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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
We report the discovery of extended X-ray emission within the young star cluster NGC 602a in the Wing of the Small Magellanic Cloud (SMC) based on observations obtained with the Chandra X-Ray Observatory. X-ray emission is detected from the cluster core area with the highest stellar density and from a dusty ridge surrounding the H II region. We use a census of massive stars in the cluster to demonstrate that a cluster wind or wind-blown bubble is unlikely to provide a significant contribution to the X-ray emission detected from the central area of the cluster. We therefore suggest that X-ray emission at the cluster core originates from an ensemble of low-and solar-mass pre-main-sequence (PMS) stars, each of which would be too weak in X-rays to be detected individually. We attribute the X-ray emission from the dusty ridge to the embedded tight cluster of the newborn stars known in this area from infrared studies. Assuming that the levels of X-ray activity in young stars in the low-metallicity environment of NGC 602a are comparable to their Galactic counterparts, then the detected spatial distribution, spectral properties, and level of X-ray emission are largely consistent with those expected from low-and solar-mass PMS stars and young stellar objects (YSOs). This is the first discovery of X-ray emission attributable to PMS stars and YSOs in the SMC, which suggests that the accretion and dynamo processes in young, low-mass objects in the SMC resemble those in the Galaxy.
Among the different types of massive stars in advanced evolutionary stages is the enigmatic WN8h type. There are only a few Wolf-Rayet (WR) stars with this spectral type in our Galaxy. It has long been suggested that WN8h-type stars are the products of binary evolution that may harbor neutron stars (NS). One of the most intriguing WN8h stars is the runaway WR 124 surrounded by its magnificent nebula M1-67. We test the presence of an accreting NS companion in WR 124 using similar to 100 ks long observations by the Chandra X-ray observatory. The hard X-ray emission from WR 124 with a luminosity of L-X similar to 10(31) erg s(-1) is marginally detected. We use the non-local thermodynamic equilibrium stellar atmosphere code PoWR to estimate the WR wind opacity to the X-rays. The wind of a WN8-type star is effectively opaque for X-rays, hence the low X-ray luminosity of WR 124 does not rule out the presence of an embedded compact object. We suggest that, in general, high-opacity WR winds could prevent X-ray detections of embedded NS, and be an explanation for the apparent lack of WR+NS systems.
We report the first-ever discovery of a Wolf-Rayet (WR) star in the Large Magellanic Cloud via detection of a circular shell with the Spitzer Space Telescope. Follow-up observations with Gemini-South resolved the central star of the shell into two components separated from each other by a parts per thousand 2 arcsec (or a parts per thousand 0.5 pc in projection). One of these components turns out to be a WN3 star with H and He lines both in emission and absorption (we named it BAT99 3a using the numbering system based on extending the Breysacher et al. catalogue). Spectroscopy of the second component showed that it is a B0 V star. Subsequent spectroscopic observations of BAT99 3a with the du Pont 2.5-m telescope and the Southern African Large Telescope revealed that it is a close, eccentric binary system, and that the absorption lines are associated with an O companion star. We analysed the spectrum of the binary system using the non-LTE Potsdam WR (powr) code, confirming that the WR component is a very hot (a parts per thousand 90 kK) WN star. For this star, we derived a luminosity of log L/ L-aS (TM) = 5.45 and a mass-loss rate of 10(- 5.8) M-aS (TM) yr(- 1), and found that the stellar wind composition is dominated by helium with 20 per cent of hydrogen. Spectroscopy of the shell revealed an He iii region centred on BAT99 3a and having the same angular radius (a parts per thousand 15 arcsec) as the shell. We thereby add a new example to a rare class of high-excitation nebulae photoionized by WR stars. Analysis of the nebular spectrum showed that the shell is composed of unprocessed material, implying that the shell was swept-up from the local interstellar medium. We discuss the physical relationship between the newly identified massive stars and their possible membership of a previously unrecognized star cluster.
We discuss our most recent findings on the diffuse X-ray emission within Wolf-Rayet (WR) nebulae. The best-quality X-ray observations of these objects are those performed by XMM- Newton and Chandra towards S 308, NGC 2359, and NGC 6888. Even though these three WR nebulae might have different formation scenarios, they all share similar characteristics: i) the main plasma temperatures of the X-ray-emitting gas is found to be T =[1–2]×^K, ii) the diffuse X-ray emission is confined inside the [O iii] shell, and iii) their X-ray luminosities and electron densities in the 0.3–2.0 keV energy range are LX ≈10^33–10^34 erg s-1 and ne ≈0.1–1 cm^-3 . These properties and the nebular-like abundances of the hot gas suggest mixing and/or thermal conduction is taking an important rôle reducing the temperature of the hot bubble.
We analyze the expansion of hydrogen-poor knots and filaments in the born-again planetary nebulae A30 and A78 based on Hubble Space Telescope ( HST) images obtained almost 20 yr apart. The proper motion of these features generally increases with distance to the central star, but the fractional expansion decreases, i.e., the expansion is not homologous. As a result, there is not a unique expansion age, which is estimated to be 610-950 yr for A30 and 600-1140 yr for A78. The knots and filaments have experienced complex dynamical processes: the current fast stellar wind is mass loaded by the material ablated from the inner knots; the ablated material is then swept up until it shocks the inner edges of the outer, hydrogen-rich nebula. The angular expansion of the outer filaments shows a clear dependence on position angle, indicating that the interaction of the stellar wind with the innermost knots channels the wind along preferred directions. The apparent angular expansion of the innermost knots seems to be dominated by the rocket effect of evaporating gas and by the propagation of the ionization front inside them. Radiation-hydrodynamical simulations show that a single ejection of material followed by a rapid onset of the stellar wind and ionizing flux can reproduce the variety of clumps and filaments at different distances from the central star found in A30 and A78.
We present the XMM-Newton discovery of X-ray emission from the planetary nebula (PN) A78, the second born-again PN detected in X-rays apart from A30. These two PNe share similar spectral and morphological characteristics: they harbor diffuse soft X-ray emission associated with the interaction between the H-poor ejecta and the current fast stellar wind and a point-like source at the position of the central star (CSPN). We present the spectral analysis of the CSPN, using for the first time an NLTE code for expanding atmospheres that takes line blanketing into account for the UV and optical spectra. The wind abundances are used for the X-ray spectral analysis of the CSPN and the diffuse emission. The X-ray emission from the CSPN in A78 can be modeled by a single C VI emission line, while the X-ray emission from its diffuse component is better described by an optically thin plasma emission model with a temperature of kT = 0.088 keV (T approximate to 1.0 x 10(6) K). We estimate X-ray luminosities in the 0.2-2.0 keV energy band of L-X,L-CSPN =(1.2 +/- 0.3) x 10(31) erg s(-1) and L-X,L-DIFF =(9.2 +/- 2.3) x 10(30) erg s(-1) for the CSPN and diffuse components, respectively.
The planetary nebula A30 is believed to have undergone a very late thermal pulse resulting in the ejection of knots of hydrogen-poor material. Using multi-epoch Hubble Space Telescope images, we have detected the angular expansion of these knots and derived an age of 850(-150)(+280) yr. To investigate the spectral and spatial properties of the soft X-ray emission detected by ROSAT, we have obtained Chandra and XMM-Newton deep observations of A30. The X-ray emission from A30 can be separated into two components: a point source at the central star and diffuse emission associated with the hydrogen-poor knots and the cloverleaf structure inside the nebular shell. To help us assess the role of the current stellar wind in powering this X-ray emission, we have determined the stellar parameters and wind properties of the central star of A30 using a non-LTE model fit to its optical and UV spectra. The spatial distribution and spectral properties of the diffuse X-ray emission are highly suggestive that it is generated by the post-born-again and present fast stellar winds interacting with the hydrogen-poor ejecta of the born-again event. This emission can be attributed to shock-heated plasma, as the hydrogen-poor knots are ablated by the stellar winds, under which circumstances the efficient mass loading of the present fast stellar wind raises its density and damps its velocity to produce the observed diffuse soft X-rays. Charge transfer reactions between the ions of the stellar winds and material of the born-again ejecta have also been considered as a possible mechanism for the production of diffuse X-ray emission, and upper limits on the expected X-ray production by this mechanism have been derived. The origin of the X-ray emission from the central star of A30 is puzzling: shocks in the present fast stellar wind and photospheric emission can be ruled out, while the development of a new, compact hot bubble confining the fast stellar wind seems implausible.