| 1. |
- Namjou, B., et al.
(författare)
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Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort
- 2011
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 12:4, s. 270-279
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutieres syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in similar to 8370 patients with SLE and similar to 7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P = 0.0008, OR = 1.73, 95% CI = 1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P = 2.99E-13, OR = 5.2, 95% CI = 3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis. Genes and Immunity (2011) 12, 270-279; doi:10.1038/gene.2010.73; published online 27 January 2011
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| 2. |
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| 3. |
- Lessard, Christopher J., et al.
(författare)
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Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as Susceptibility Loci for Systemic Lupus Erythematosus in a Large-Scale Multiracial Replication Study
- 2012
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 90:4, s. 648-660
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 x 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) 8.62 x 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 x 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 x 10(-8) < p(meta-Euro) < 9.99 x 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4 FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.
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| 4. |
- Luhmann, J. G., et al.
(författare)
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Investigating magnetospheric interaction effects on Titan's ionosphere with the Cassini orbiter Ion Neutral Mass Spectrometer, Langmuir Probe and magnetometer observations during targeted flybys
- 2012
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Ingår i: Icarus. - : Elsevier BV. - 0019-1035 .- 1090-2643. ; 219:2, s. 534-555
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Tidskriftsartikel (refereegranskat)abstract
- In the similar to 6 years since the Cassini spacecraft went into orbit around Saturn in 2004, roughly a dozen Titan flybys have occurred for which the Ion Neutral Mass Spectrometer (INMS) measured that moon's ionospheric density and composition. For these, and for the majority of the similar to 60 close flybys probing to altitudes down to similar to 950 km, Langmuir Probe electron densities were also obtained. These were all complemented by Cassini magnetometer observations of the magnetic fields affected by the Titan plasma interaction. Titan's ionosphere was expected to differ from those of other unmagnetized planetary bodies because of significant contributions from particle impact due to its magnetospheric environment. However, previous analyses of these data clearly showed the dominance of the solar photon source, with the possible exception of the nightside. This paper describes the collected ionospheric data obtained in the period between Cassini's Saturn Orbit Insertion in 2004 and 2009, and examines some of their basic characteristics with the goal of searching for magnetospheric influences. These influences might include effects on the altitude profiles of impact ionization by magnetospheric particles at the Titan orbit location, or by locally produced pickup ions freshly created in Titan's upper atmosphere. The effects of forces on the ionosphere associated with both the draped and penetrating external magnetic fields might also be discernable. A number of challenges arise in such investigations given both the observed order of magnitude variations in the magnetospheric particle sources and the unsteadiness of the magnetospheric magnetic field and plasma flows at Titan's (similar to 20Rs (Saturn Radius)) orbit. Transterminator flow of ionospheric plasma from the dayside may also supply some of the nightside ionosphere, complicating determination of the magnetospheric contribution. Moreover, we are limited by the sparse sampling of the ionosphere during the mission as the Titan interaction also depends on Saturn Local Time as well as possible intrinsic asymmetries and variations of Titan's neutral atmosphere. We use organizations of the data by key coordinate systems of the plasma interaction with Titan's ionosphere to help interpret the observations. The present analysis does not find clear characteristics of the magnetosphere's role in defining Titan's ionosphere. The observations confirm the presence of an ionosphere produced mainly by sunlight, and an absence of expected ionospheric field signatures in the data. Further investigation of the latter, in particular, may benefit from numerical experiments on the inner boundary conditions of 3D models including the plasma interaction and features such as neutral winds.
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| 5. |
- Ulusen, D., et al.
(författare)
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Comparisons of Cassini flybys of the Titan magnetospheric interaction with an MHD model : Evidence for organized behavior at high altitudes
- 2012
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Ingår i: Icarus. - : Elsevier BV. - 0019-1035 .- 1090-2643. ; 217:1, s. 43-54
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Tidskriftsartikel (refereegranskat)abstract
- Recent papers suggest the significant variability of conditions in Saturn's magnetosphere at the orbit of Titan. Because of this variability, it was expected that models would generally have a difficult time regularly comparing to data from the Titan flybys. However, we find that in contrast to this expectation, it appears that there is underlying organization of the interaction features roughly above similar to 1800 km (1.7 Rt) altitude by the average external field due to Saturn's dipole moment. In this study, we analyze Cassini's plasma and magnetic field data collected at 9 Titan encounters during which the external field is close to the ideal southward direction and compare these observations to the results from a 2-fluid (1 ion, 1 electron) 7-species MHD model simulations obtained under noon SLT conditions. Our comparative analysis shows that under noon SLT conditions the Titan plasma interaction can be viewed in two layers: an outer layer between 6400 and 1800 km where interaction features observed in the magnetic field are in basic agreement with a purely southward external field interaction and an inner layer below 1800 km where the magnetic field measurements show strong variations and deviate from the model predictions. Thus the basic features inferred from the Voyager 1 flyby seem to be generally present above similar to 1800 km in spite of the ongoing external variations from SLT excursions, time variability and magnetospheric current systems as long as a significant southward external field component is present. At around similar to 1800 km kinetic effects (such as mass loading and heavy ion pickup) and below 1800 km ionospheric effects (such as drag of ionospheric plasma due to coupling with neutral winds and/or magnetic memory of Titan's ionosphere) complicate what is observed.
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| 6. |
- Andrews, David J., et al.
(författare)
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Oblique reflections in the Mars Express MARSIS data set : Stable density structures in the Martian ionosphere
- 2014
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Ingår i: Journal of Geophysical Research-Space Physics. - 2169-9380. ; 119:5, s. 3944-3960
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Tidskriftsartikel (refereegranskat)abstract
- The Mars Advanced Radar for Subsurface and Ionospheric Sounding (MARSIS) onboard the European Space Agency's Mars Express (MEX) spacecraft routinely detects evidence of localized plasma density structures in the Martian dayside ionosphere. Such structures, likely taking the form of spatially extended elevations in the plasma density at a given altitude, give rise to oblique reflections in the Active Ionospheric Sounder data. These structures are likely related to the highly varied Martian crustal magnetic field. In this study we use the polar orbit of MEX to investigate the repeatability of the ionospheric structures producing these anomalous reflections, examining data taken in sequences of multiple orbits which pass over the same regions of the Martian surface under similar solar illuminations, within intervals lasting tens of days. Presenting three such examples, or case studies, we show for the first time that these oblique reflections are often incredibly stable, indicating that the underlying ionospheric structures are reliably reformed in the same locations and with qualitatively similar parameters. The visibility, or lack thereof, of a given oblique reflection on a single orbit can generally be attributed to variations in the crustal field within the ionosphere along the spacecraft trajectory. We show that, within these examples, oblique reflections are generally detected whenever the spacecraft passes over regions of intense near-radial crustal magnetic fields (i.e., with a cusp-like configuration). The apparent stability of these structures is an important feature that must be accounted for in models of their origin.
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| 7. |
- Broen, Jasper C A, et al.
(författare)
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The Functional Polymorphism 844 A>G in Fc{alpha}RI (CD89) Does Not Contribute to Systemic Sclerosis or Rheumatoid Arthritis Susceptibility.
- 2011
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 38:3, s. 446-449
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the role of the Fc(α)RI 844 A>G functional polymorphism in the genetic predisposition to rheumatoid arthritis (RA) and systemic sclerosis (SSc) susceptibility. METHODS: The study population was composed of 1401 patients with SSc, 642 patients with RA, and 1317 healthy controls. The Fc(α)RI (CD89) single-nucleotide polymorphism rs16986050 was genotyped by pyrosequencing. RESULTS: We observed no significant deviation of the genotype and allele frequencies in RA and SSc compared to controls. A metaanalysis and a recessive and dominant model yielded similar negative results. CONCLUSION: Our data show that the Fc(α)RI 844 A>G polymorphism is not associated with SSc or RA susceptibility.
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| 8. |
- Edberg, Niklas J. T., et al.
(författare)
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Extreme densities in Titan's ionosphere during the T85 magnetosheath encounter
- 2013
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Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 40:12, s. 2879-2883
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Tidskriftsartikel (refereegranskat)abstract
- We present Cassini Langmuir probe measurements of the highest electron number densities ever reported from the ionosphere of Titan. The measured density reached 4310cm(-3) during the T85 Titan flyby. This is at least 500cm(-3) higher than ever observed before and at least 50% above the average density for similar solar zenith angles. The peak of the ionospheric density is not reached on this flyby, making the maximum measured density a lower limit. During this flyby, we also report that an impacting coronal mass ejection (CME) leaves Titan in the magnetosheath of Saturn, where it is exposed to shocked solar wind plasma for at least 2 h 45 min. We suggest that the solar wind plasma in the magnetosheath during the CME conditions significantly modifies Titan's ionosphere by an addition of particle impact ionization by precipitating protons.
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| 9. |
- Edberg, Niklas J. T., et al.
(författare)
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Structured ionospheric outflow during the Cassini T55-T59 Titan flybys
- 2011
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Ingår i: Planetary and Space Science. - : Elsevier BV. - 0032-0633 .- 1873-5088. ; 59:8, s. 788-797
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Tidskriftsartikel (refereegranskat)abstract
- During the final three of the five consecutive and similar Cassini Titan flybys T55-T59 we observe a region characterized by high plasma densities (electron densities of 1-8 cm(-3)) in the tail/nightside of Titan. This region is observed progressively farther downtail from pass to pass and is interpreted as a plume of ionospheric plasma escaping Titan, which appears steady in both location and time. The ions in this plasma plume are moving in the direction away from Titan and are a mixture of both light and heavy ions with composition revealing that their origin are in Titan's ionosphere, while the electrons are more isotropically distributed. Magnetic field measurements indicate the presence of a current sheet at the inner edge of this region. We discuss the mechanisms behind this outflow, and suggest that it could be caused by ambipolar diffusion, magnetic moment pumping or dispersive Alfven waves.
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| 10. |
- Lessard, Christopher J., et al.
(författare)
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Identification of a Systemic Lupus Erythematosus Susceptibility Locus at 11p13 between PDHX and CD44 in a Multiethnic Study
- 2011
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 88:1, s. 83-91
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 x 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 x 10(-8), OR = 0.83) and rs387619 (p = 7.7 x 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 x 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 x 10(-3), OR = 0.81 and p = 4.3 x 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 x 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex.
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