| 1. |
- Ingelsson, Erik, et al.
(författare)
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Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans
- 2010
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Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 59:5, s. 1266-1275
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Konferensbidrag (refereegranskat)abstract
- OBJECTIVE-Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS-We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS-The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS-Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. Diabetes 59:1266-1275, 2010
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| 2. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 3. |
- Wheeler, Eleanor, et al.
(författare)
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Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis
- 2017
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Ingår i: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 x 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI0.55-0.74) of African American adults with T2Dto remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
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| 4. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 5. |
- Abdalla, H., et al.
(författare)
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A search for new supernova remnant shells in the Galactic plane with HESS
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 612
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Tidskriftsartikel (refereegranskat)abstract
- A search for new supernova remnants (SNRs) has been conducted using TeV gamma-ray data from the H.E.S.S. Galactic plane survey. As an identification criterion, shell morphologies that are characteristic for known resolved TeV SNRs have been used. Three new SNR candidates were identified in the H.E.S.S. data set with this method. Extensive multiwavelength searches for counterparts were conducted. A radio SNR candidate has been identified to be a counterpart to HESS J1534-571. The TeV source is therefore classified as a SNR. For the other two sources, HESS J1614-518 and HESS J1912 + 101, no identifying counterparts have been found, thus they remain SNR candidates for the time being. TeV-emitting SNRs are key objects in the context of identifying the accelerators of Galactic cosmic rays. The TeV emission of the relativistic particles in the new sources is examined in view of possible leptonic and hadronic emission scenarios, taking the current multiwavelength knowledge into account.
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| 6. |
- Abdalla, H., et al.
(författare)
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A search for very high-energy flares from the microquasars GRS 1915+105, Circinus X-1, and V4641 Sgr using contemporaneous HESS and RXTE observations
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 612
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Tidskriftsartikel (refereegranskat)abstract
- Context. Microquasars are potential gamma-ray emitters. Indications of transient episodes of gamma-ray emission were recently reported in at least two systems: Cyg X-1 and Cyg X-3. The identification of additional gamma-ray-emitting microquasars is required to better understand how gamma-ray emission can be produced in these systems. Aims. Theoretical models have predicted very high-energy (VHE) gamma-ray emission from microquasars during periods of transient outburst. Observations reported herein were undertaken with the objective of observing a broadband flaring event in the gamma-ray and X-ray bands. Methods. Contemporaneous observations of three microquasars, GRS 1915+105, Circinus X-1, and V4641 Sgr, were obtained using the High Energy Spectroscopic System (H.E.S.S.) telescope array and the Rossi X-ray Timing Explorer (RXTE) satellite. X-ray analyses for each microquasar were performed and VHE gamma-ray upper limits from contemporaneous H.E.S.S. observations were derived. Results. No significant gamma-ray signal has been detected in any of the three systems. The integral gamma-ray photon flux at the observational epochs is constrained to be I(>560 GeV) < 7.3 x 10(-13) cm(-2) S-1, I(>560 GeV) < 1.2 x 10-(12) cm s(-1), and I(>240 GeV) < 4.5 x 10(-12) cm(-2) s(-1) for GRS 1915+105, Circinus X-1, and V4641 Sgr, respectively. Conclusions. The gamma-ray upper limits obtained using H.E.S.S. are examined in the context of previous Cherenkov telescope observations of microquasars. The effect of intrinsic absorption is modelled for each target and found to have negligible impact on the flux of escaping gamma-rays. When combined with the X-ray behaviour observed using RXTE, the derived results indicate that if detectable VHE gamma-ray emission from microquasars is commonplace, then it is likely to be highly transient.
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| 7. |
- Abdalla, H., et al.
(författare)
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A very-high-energy component deep in the gamma-ray burst afterglow
- 2019
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 575:7783, s. 464-467
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Tidskriftsartikel (refereegranskat)abstract
- Gamma-ray bursts (GRBs) are brief flashes of gamma-rays and are considered to be the most energetic explosive phenomena in the Universe(1). The emission from GRBs comprises a short (typically tens of seconds) and bright prompt emission, followed by a much longer afterglow phase. During the afterglow phase, the shocked outflow-produced by the interaction between the ejected matter and the circumburst medium-slows down, and a gradual decrease in brightness is observed(2). GRBs typically emit most of their energy via.-rays with energies in the kiloelectronvolt-to-megaelectronvolt range, but a few photons with energies of tens of gigaelectronvolts have been detected by space-based instruments(3). However, the origins of such high-energy (above one gigaelectronvolt) photons and the presence of very-high-energy (more than 100 gigaelectronvolts) emission have remained elusive(4). Here we report observations of very-high-energy emission in the bright GRB 180720B deep in the GRB afterglow-ten hours after the end of the prompt emission phase, when the X-ray flux had already decayed by four orders of magnitude. Two possible explanations exist for the observed radiation: inverse Compton emission and synchrotron emission of ultrarelativistic electrons. Our observations show that the energy fluxes in the X-ray and gamma-ray range and their photon indices remain comparable to each other throughout the afterglow. This discovery places distinct constraints on the GRB environment for both emission mechanisms, with the inverse Compton explanation alleviating the particle energy requirements for the emission observed at late times. The late timing of this detection has consequences for the future observations of GRBs at the highest energies.
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| 8. |
- Abdalla, H., et al.
(författare)
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Characterising the VHE diffuse emission in the central 200 parsecs of our Galaxy with HESS
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 612
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Tidskriftsartikel (refereegranskat)abstract
- The diffuse very high-energy (VHE; > 100 GeV) gamma-ray emission observed in the central 200 pc of the Milky Way by H.E.S.S. was found to follow dense matter distribution in the central molecular zone (CMZ) up to a longitudinal distance of about 130 pc to the Galactic centre (GC), where the flux rapidly decreases. This was initially interpreted as the result of a burst-like injection of energetic particles 104 yr ago, but a recent more sensitive H.E.S.S. analysis revealed that the cosmic-ray (CR) density profile drops with the distance to the centre, making data compatible with a steady cosmic PeVatron at the GC. In this paper, we extend this analysis to obtain, for the first time, a detailed characterisation of the correlation with matter and to search for additional features and individual gamma-ray sources in the inner 200 pc. Taking advantage of 250 h of H.E.S.S. data and improved analysis techniques, we perform a detailed morphology study of the diffuse VHE emission observed from the GC ridge and reconstruct its total spectrum. To test the various contributions to the total gamma-ray emission, we used an iterative 2D maximum-likelihood approach that allows us to build a phenomenological model of the emission by summing a number of different spatial components. We show that the emission correlated with dense matter covers the full CMZ and that its flux is about half the total diffuse emission flux. We also detect some emission at higher latitude that is likely produced by hadronic collisions of CRs in less dense regions of the GC interstellar medium. We detect an additional emission component centred on the GC and extending over about 15 pc that is consistent with the existence of a strong CR density gradient and confirms the presence of a CR accelerator at the very centre of our Galaxy. We show that the spectrum of full ridge diffuse emission is compatible with that previously derived from the central regions, suggesting that a single population of particles fills the entire CMZ. Finally, we report the discovery of a VHE gamma-ray source near the GC radio arc and argue that it is produced by the pulsar wind nebula candidate G0.13-0.11.
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| 9. |
- Abdalla, H., et al.
(författare)
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Deeper HESS observations of Vela Junior (RX J0852.0-4622) : Morphology studies and resolved spectroscopy
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 612
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We study gamma-ray emission from the shell-type supernova remnant (SNR) RXJ0852.0-4622 to better characterize its spectral properties and its distribution over the SNR. Methods. The analysis of an extended High Energy Spectroscopic System (H.E.S.S.) data set at very high energies (E > 100 GeV) permits detailed studies, as well as spatially resolved spectroscopy, of the morphology and spectrum of the whole RXJ0852.0-4622 region. The H.E.S.S. data are combined with archival data from other wavebands and interpreted in the framework of leptonic and hadronic models. The joint Fermi-LAT-H.E.S.S. spectrum allows the direct determination of the spectral characteristics of the parent particle population in leptonic and hadronic scenarios using only GeV-TeV data. Results. An updated analysis of the H.E.S.S. data shows that the spectrum of the entire SNR connects smoothly to the high-energy spectrum measured by Fermi-LAT. The increased data set makes it possible to demonstrate that the H.E.S.S. spectrum deviates significantly from a power law and is well described by both a curved power law and a power law with an exponential cutoff at an energy of E-cut = (6.7 +/- 1.2(stat) +/- 1.2(syst)) TeV. The joint Fermi-LAT-H.E.S.S. spectrum allows the unambiguous identification of the spectral shape as a power law with an exponential cutoff. No significant evidence is found for a variation of the spectral parameters across the SNR, suggesting similar conditions of particle acceleration across the remnant. A simple modeling using one particle population to model the SNR emission demonstrates that both leptonic and hadronic emission scenarios remain plausible. It is also shown that at least a part of the shell emission is likely due to the presence of a pulsar wind nebula around PSR J0855-4644.
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| 10. |
- Abdalla, H., et al.
(författare)
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First limits on the very-high energy gamma-ray afterglow emission of a fast radio burst HESS observations of FRB 150418
- 2017
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Ingår i: Astronomy and Astrophysics. - : The European Southern Observatory (ESO). - 0004-6361 .- 1432-0746. ; 597
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Tidskriftsartikel (refereegranskat)abstract
- Aims. Following the detection of the fast radio burst FRB150418 by the SUPERB project at the Parkes radio telescope, we aim to search for very-high energy gamma-ray afterglow emission. Methods. Follow-up observations in the very-high energy gamma-ray domain were obtained with the H.E.S.S. imaging atmospheric Cherenkov telescope system within 14.5 h of the radio burst. Results. The obtained 1.4 h of gamma-ray observations are presented and discussed. At the 99% C.L. we obtained an integral upper limit on the gamma-ray flux of Phi(gamma)(E > 350 GeV) < 1.33 x 10(-8) m(-2) s(-1). Differential flux upper limits as function of the photon energy were derived and used to constrain the intrinsic high-energy afterglow emission of FRB 150418. Conclusions. No hints for high-energy afterglow emission of FRB 150418 were found. Taking absorption on the extragalactic background light into account and assuming a distance of z = 0 : 492 based on radio and optical counterpart studies and consistent with the FRB dispersion, we constrain the gamma-ray luminosity at 1 TeV to L < 5 : 1 x 10(47) erg/s at 99% C.L.
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