| 1. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 2. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 3. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 4. |
- Bruhn, Sören, et al.
(författare)
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A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy
- 2014
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 6:218
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Tidskriftsartikel (refereegranskat)abstract
- The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (T(H)2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.
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| 5. |
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| 6. |
- Maercker, Matthias, 1979, et al.
(författare)
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The detached dust and gas shells around the carbon star U Antliae
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 511:1, s. A37-
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Tidskriftsartikel (refereegranskat)abstract
- Context. Geometrically thin, detached shells of gas have been found around a handful of carbon stars. The current knowledge on these shells is mostly based on CO radio line data. However, imaging in scattered stellar light adds important new information as well as allows studies of the dust shells. Aims. Previous observations of scattered stellar light in the circumstellar medium around the carbon star U Ant were taken through filters centred on the resonance lines of K and Na. These observations could not separate the scattering by dust and atoms. The aim of this paper is to remedy this situation. Methods. We have obtained polarization data on stellar light scattered in the circumstellar medium around U Ant through filters which contain no strong lines, making it possible to differentiate between the two scattering agents. Kinematic, as well as spatial, information on the gas shells were obtained through high-resolution echelle spectrograph observations of the KI and NaD lines. Results. We confirm the existence of two detached shells around U Ant. The inner shell (at a radius of approximate to 43 '' and a width of approximate to 2 '') consists mainly of gas, while the outer shell (at a radius of approximate to 50 '' and a width of approximate to 7 '') appears to consist exclusively of dust. Both shells appear to have an over-all spherical geometry. The gas shell mass is estimated to be 2 x 10(-3) M-circle dot, while the mass of the dust shell is estimated to be 5 x 10(-5) M-circle dot. The derived expansion velocity, from the KI and NaD lines, of the gas shell, 19.5 km s(-1), agrees with that obtained from CO radio line data. The inferred shell age is 2700 years. There is structure, e.g. in the form of arcs, inside the gas shell, but it is not clear whether these are due to additional shells. Conclusions. Our results support the hypothesis that the observed geometrically thin, detached shells around carbon stars are the results of brief periods of intense mass loss, probably associated with thermal pulses, and subsequent wind-wind interactions. The separation into a gas and a dust shell, with different widths, is most likely the effect of different dynamical evolutions of the two media after their ejection.
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| 7. |
- Olofsson, Hans, 1952, et al.
(författare)
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High-resolution HST/ACS images of detached shells around carbon stars
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 515:JUN 2010, s. A270-
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Tidskriftsartikel (refereegranskat)abstract
- Context. Overall spherically symmetric, geometrically thin gas and dust shells have been found around a handful of asymptotic giant branch (AGB) carbon stars. Their dynamical ages lie in the range of 10(3) to 10(4) years. A tentative explanation for their existence is that they have formed as a consequence of mass-loss-rate modulations during a He-shell flash. Aims. The detached shells carry information on their formation process, as well as on the small-scale structure of the circumstellar medium around AGB stars due to the absence of significant line-of-sight confusion. Methods. The youngest detached shells, those around the carbon stars R Scl and U Cam, are studied here in great detail in scattered stellar light with the Advanced Survey Camera on the Hubble Space Telescope. Quantitative results are derived assuming optically thin dust scattering. Results. The detached dust shells around R Scl and U Cam are found to be consistent with an overall spherical symmetry. They have radii of 19 ''.2 (corresponding to a linear size of 8 x 10(16) cm) and 7 ''.7 (5 x 10(16) cm), widths of 1 ''.2 (5 x 10(15) cm) and 0 ''.6 (4 x 10(15) cm), and dust masses of 3 x 10(-6) and 3 x 10(-7) M-circle dot, respectively. The dynamical ages of the R Scl and U Cam shells are estimated to be 1700 and 700 yr, respectively, and the shell widths correspond to time scales of 100 and 50 yr, respectively. Small-scale structure in the form of less than arcsec-sized clumps is clearly seen in the images of the R Scl shell. Average clump dust masses are estimated to be about 2 x 10(-9) M-circle dot. Comparisons with CO line interferometer data show that the dust and gas shells coincide spatially, within the errors (
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