| 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. |
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| 4. |
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| 5. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 6. |
- 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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| 7. |
- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 8. |
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| 11. |
- Willer, Cristen J., et al.
(författare)
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Discovery and refinement of loci associated with lipid levels
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
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Tidskriftsartikel (refereegranskat)abstract
- Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Scott, Robert A., et al.
(författare)
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Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
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Tidskriftsartikel (refereegranskat)abstract
- Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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| 16. |
- Smiljanic, R., et al.
(författare)
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The Gaia-ESO Survey: The analysis of high-resolution UVES spectra of FGK-type stars
- 2014
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 570
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Tidskriftsartikel (refereegranskat)abstract
- Context. The ongoing Gaia-ESO Public Spectroscopic Survey is using FLAMES at the VLT to obtain high-quality medium-resolution Giraffe spectra for about 10(5) stars and high-resolution UVES spectra for about 5000 stars. With UVES, the Survey has already observed 1447 FGK-type stars. Aims. These UVES spectra are analyzed in parallel by several state-of-the-art methodologies. Our aim is to present how these analyses were implemented, to discuss their results, and to describe how a final recommended parameter scale is defined. We also discuss the precision (method-to-method dispersion) and accuracy (biases with respect to the reference values) of the final parameters. These results are part of the Gaia-ESO second internal release and will be part of its first public release of advanced data products. Methods. The final parameter scale is tied to the scale defined by the Gaia benchmark stars, a set of stars with fundamental atmospheric parameters. In addition, a set of open and globular clusters is used to evaluate the physical soundness of the results. Each of the implemented methodologies is judged against the benchmark stars to define weights in three different regions of the parameter space. The final recommended results are the weighted medians of those from the individual methods. Results. The recommended results successfully reproduce the atmospheric parameters of the benchmark stars and the expected T-eff-log g relation of the calibrating clusters. Atmospheric parameters and abundances have been determined for 1301 FGK-type stars observed with UVES. The median of the method-to-method dispersion of the atmospheric parameters is 55K for T-eff, 0.13dex for log g and 0.07 dex for [Fe/H]. Systematic biases are estimated to be between 50-100 K for T-eff, 0.10-0.25 dex for log g and 0.05-0.10 dex for [Fe/H]. Abundances for 24 elements were derived: C, N, O, Na, Mg, Al, Si, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ba, Nd, and Eu. The typical method-to-method dispersion of the abundances varies between 0.10 and 0.20 dex. Conclusions. The Gaia-ESO sample of high-resolution spectra of FGK-type stars will be among the largest of its kind analyzed in a homogeneous way. The extensive list of elemental abundances derived in these stars will enable significant advances in the areas of stellar evolution and Milky Way formation and evolution.
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| 17. |
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| 19. |
- Vimaleswaran, K. S., et al.
(författare)
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Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts
- 2013
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Ingår i: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n=123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p=6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p=6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p=0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p=0.88; metabolism score, p=0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p=0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
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| 20. |
- Loth, Daan W, et al.
(författare)
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Genome-wide association analysis identifies six new loci associated with forced vital capacity
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
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Tidskriftsartikel (refereegranskat)abstract
- Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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| 21. |
- Howes, Louise, et al.
(författare)
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The Gaia-ESO Survey: the most metal-poor stars in the Galactic bulge
- 2014
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 1365-2966 .- 0035-8711. ; 445:4, s. 4241-4246
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Tidskriftsartikel (refereegranskat)abstract
- We present the first results of the EMBLA survey (Extremely Metal-poor BuLge stars with AAOmega), aimed at finding metal-poor stars in the Milky Way bulge, where the oldest stars should now preferentially reside. EMBLA utilizes SkyMapper photometry to pre-select metal-poor candidates, which are subsequently confirmed using AAOmega spectroscopy. We describe the discovery and analysis of four bulge giants with -2.72 <= [Fe/H] <= -2.48, the lowest metallicity bulge stars studied with high-resolution spectroscopy to date. Using FLAMES/UVES spectra through the Gaia-ESO Survey we have derived abundances of twelve elements. Given the uncertainties, we find a chemical similarity between these bulge stars and halo stars of the same metallicity, although the abundance scatter may be larger, with some of the stars showing unusual [alpha/Fe] ratios.
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| 22. |
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| 23. |
- Magrini, L., et al.
(författare)
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The Gaia-ESO Survey: Abundance ratios in the inner-disk open clusters Trumpler 20, NGC 4815, NGC 6705
- 2014
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 563
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Tidskriftsartikel (refereegranskat)abstract
- Context. Open clusters are key tools to study the spatial distribution of abundances in the disk and their evolution with time. Aims. Using the first release of stellar parameters and abundances of the Gaia-ESO Survey, we analyse the chemical properties of stars in three old/intermediate-age open clusters, namely NGC 6705, NGC 4815, and Trumpler 20, which are all located in the inner part of the Galactic disk at Galactocentric radius R-GC similar to 7 kpc. We aim to prove their homogeneity and to compare them with the field population. Methods. We study the abundance ratios of elements belonging to two different nucleosynthetic channels: alpha-elements and iron-peak elements. For each element, we analyse the internal chemical homogeneity of cluster members, and we compare the cumulative distributions of cluster abundance ratios with those of solar neighbourhood turn-off stars and of inner-disk/bulge giants. We compare the abundance ratios of field and cluster stars with two chemical evolution models that predict different alpha-enhancement dependences on the Galactocentric distance due to different assumptions on the infall and star-formation rates. Results. The main results can be summarised as follows: i) cluster members are chemically homogeneous within 3 sigma in all analysed elements; ii) the three clusters have comparable [El/Fe] patterns within similar to 1 sigma, but they differ in their global metal content [El/H] with NGC 4815 having the lowest metallicity; their [El/Fe] ratios show differences and analogies with those of the field population, in both the solar neighbourhood and the bulge/inner disk; iii) comparing the abundance ratios with the results of two chemical evolution models and with field star abundance distributions, we find that the abundance ratios of Mg, Ni, and Ca in NGC 6705 might require an inner birthplace, implying a subsequent variation in its R-GC during its lifetime, which is consistent with previous orbit determination. Conclusions. Using the results of the first internal data release, we show the potential of the Gaia-ESO Survey through a homogeneous and detailed analysis of the cluster versus field populations to reveal the chemical structure of our Galaxy using a completely uniform analysis of different populations. We verify that the Gaia-ESO Survey data are able to identify the unique chemical properties of each cluster by pinpointing the composition of the interstellar medium at the epoch and place of formation. The full dataset of the Gaia-ESO Survey is a superlative tool to constrain the chemical evolution of our Galaxy by disentangling different formation and evolution scenarios.
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| 24. |
- 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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| 25. |
- 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. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:5, s. 1266-1275
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Tidskriftsartikel (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.
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| 26. |
- Jeffries, R. D., et al.
(författare)
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The Gaia-ESO Survey: Kinematic structure in the Gamma Velorum cluster
- 2014
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 563
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Tidskriftsartikel (refereegranskat)abstract
- Context. A key science goal of the Gaia-ESO survey (GES) at the VLT is to use the kinematics of low-mass stars in young clusters and star forming regions to probe their dynamical histories and how they populate the field as they become unbound. The clustering of low-mass stars around the massive Wolf-Rayet binary system gamma(2) Velorum was one of the first GES targets. Aims. We empirically determine the radial velocity precision of GES data, construct a kinematically unbiased sample of cluster members and characterise their dynamical state. Methods. Targets were selected from colour-magnitude diagrams and intermediate resolution spectroscopy was used to derive radial velocities and assess membership from the strength of the Li I 6708 angstrom line. The radial velocity distribution was analysed using a maximum likelihood technique that accounts for unresolved binaries. Results. The GES radial velocity precision is about 0.25 km s(-1) and sufficient to resolve velocity structure in the low-mass population around gamma(2) Vel. The structure is well fitted by two kinematic components with roughly equal numbers of stars; the first has an intrinsic dispersion of 0.34 +/- 0.16 km s(-1), consistent with virial equilibrium. The second has a broader dispersion of 1.60 +/- 0.37 km s(-1) and is offset from the first by congruent to 2 kms(-1). The first population is older by 1-2 Myr based on a greater level of Li depletion seen among its M-type stars and is probably more centrally concentrated around gamma(2) Vel. Conclusions. We consider several formation scenarios, concluding that the two kinematic components are a bound remnant of the original, denser cluster that formed gamma(2) Vel, and a dispersed population from the wider Vela OB2 association, of which gamma(2) Vel is the most massive member. The apparent youth of gamma(2) Vel compared to the older (>= 10 Myr) low-mass population surrounding it suggests a scenario in which the massive binary formed in a clustered environment after the formation of the bulk of the low-mass stars.
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| 27. |
- Lind, Lars, et al.
(författare)
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Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin.
- 2014
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
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| 28. |
- Sacco, G. G., et al.
(författare)
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The Gaia-ESO Survey: processing FLAMES-UVES spectra
- 2014
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 565
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Tidskriftsartikel (refereegranskat)abstract
- The Gaia-ESO Survey is a large public spectroscopic survey that aims to derive radial velocities and fundamental parameters of about 10(5) Milky Way stars in the field and in clusters. Observations are carried out with the multi-object optical spectrograph FLAMES, using simultaneously the medium-resolution (R similar to 20 000) GIRAFFE spectrograph and the high-resolution (R similar to 47 000) UVES spectrograph. In this paper we describe the methods and the software used for the data reduction, the derivation of the radial velocities, and the quality control of the FLAMES-UVES spectra. Data reduction has been performed using a workflow specifically developed for this project. This workflow runs the ESO public pipeline optimizing the data reduction for the Gaia-ESO Survey, automatically performs sky subtraction, barycentric correction and normalisation, and calculates radial velocities and a first guess of the rotational velocities. The quality control is performed using the output parameters from the ESO pipeline, by a visual inspection of the spectra and by the analysis of the signal-to-noise ratio of the spectra. Using the observations of the first 18 months, specifically targets observed multiple times at different epochs, stars observed with both GIRAFFE and UVES, and observations of radial velocity standards, we estimated the precision and the accuracy of the radial velocities. The statistical error on the radial velocities is sigma similar to 0.4 km s(-1) and is mainly due to uncertainties in the zero point of the wavelength calibration. However, we found a systematic bias with respect to the GIRAFFE spectra (similar to 0.9 km s(-1)) and to the radial velocities of the standard stars (similar to 0.5 km s(-1)) retrieved from the literature. This bias will be corrected in the future data releases, when a common zero point for all the set-ups and instruments used for the survey is be established.
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| 29. |
- Bergemann, M., et al.
(författare)
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The Gaia-ESO Survey : radial metallicity gradients and age-metallicity relation of stars in the Milky Way disk
- 2014
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 565, s. A89-
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Tidskriftsartikel (refereegranskat)abstract
- We study the relationship between age, metallicity, and alpha-enhancement of FGK stars in the Galactic disk. The results are based upon the analysis of high-resolution UVES spectra from the Gaia-ESO large stellar survey. We explore the limitations of the observed dataset, i.e. the accuracy of stellar parameters and the selection effects that are caused by the photometric target preselection. We find that the colour and magnitude cuts in the survey suppress old metal-rich stars and young metal-poor stars. This suppression may be as high as 97% in some regions of the age-metallicity relationship. The dataset consists of 144 stars with a wide range of ages from 0.5 Gyr to 13.5 Gyr, Galactocentric distances from 6 kpc to 9.5 kpc, and vertical distances from the plane 0 < vertical bar Z vertical bar < 1.5 kpc. On this basis, we find that i) the observed age-metallicity relation is nearly flat in the range of ages between 0 Gyr and 8 Gyr; ii) at ages older than 9 Gyr, we see a decrease in [Fe/H] and a clear absence of metal-rich stars; this cannot be explained by the survey selection functions; iii) there is a significant scatter of [Fe/H] at any age; and iv) [Mg/Fe] increases with age, but the dispersion of [Mg/Fe] at ages > 9 Gyr is not as small as advocated by some other studies. In agreement with earlier work, we find that radial abundance gradients change as a function of vertical distance from the plane. The [Mg/Fe] gradient steepens and becomes negative. In addition, we show that the inner disk is not only more alpha-rich compared to the outer disk, but also older, as traced independently by the ages and Mg abundances of stars.
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| 30. |
- Fall, Tove, et al.
(författare)
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The Role of Adiposity in Cardiometabolic Traits : A Mendelian Randomization Analysis
- 2013
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 10:6, s. e1001474-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
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| 31. |
- Friel, E. D., et al.
(författare)
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Gaia-ESO Survey : Properties of the intermediate age open cluster NGC 4815
- 2014
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 563, s. A117-
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Tidskriftsartikel (refereegranskat)abstract
- Context. NGC 4815 is a populous similar to 500 Myr open cluster at R-gc similar to 7 kpc observed in the first six months of the Gaia-ESO Survey. Located in the inner Galactic disk, NGC 4815 is an important potential tracer of the abundance gradient, where relatively few intermediate age open clusters are found. Aims. The Gaia-ESO Survey data can provide an improved characterization of the cluster properties, such as age, distance, reddening, and abundance profile. Methods. We use the survey derived radial velocities, stellar atmospheric parameters, metallicity, and elemental abundances for stars targeted as potential members of this cluster to carry out an analysis of cluster properties. The radial velocity distribution of stars in the cluster field is used to define the cluster systemic velocity and derive likely cluster membership for stars observed by the Gaia-ESO Survey. We investigate the distributions of Fe and Fe-peak elements, alpha-elements, and the light elements Na and Al and characterize the cluster's internal chemical homogeneity comparing it to the properties of radial velocity non-member stars. Utilizing these cluster properties, the cluster color-magnitude diagram is analyzed and theoretical isochrones are fit to derive cluster reddening, distance, and age. Results. NGC 4815 is found to have a mean metallicity of [Fe/H] = +0.03 +/- 0.05 dex (s.d.). Elemental abundances of cluster members show typically very small internal variation, with internal dispersions of similar to 0.05 dex. The alpha-elements [Ca/Fe] and [Si/Fe] show solar ratios, but [Mg/Fe] is moderately enhanced, while [Ti/Fe] appears slightly deficient. As with many open clusters, the light elements [Na/Fe] and [Al/Fe] are enhanced, [Na/Fe] significantly so, although the role of internal mixing and the assumption of local thermodynamical equilibrium in the analysis remain to be investigated. From isochrone fits to color-magnitude diagrams, we find a cluster age of 0.5 to 0.63 Gyr, a reddening of E(B-V) = 0.59 to 0.65, and a distance modulus (m -M)(0) = 11.95 to 12.20, depending on the choice of theoretical models, leading to a Galactocentric distance of 6.9 kpc.
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| 32. |
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| 33. |
- Recio-Blanco, A., et al.
(författare)
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The Gaia-ESO Survey: the Galactic thick to thin disc transition
- 2014
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 567
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Tidskriftsartikel (refereegranskat)abstract
- Aims. The nature of the thick disc and its relation to the thin disc is presently an important subject of debate. In fact, the structural and chemo-dynamical transition between disc populations can be used as a test of the proposed models of Galactic disc formation and evolution. Methods. We used the atmospheric parameters, [alpha/Fe] abundances, and radial velocities, which were determined from the Gaia-ESO Survey GIRAFFE spectra of FGK-type stars (first nine months of observations) to provide a chemo-kinematical characterisation of the disc stellar populations. We focussed on a subsample of 1016 stars with high-quality parameters, covering the volume vertical bar Z vertical bar < 4.5 kpc and R in the range 2-13 kpc. Results. We have identified a thin to thick disc separation in the [alpha/Fe] vs. [M/H] plane, thanks to the presence of a low-density region in the number density distribution. The thick disc stars seem to lie in progressively thinner layers above the Galactic plane, as metallicity increases and [alpha/Fe] decreases. In contrast, the thin disc population presents a constant value of the mean distance to the Galactic plane at all metallicities. In addition, our data confirm the already known correlations between V-phi and [M/H] for the two discs. For the thick disc sequence, a study of the possible contamination by thin disc stars suggests a gradient up to 64 +/- 9 km s(-1) dex(-1). The distributions of azimuthal velocity, vertical velocity, and orbital parameters are also analysed for the chemically separated samples. Concerning the gradients with galactocentric radius, we find, for the thin disc, a flat behaviour of the azimuthal velocity, a metallicity gradient equal to -0.058 +/- 0.008 dex kpc(-1) and a very small positive [alpha/Fe] gradient. For the thick disc, flat gradients in [M/H] and [alpha/Fe] are derived. Conclusions. Our chemo-kinematical analysis suggests a picture where the thick disc seems to have experienced a settling process, during which its rotation increased progressively and, possibly, the azimuthal velocity dispersion decreased. At [M/H] approximate to -0.25 dex and [alpha/Fe] approximate to 0.1 dex, the mean characteristics of the thick disc in vertical distance to the Galactic plane, rotation, rotational dispersion, and stellar orbits' eccentricity agree with that of the thin disc stars of the same metallicity, suggesting a possible connection between these two populations at a certain epoch of the disc evolution. Finally, the results presented here, based only on the first months of the Gaia-ESO Survey observations, confirm how crucial large high-resolution spectroscopic surveys outside the solar neighbourhood are today for our understanding of the Milky Way history.
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| 34. |
- Su, Zhan, et al.
(författare)
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Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)abstract
- Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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| 35. |
- Wang, C. H., et al.
(författare)
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High-k dielectrics on (100) and (110) n-InAs: Physical and electrical characterizations
- 2014
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Ingår i: AIP Advances. - : AIP Publishing. - 2158-3226. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- Two high-k dielectric materials (Al2O3 and HfO2) were deposited on n-type (100) and (110) InAs surface orientations to investigate physical properties of the oxide/semiconductor interfaces and the interface trap density (D-it). X-ray photoelectron spectroscopy analyses (XPS) for native oxides of (100) and (110) as-grown n-InAs epi wafers show an increase in As-oxide on the (100) surface and an increase in InOx on the (110) surface. In addition, XPS analyses of high-k (Al2O3 and HfO2) on n-InAs epi show that the intrinsic native oxide difference between (100) and (110) epi surfaces were eliminated by applying conventional in-situ pre-treatment (TriMethyAluminium (TMA)) before the high-k deposition. The capacitance-voltage (C-V) characterization of HfO2 and Al2O3 MOSCAPs on both types of n-InAs surfaces shows very similar C-V curves. The interface trap density (D-it) profiles show D-it minima of 6.1 x 10(12/)6.5 x 10(12) and 6.6 x 10(12)/7.3 x 10(12) cm(-2) eV(-1) for Al2O3 and HfO2, respectively for (100) and (110) InAs surfaces. The similar interface trap density (D-it) on (100) and (110) surface orientation were observed, which is beneficial to future InAs FinFET device with both (100) and (110) surface channel orientations present. (C) 2014 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 Unported License.
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| 36. |
- Dimas, Antigone S, et al.
(författare)
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Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:6, s. 2158-2171
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Tidskriftsartikel (refereegranskat)abstract
- Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
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| 37. |
- Ho, J. E., et al.
(författare)
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Clinical and genetic correlates of growth differentiation factor 15 in the community
- 2012
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 58:11, s. 1582-1591
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Growth differentiation factor 15(GDF15), a stress-responsive cytokine produced in cardiovascular cells under conditions of inflammation and oxidative stress, is emerging as an important prognostic marker in individuals with and without existing cardiovascular disease (CVD). We therefore examined the clinical and genetic correlates of circulating GDF15 concentrations, which have not been investigated collectively. METHODS: Plasma GDF15 concentrations were measured in 2991 participants in the Framingham Offspring Study who were free of clinically overt CVD (mean age, 59 years; 56% women). Clinical correlates of GDF15 were examined in multivariable analyses. We then conducted a genomewide association study of the GDF15 concentration that included participants in the Framingham Offspring Study and participants in the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. RESULTS: GDF15 was positively associated with age, smoking, antihypertensive treatment, diabetes, worse kidney function, and use of nonsteroidal antiinflammatory drugs (NSAIDs), but it was negatively associated with total cholesterol and HDL cholesterol. Clinical correlates accounted for 38% of interindividual variation in the circulating GDF15 concentration, whereas genetic factors accounted for up to 38% of the residual variability (h 2 = 0.38; P = 2.5 X 10 -11). We identified 1 locus of genomewide significance. This locus, which is on chromosome 19p13.11 and includes the GDF15 gene, is associated with GDF15 concentration (smallest P = 2.74 X 10 -32 for rs888663). Conditional analyses revealed 2 independent association signals at this locus (rs888663 and rs1054564), which were associated with altered cis gene expression in blood cell lines. CONCLUSIONS: In ambulatory individuals, both cardiometabolic risk factors and genetic factors play important roles in determining circulating GDF15 concentrations and contribute similarly to the overall variation.
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| 38. |
- Hruby, Adela, et al.
(författare)
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Higher Magnesium Intake Is Associated with Lower Fasting Glucose and Insulin, with No Evidence of Interaction with Select Genetic Loci, in a Meta-Analysis of 15 CHARGE Consortium Studies
- 2013
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Ingår i: Journal of Nutrition. - : Elsevier BV. - 0022-3166 .- 1541-6100. ; 143:3, s. 345-353
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Tidskriftsartikel (refereegranskat)abstract
- Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (In-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [beta = -0.009 mmol/L (95% CI: -0.013, -0.005), P< 0.0001] and insulin (-0.020 In-pmo/L (95% CI: -0.024, -0.017), P< 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P= 0.03) with glucose, and rs11558471 in SLC30A8and rs3740393 near CNNM2showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted. J. Nutr. 143: 345-353, 2013.
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| 39. |
- Peters, S. A. E., et al.
(författare)
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Increased age, high body mass index and low HDL-C levels are related to an echolucent carotid intima-media : the METEOR study
- 2012
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 272:3, s. 257-266
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. Echolucent plaques are related to a higher cardiovascular risk. Studies to investigate the relationship between echolucency and cardiovascular risk in the early stages of atherosclerosis are limited. We studied the relationship between cardiovascular risk factors and echolucency of the carotid intimamedia in low-risk individuals.Methods. Data were analysed from the Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) study, a randomized placebo-controlled trial including 984 individuals which showed that rosuvastatin attenuated the rate of change of carotid intimamedia thickness (CIMT). In this post hoc analysis, duplicate baseline ultrasound images from the far wall of the left and right common carotid arteries were used for the evaluation of the echolucency of the carotid intimamedia, measured by grey-scale median (GSM) on a scale of 0256. Low GSM values reflect echolucent, whereas high values reflect echogenic structures. The relationship between baseline GSM and cardiovascular risk factors was evaluated using linear regression models.Results. Mean baseline GSM (+/- SD) was 84 +/- 29. Lower GSM of the carotid intimamedia was associated with older age, high body mass index (BMI) and low levels of high-density lipoprotein cholesterol (HDL-C) [beta -4.49, 95% confidence interval (CI) -6.50 to -2.49; beta -4.51, 95% CI -6.43 to -2.60; beta 2.45, 95% CI 0.47 to 4.42, respectively]. Common CIMT was inversely related to GSM of the carotid intimamedia (beta -3.94, 95% CI -1.98 to -5.89).Conclusion. Older age, high BMI and low levels of HDL-C are related to echolucency of the carotid intimamedia. Hence, echolucency of the carotid intimamedia may be used as a marker of cardiovascular risk profile to provide more information than thickness alone.
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| 40. |
- Peters, S A E, et al.
(författare)
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Manual or semi-automated edge detection of the maximal far wall common carotid intima-media thickness : a direct comparison
- 2012
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 271:3, s. 247-256
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Tidskriftsartikel (refereegranskat)abstract
- Background: Automated edge detection is thought to be superior to manual edge detection in quantification of the far wall common carotid intima-media thickness (CIMT), yet published evidence making a direct comparison is not available. Methods: Data were used from the METEOR study, a randomized placebo-controlled trial among 984 individuals showing that rosuvastatin attenuated the rate of change of 2 year change in CIMT among low-risk individuals with subclinical atherosclerosis. For this post hoc analysis, CIMT images of the far wall of the common carotid artery were evaluated using manual and semi-automated edge detection and reproducibility, relation to cardiovascular risk factors, rates of change over time and effects of lipid-lowering therapy were assessed. Results: Reproducibility was high for both reading methods. Direction, magnitude and statistical significance of risk factor relations were similar across methods. Rate of change in CIMT in participants assigned to placebo was 0.0066 mm per year (SE: 0.0027) for manually and 0.0072 mm per year (SE: 0.0029) for semi-automatically read images. The effect of lipid-lowering therapy on CIMT changes was -0.0103 mm per year (SE: 0.0032) for manual reading and -0.0111 mm per year (SE: 0.0034) for semi-automated reading. Conclusion: Manual and semi-automated readings of the maximal far wall of the common CIMT images both result in high reproducibility, show similar risk factor relations, rates of change and treatment effects. Hence, choices between semi-automated and manual reading software for CIMT studies likely should be based on logistical and cost considerations rather than differences in expected data quality when the choice is made to use far wall common CIMT measurements.
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| 41. |
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| 42. |
- Tang, Wenbo, et al.
(författare)
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Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:7, s. e100776-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 x 10(-7)). In addition, meta-analysis using the five cohorts with >= 3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 x 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
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| 43. |
- Warden, Diane, et al.
(författare)
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Anticipated Benefits of Care (ABC) : psychometrics and predictive value in psychiatric disorders
- 2010
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Ingår i: Psychological Medicine. - 0033-2917 .- 1469-8978. ; 40:6, s. 955-965
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Attitudes and expectations about treatment have been associated with symptomatic outcomes, adherence and utilization in patients with psychiatric disorders. No measure of patients' anticipated benefits of treatment on domains of everyday functioning has previously been available.MethodThe Anticipated Benefits of Care (ABC) is a new, 10-item questionnaire used to measure patient expectations about the impact of treatment on domains of everyday functioning. The ABC was collected at baseline in adult out-patients with major depressive disorder (MDD) (n=528), bipolar disorder (n=395) and schizophrenia (n=447) in the Texas Medication Algorithm Project (TMAP). Psychometric properties of the ABC were assessed, and the association of ABC scores with treatment response at 3 months was evaluated. RESULTS: Evaluation of the ABC's internal consistency yielded Cronbach's alpha of 0.90-0.92 for patients across disorders. Factor analysis showed that the ABC was unidimensional for all patients and for patients with each disorder. For patients with MDD, lower anticipated benefits of treatment was associated with less symptom improvement and lower odds of treatment response [odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57-0.87, p=0.0011]. There was no association between ABC and symptom improvement or treatment response for patients with bipolar disorder or schizophrenia, possibly because these patients had modest benefits with treatment. CONCLUSIONS: The ABC is the first self-report that measures patient expectations about the benefits of treatment on everyday functioning, filling an important gap in available assessments of attitudes and expectations about treatment. The ABC is simple, easy to use, and has acceptable psychometric properties for use in research or clinical settings.
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| 44. |
- Yamamoto, T., et al.
(författare)
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Changes in circulating biomarkers during a single hemodialysis session
- 2013
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Ingår i: Hemodialysis International. - : Wiley. - 1492-7535 .- 1542-4758. ; 17:1, s. 59-66
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Tidskriftsartikel (refereegranskat)abstract
- The hemodialysis (HD) procedure induces an inflammatory response potentially contributing to cardiovascular disease. Here we investigated the acute impact of HD on circulating biomarkers. Circulating biomarkers (small solutes, middle molecular-sized peptides, and proteins) related to inflammation, oxidative stress, and vascular calcification (VC) were measured before and after a single session of HD in 45 clinically stable patients. Concentrations were corrected for ultrafiltration-induced hemoconcentration. Among vascular calcification-related biomarkers, osteoprotegerin and fetuin-A remained unchanged while fibroblast growth factor-23 (FGF23) decreased by -19%. Changes of FGF23 and changes of phosphate correlated (ρ=0.61, P<0.001). While C-reactive protein did not change, interleukin-6 (IL-6) increased by 14% and pentraxin 3 (PTX3) increased by 45%. IL-6 and PTX3 appear to be valid biomarkers of the intradialytic inflammatory response. VC-related markers were in general not affected by the single HD session; however, the observed correlation between acute changes of FGF-23 and phosphate during HD warrants further studies.
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| 45. |
- Ayesa, S., et al.
(författare)
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CYSTEINE PROTEASE INHIBITORS
- 2011
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Patent (populärvet., debatt m.m.)abstract
- Compounds of the formula IwhereinR1a is H; and R1b is C1-C6 alkyl, Carbocyclyl or Het; orR1a and R1b together define a saturated cyclic amine with 3-6 ring atoms;R2a and R2b are H, halo, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy; orR2a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl;R3 is a branched C5-C10alkyl chain, C2-C4haloalkyl or C3-C7cycloalkylmethyl,R4 is Het, Carbocyclyl,optionally substituted as defined in the specification and pharmaceutically acceptable salts,hydrates and N-oxides thereof; are inhibitors of cathepsin S and have utility in the treatment of psoriasis, autoimmune disorders and other disorders such as asthma, arteriosclerosis, COPD and chronic pain.
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| 46. |
- Damiani, F., et al.
(författare)
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Gaia-ESO Survey: Empirical classification of VLT/Giraffe stellar spectra in the wavelength range 6440-6810 angstrom in the gamma Velorum cluster, and calibration of spectral indices
- 2014
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 566
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Tidskriftsartikel (refereegranskat)abstract
- We present a study of spectral diagnostics available from optical spectra with R = 17 000 obtained with the VLT/Giraffe HR15n setup, using observations from the Gaia-ESO Survey, on the gamma Vel young cluster, with the purpose of classifying these stars and finding their fundamental parameters. We define several spectroscopic indices, sampling the amplitude of TiO bands, the H alpha line core and wings, and temperature- and gravity-sensitive sets of lines, each useful as a T-eff or log g indicator over a limited range of stellar spectral types. H alpha line indices are also useful as chromospheric activity or accretion indicators. Furthermore, we use all indices to define additional global T-eff - and logg-sensitive indices tau and gamma, valid for the entire range of types in the observed sample. We find a clear difference between gravity indices of main-sequence and pre-main-sequence stars, as well as a much larger difference between these and giant stars. The potentially great usefulness of the (gamma, t) diagram as a distance-independent age measurement tool for young clusters is discussed. We discuss the effect on the defined indices of classical T Tauri star veiling, which is however detected in only a few stars in the present sample. Then, we present tests and calibrations of these indices, on the basis of both photometry and literature reference spectra, from the UVES Paranal Observatory Project and the ELODIE 3.1 Library. The known properties of these stars, spanning a wide range of stellar parameters, enable us to obtain a good understanding of the performances of our new spectral indices. For non-peculiar stars with known temperature, gravity, and metallicity, we are able to calibrate quantitatively our indices, and derive stellar parameters for a wide range of stellar types. To this aim, a new composite index is defined, providing a good metallicity indicator. The ability of our indices to select peculiar, or otherwise rare classes of stars is also established. For pre-main-sequence stars outside the parameter range of the ELODIE dataset, index calibration relies on model isochrones. We check our calibrations against current Gaia-ESO UVES results, plus a number of Survey benchmark stars, and also against Gaia-ESO observations of young clusters, which contribute to establishing the good performance of our method across a wide range of stellar parameters. Our gravity determination for late-type PMS stars is found to be accurate enough to let us obtain gravity-based age estimates for PMS clusters. Finally, our gravity determinations support the existence of an older pre-main-sequence population in the gamma Vel sky region, in agreement with evidence obtained from the lithium depletion pattern of the same stars.
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| 47. |
- Flannick, Jason, et al.
(författare)
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
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Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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| 48. |
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| 49. |
- Gifstad, T, et al.
(författare)
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Lower risk of revision with patellar tendon autografts compared with hamstring autografts: a registry study based on 45,998 primary ACL reconstructions in Scandinavia
- 2014
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Ingår i: The American journal of sports medicine. - : SAGE Publications. - 1552-3365 .- 0363-5465. ; 42:10, s. 2319-2328
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Tidskriftsartikel (refereegranskat)abstract
- A number of studies have found comparable results after anterior cruciate ligament (ACL) reconstruction with patellar tendon autografts and hamstring autografts; however, few studies have been large enough to reveal differences in risk of revision with regard to clinical and demographic factors. Purpose: To present the distribution of grafts for ACL reconstruction based on data in the Scandinavian ACL registries and to compare the risk of revision between patellar tendon autografts and hamstring autografts. Potential associations with other clinical and demographic factors were also explored. Study design: Cohort study; Level of evidence, 2. Methods: A total of 45,998 primary ACL reconstructions, including 6736 patellar tendon autografts and 38,666 hamstring autografts, were identified in the Scandinavian ACL registries. The overall median follow-up time was 3 years (range, 0-8 years). To compare the risk of revision between groups of patients, univariate Kaplan-Meier analysis (with log-rank test) and the Cox proportional hazard regression model were applied. The hazard rate ratio with 95% CI was reported as a measure of effect. Results: Patellar tendon and hamstring autografts were used in 14.6% and 84.1% of the patients, respectively. The remaining patients received allografts, direct sutures, or other graft types (1.3%). The primary ACL injury occurred during soccer, team handball, or alpine activities in 67.5% of the patients in the patellar tendon group and 66.2% in the hamstring group. A total of 156 patients in the patellar tendon group and 1042 patients in the hamstring group underwent revision. The overall risk of revision was significantly lower in the patellar tendon group versus the hamstring group (hazard rate ratio = 0.63; 95% CI, 0.53-0.74), and it decreased with increasing age at surgery, although not strictly linearly. The lower risk of revision in the patellar tendon group was consistently observed across subgroups of patient sex, age, and concomitant cartilage injury ( P > .05, test for interaction) but seemed to be slightly more pronounced for patients injured during certain pivoting activities (soccer, team handball, and alpine activities) compared with other activities (hazard rate ratio = 0.57 vs 0.81; P = .058, test for interaction). Conclusion: The majority of primary ACL reconstructions in Scandinavia are performed with hamstring autografts. Results from the present large prospective study show that patients receiving patellar tendon autografts have a statistically significantly lower risk of revision compared with patients receiving hamstring autografts.
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