| 1. |
- Liu, Kui, et al.
(författare)
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Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans
- 2009
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 119:4, s. 911-923
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Tidskriftsartikel (refereegranskat)abstract
- Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody-induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that maybe responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody-induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family,which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody-induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms,some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody-induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus.
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| 2. |
- Sánchez, Elena, et al.
(författare)
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Association of a CD24 Gene Polymorphism with Susceptibility to Systemic Lupus Erythematosus
- 2007
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 56:9, s. 3080-3086
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To determine the potential role of the CD24 A57V gene polymorphism in systemic lupus erythematosus (SLE). Methods. We studied 3 cohorts of Caucasian patients and controls. The Spanish cohort included 696 SLE patients and 539 controls, the German cohort included 257 SLE patients and 317 controls, and the Swedish cohort included 310 SLE patients and 247 controls. The CD24 A57V polymorphism was genotyped by polymerase chain reaction, using a predeveloped TaqMan allele discrimination assay. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results. In the Spanish cohort there was a statistically significant difference in the distribution of the CD24 V allele between SLE patients and controls (OR 3.6 [95% CI 2.13-6.16], P < 0.0001). In addition, frequency of the CD24 V/V genotype was increased in SLE patients compared with controls (OR 3.7 [95% CI 2.16-6.34], P < 0.00001). We sought to replicate this association with SLE in a German population and a Swedish population. A similar trend was found in the German group. The CD24 V/V genotype and the CD24 V allele were more frequent in SLE patients than in controls, although this difference was not statistically significant. No differences were observed in the Swedish group. A meta-analysis of the Spanish and German cohorts demonstrated that the CD24 V allele has a risk effect in SLE patients (pooled OR 1.25 [95% Cl 1.08-1.46], P = 0.003). In addition, homozygosity for the CD24 V risk allele significantly increased the effect (pooled OR 2.1,9 [95% Cl 1.50-3.22], P = 0.00007). Conclusion. These findings suggest that the CD24 A57V polymorphism plays a role in susceptibility to SLE in a Spanish population.
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| 3. |
- Sánchez, Elena, et al.
(författare)
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Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus
- 2009
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:19, s. 3739-3748
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in chronic inflammation and autoimmune disorders. In this study, we aimed to determine the potential role of the IL18 gene in SLE. To define the genetic association of the IL18 and SLE, we have genotyped nine SNPs in an independent set of Spanish cases and controls. The IL18 polymorphisms were genotyped by PCR, using a predeveloped TaqMan allele discrimination assay. Two SNPs were still significant after fine mapping of the IL18 gene. The SNP (rs360719) surviving correction for multiple tests was genotyped in two replication cohorts from Italy and Argentina. After the analysis, a significance with rs360719 C-allele remained across the sets and after the meta-analysis (Pooled OR = 1.37, 95% CI 1.21-1.54, combined P = 3.8E-07, Pc = 1.16E-06). Quantitative real-time PCR was performed to assess IL18 mRNA expression in PBMC from subjects with different IL18 rs360719 genotypes. We tested the effect of the IL18 rs360719 polymorphism on the transcription of IL18 by electrophoretic mobility shift assay and western blot. We found a significant increase in the relative expression of IL18 mRNA in individuals carrying the rs360719 C-risk allele; in addition we show that the polymorphism creates a binding site for the transcriptional factor OCT-1. These findings suggest that the novel IL18 rs360719 variant may play an important role in determining the susceptibility to SLE and it could be a key factor in the expression of the IL18 gene.
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| 4. |
- Abdo, A. A., et al.
(författare)
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A limit on the variation of the speed of light arising from quantum gravity effects
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 462:7271, s. 331-334
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Tidskriftsartikel (refereegranskat)abstract
- A cornerstone of Einstein’s special relativity is Lorentz invariance—the postulate that all observers measure exactly the same speed of light in vacuum, independent of photon-energy. While special relativity assumes that there is no fundamental length-scale associated with such invariance, there is a fundamental scale (the Planck scale, lPlanck~1.62×10-33cm or EPlanck = MPlanckc2~1.22×1019GeV), at which quantum effects are expected to strongly affect the nature of space–time. There is great interest in the (not yet validated) idea that Lorentz invariance might break near the Planck scale. A key test of such violation of Lorentz invariance is a possible variation of photon speed with energy. Even a tiny variation in photon speed, when accumulated over cosmological light-travel times, may be revealed by observing sharp features in γ-ray burst (GRB) light-curves. Here we report the detection of emission up to ~31GeV from the distant and short GRB090510. We find no evidence for the violation of Lorentz invariance, and place a lower limit of 1.2EPlanck on the scale of a linear energy dependence (or an inverse wavelength dependence), subject to reasonable assumptions about the emission (equivalently we have an upper limit of lPlanck/1.2 on the length scale of the effect). Our results disfavour quantum-gravity theories in which the quantum nature of space–time on a very small scale linearly alters the speed of light.
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| 5. |
- Abdo, A. A., et al.
(författare)
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BRIGHT ACTIVE GALACTIC NUCLEI SOURCE LIST FROM THE FIRST THREE MONTHS OF THE FERMI LARGE AREA TELESCOPE ALL-SKY SURVEY
- 2009
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 700:1, s. 597-622
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Tidskriftsartikel (refereegranskat)abstract
- The first three months of sky-survey operation with the Large Area Telescope (LAT) onboard the Fermi Gamma-Ray Space Telescope reveal 132 bright sources at |b| > 10 degrees with test statistic greater than 100 ( corresponding to about 10 sigma). Two methods, based on the CGRaBS, CRATES, and BZCat catalogs, indicate high-confidence associations of 106 of these sources with known active galactic nuclei (AGNs). This sample is referred to as the LAT Bright AGN Sample (LBAS). It contains two radio galaxies, namely, Centaurus A and NGC 1275, and 104 blazars consisting of 58 flat spectrum radio quasars (FSRQs), 42 BL Lac objects, and 4 blazars with unknown classification. Four new blazars were discovered on the basis of the LAT detections. Remarkably, the LBAS includes 10 high-energy-peaked BL Lacs (HBLs), sources which were previously difficult to detect in the GeV range. Another 10 lower-confidence associations are found. Only 33 of the sources, plus two at |b| < 10 degrees, were previously detected with Energetic Gamma-Ray Experiment Telescope( EGRET), probably due to variability. The analysis of the gamma-ray properties of the LBAS sources reveals that the average GeV spectra of BL Lac objects are significantly harder than the spectra of FSRQs. No significant correlation between radio and peak gamma-ray fluxes is observed. Blazar log N-log S distributions and luminosity functions are constructed to investigate the evolution of the different blazar classes, with positive evolution indicated for FSRQs but none for BL Lacs. The contribution of LAT blazars to the total extragalactic gamma-ray intensity is estimated.
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| 6. |
- Abdo, A. A., et al.
(författare)
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FERMI/LARGE AREA TELESCOPE BRIGHT GAMMA-RAY SOURCE LIST
- 2009
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Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 183:1, s. 46-66
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Tidskriftsartikel (refereegranskat)abstract
- Following its launch in 2008 June, the Fermi Gamma-ray Space Telescope (Fermi) began a sky survey in August. The Large Area Telescope (LAT) on Fermi in three months produced a deeper and better resolved map of the gamma-ray sky than any previous space mission. We present here initial results for energies above 100 MeV for the 205 most significant (statistical significance greater than similar to 10 sigma) gamma-ray sources in these data. These are the best characterized and best localized point-like (i.e., spatially unresolved) gamma-ray sources in the early mission data.
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| 7. |
- Abdo, A. A., et al.
(författare)
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Fermi Observations of High-Energy Gamma-Ray Emission from GRB 080916C
- 2009
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 323:5922, s. 1688-1693
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Tidskriftsartikel (refereegranskat)abstract
- Gamma-ray bursts (GRBs) are highly energetic explosions signaling the death of massive stars in distant galaxies. The Gamma-ray Burst Monitor and Large Area Telescope onboard the Fermi Observatory together record GRBs over a broad energy range spanning about 7 decades of gamma-ray energy. In September 2008, Fermi observed the exceptionally luminous GRB 080916C, with the largest apparent energy release yet measured. The high-energy gamma rays are observed to start later and persist longer than the lower energy photons. A simple spectral form fits the entire GRB spectrum, providing strong constraints on emission models. The known distance of the burst enables placing lower limits on the bulk Lorentz factor of the outflow and on the quantum gravity mass.
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| 8. |
- Abdo, A. A., et al.
(författare)
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Measurement of the Cosmic Ray e(+)+e(-) Spectrum from 20 GeV to 1 TeV with the Fermi Large Area Telescope
- 2009
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 102:Article number: 181101
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Tidskriftsartikel (refereegranskat)abstract
- Designed as a high-sensitivity gamma-ray observatory, the Fermi Large Area Telescope is also an electron detector with a large acceptance exceeding 2 m(2) sr at 300 GeV. Building on the gamma-ray analysis, we have developed an efficient electron detection strategy which provides sufficient background rejection for measurement of the steeply falling electron spectrum up to 1 TeV. Our high precision data show that the electron spectrum falls with energy as E-3.0 and does not exhibit prominent spectral features. Interpretations in terms of a conventional diffusive model as well as a potential local extra component are briefly discussed.
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| 9. |
- Abdo, A. A., et al.
(författare)
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The on-orbit calibration of the Fermi Large Area Telescope
- 2009
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Ingår i: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 32:3-4, s. 193-219
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Tidskriftsartikel (refereegranskat)abstract
- The Large Area Telescope (LAT) on-board the Fermi Gamma-ray Space Telescope began its on-orbit operations on June 23, 2008. Calibrations, defined in a generic sense, correspond to synchronization of trigger signals, optimization of delays for latching data, determination of detector thresholds, gains and responses, evaluation of the perimeter of the South Atlantic Anomaly (SAA), measurements of live time, of absolute time, and internal and spacecraft boresight alignments. Here we describe on-orbit calibration results obtained using known astrophysical sources, galactic cosmic rays, and charge injection into the front-end electronics of each detector. Instrument response functions will be described in a separate publication. This paper demonstrates the stability of calibrations and describes minor changes observed since launch. These results have been used to calibrate the LAT datasets to be publicly released in August 2009.
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| 10. |
- Abelson, Anna-Karin, et al.
(författare)
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STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
- 2009
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 68:11, s. 1746-1753
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.
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