the Cassini Radar flyby of Titan on 22 July 2006 (T16). The radar imaging polewards of 70 degrees north shows more than 75 circular to irregular radar-dark patches, in a region where liquid methane and ethane are expected to be abundant and stable on the surface. The radar-dark patches are interpreted as lakes on the basis of their very low radar reflectivity and morphological similarities to lakes, including associated channels and location in topographic depressions. Some of the lakes do not completely fill the depressions in which they lie, and apparently dry depressions are present. We interpret this to indicate that lakes are present in a number of states, including partly dry and liquid-filled. These northern-hemisphere lakes constitute the strongest evidence yet that a condensable-liquid hydrological cycle is active in Titan's surface and atmosphere, in which the lakes are filled through rainfall and/or intersection with the subsurface 'liquid methane' table. 相似文献
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Metallo CM Gameiro PA Bell EL Mattaini KR Yang J Hiller K Jewell CM Johnson ZR Irvine DJ Guarente L Kelleher JK Vander Heiden MG Iliopoulos O Stephanopoulos G 《Nature》2012,481(7381):380-384
Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells. 相似文献
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Elachi C Wall S Janssen M Stofan E Lopes R Kirk R Lorenz R Lunine J Paganelli F Soderblom L Wood C Wye L Zebker H Anderson Y Ostro S Allison M Boehmer R Callahan P Encrenaz P Flamini E Francescetti G Gim Y Hamilton G Hensley S Johnson W Kelleher K Muhleman D Picardi G Posa F Roth L Seu R Shaffer S Stiles B Vetrella S West R 《Nature》2006,441(7094):709-713
Cassini's Titan Radar Mapper imaged the surface of Saturn's moon Titan on its February 2005 fly-by (denoted T3), collecting high-resolution synthetic-aperture radar and larger-scale radiometry and scatterometry data. These data provide the first definitive identification of impact craters on the surface of Titan, networks of fluvial channels and surficial dark streaks that may be longitudinal dunes. Here we describe this great diversity of landforms. We conclude that much of the surface thus far imaged by radar of the haze-shrouded Titan is very young, with persistent geologic activity. 相似文献
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Hunt KA Zhernakova A Turner G Heap GA Franke L Bruinenberg M Romanos J Dinesen LC Ryan AW Panesar D Gwilliam R Takeuchi F McLaren WM Holmes GK Howdle PD Walters JR Sanders DS Playford RJ Trynka G Mulder CJ Mearin ML Verbeek WH Trimble V Stevens FM O'Morain C Kennedy NP Kelleher D Pennington DJ Strachan DP McArdle WL Mein CA Wapenaar MC Deloukas P McGinnis R McManus R Wijmenga C van Heel DA 《Nature genetics》2008,40(4):395-402
Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways. 相似文献
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