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1.	Heid, Iris M, et al. (author) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution 2010 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960 Journal article (peer-reviewed)abstract Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
2.	Kanoni, Stavroula, et al. (author) Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. 2022 In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1 Journal article (peer-reviewed)abstract Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
3.	Speliotes, Elizabeth K., et al. (author) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index 2010 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948 Journal article (peer-reviewed)abstract Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
4.	Birney, Ewan, et al. (author) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project 2007 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816 Journal article (peer-reviewed)abstract We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
5.	Locke, Adam E, et al. (author) Genetic studies of body mass index yield new insights for obesity biology. 2015 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401 Journal article (peer-reviewed)abstract Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
6.	Ried, Janina S., et al. (author) A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape 2016 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Journal article (peer-reviewed)abstract Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
7.	Shungin, Dmitry, et al. (author) New genetic loci link adipose and insulin biology to body fat distribution. 2015 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378 Journal article (peer-reviewed)abstract Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
8.	van de Vegte, Yordi, et al. (author) Genetic insights into resting heart rate and its role in cardiovascular disease 2023 In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1 Journal article (peer-reviewed)abstract The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
9.	Wang, Xiaofeng, et al. (author) Evidence for type ia supernova diversity from ultraviolet observations with the hubble space telescope 2012 In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 749:2, s. 126- Journal article (peer-reviewed)abstract We present ultraviolet (UV) spectroscopy and photometry of four Type Ia supernovae (SNe 2004dt, 2004ef, 2005M, and 2005cf) obtained with the UV prism of the Advanced Camera for Surveys on the Hubble Space Telescope. This data set provides unique spectral time series down to 2000 angstrom. Significant diversity is seen in the near-maximum-light spectra (similar to 2000-3500 angstrom) for this small sample. The corresponding photometric data, together with archival data from Swift Ultraviolet/Optical Telescope observations, provide further evidence of increased dispersion in the UV emission with respect to the optical. The peak luminositiesmeasured in the uvw1/F250W filter are found to correlate with the B-band light-curve shape parameter Delta m(15)(B), but with much larger scatter relative to the correlation in the broadband B band (e.g., similar to 0.4 mag versus similar to 0.2 mag for those with 0.8 mag < Delta m(15)(B) < 1.7 mag). SN 2004dt is found as an outlier of this correlation (at > 3 sigma), being brighter than normal SNe Ia such as SN 2005cf by similar to 0.9 mag and similar to 2.0 mag in the uvw1/F250W and uvm2/F220W filters, respectively. We show that different progenitor metallicity or line-expansion velocities alone cannot explain such a large discrepancy. Viewing-angle effects, such as due to an asymmetric explosion, may have a significant influence on the flux emitted in the UV region. Detailed modeling is needed to disentangle and quantify the above effects.
10.	Zeng, Chenjie, et al. (author) Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus 2016 In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18 Journal article (peer-reviewed)abstract Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
11.	Lango Allen, Hana, et al. (author) Hundreds of variants clustered in genomic loci and biological pathways affect human height. 2010 In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8 Journal article (peer-reviewed)abstract Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
12.	Berndt, Sonja I., et al. (author) Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 2013 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69 Journal article (peer-reviewed)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.
13.	Ingelsson, Erik, et al. (author) Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans 2010 In: Diabetes. - 0012-1797 .- 1939-327X. ; 59:5, s. 1266-1275 Conference paper (peer-reviewed)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
14.	Ingelsson, Erik, et al. (author) Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans 2010 In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:5, s. 1266-1275 Journal article (peer-reviewed)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.
15.	Kilpeläinen, Tuomas O, et al. (author) Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels 2016 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Journal article (peer-reviewed)abstract Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
16.	Lu, Yingchang, et al. (author) New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk 2016 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Journal article (peer-reviewed)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.
17.	Patel, Riyaz S., et al. (author) Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium 2019 In: Circulation. - 2574-8300. ; 12:4 Journal article (peer-reviewed)abstract BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
18.	Clocchiatti, Alejandro, et al. (author) Late-time HST photometry of SN1994I : Hints of positron annihilation energy deposition 2008 In: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 120:865, s. 290-300 Journal article (peer-reviewed)abstract We present multicolor Hubble Space Telescope ( HST) WFPC2 broadband observations of the Type Ic SN 1994I obtained similar to 280 d after maximum light. We measure the brightness of the SN and, relying on the detailed spectroscopic database of SN 1994I, we transform the ground-based photometry obtained at early times to the HST photometric system, deriving light curves for the WFPC2 F439W, F555W, F675W, and F814W passbands that extend from 7 days before to 280 days after maximum. We use the multicolor photometry to build a quasi-bolometric light curve of SN 1994I, and compare it with similarly constructed light curves of other supernovae. In doing so, we propose and test a scaling in energy and time that allows for a more meaningful comparison of the exponential tails of different events. Through comparison with models, we find that the late-time light curve of SN 1994I is consistent with that of spherically symmetric ejecta in homologous expansion, for which the ability to trap the gamma-rays produced by the radioactive decay of Co-56 diminishes roughly as the inverse of time squared. We also find that by the time of the HST photometry, the light curve was significantly energized by the annihilation of positrons.
19.	Couch, Fergus J., et al. (author) Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer 2016 In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13 Journal article (peer-reviewed)abstract Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
20.	Fall, Tove, et al. (author) Age- and sex-specific causal effects of adiposity on cardiovascular risk factors 2015 In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 64:5, s. 1841-1852 Journal article (peer-reviewed)abstract Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
21.	Flannick, Jason, et al. (author) Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls 2017 In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4 Journal article (peer-reviewed)abstract To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
22.	France, Kevin, et al. (author) HST-COS Observations of Hydrogen, Helium, Carbon, and Nitrogen Emission from the SN 1987A Reverse Shock 2011 In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 743:2, s. 186- Journal article (peer-reviewed)abstract We present the most sensitive ultraviolet observations of Supernova 1987A to date. Imaging spectroscopy from the Hubble Space Telescope-Cosmic Origins Spectrograph shows many narrow (Δv ~ 300 km s-1) emission lines from the circumstellar ring, broad (Δv ~ 10-20 × 103 km s-1) emission lines from the reverse shock, and ultraviolet continuum emission. The high signal-to-noise ratio (>40 per resolution element) broad Lyα emission is excited by soft X-ray and EUV heating of mostly neutral gas in the circumstellar ring and outer supernova debris. The ultraviolet continuum at λ > 1350 Å can be explained by H I two-photon (2s 2 S 1/2-1s 2 S 1/2) emission from the same region. We confirm our earlier, tentative detection of N V λ1240 emission from the reverse shock and present the first detections of broad He II λ1640, C IV λ1550, and N IV] λ1486 emission lines from the reverse shock. The helium abundance in the high-velocity material is He/H = 0.14 ± 0.06. The N V/Hα line ratio requires partial ion-electron equilibration (Te /Tp ≈ 0.14-0.35). We find that the N/C abundance ratio in the gas crossing the reverse shock is significantly higher than that in the circumstellar ring, a result that may be attributed to chemical stratification in the outer envelope of the supernova progenitor. The N/C abundance may have been stratified prior to the ring expulsion, or this result may indicate continued CNO processing in the progenitor subsequent to the expulsion of the circumstellar ring. Based on observations made with the NASA/ESA Hubble Space Telescope, obtained from the data archive at the Space Telescope Science Institute. STScI is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555.
23.	France, Kevin, et al. (author) MAPPING HIGH-VELOCITY H alpha AND Ly alpha EMISSION FROM SUPERNOVA 1987A 2015 In: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 801:1 Journal article (peer-reviewed)abstract We present new Hubble Space Telescope images of high-velocity H alpha and Ly alpha emission in the outer debris of SN 1987 A. The Ha images are dominated by emission from hydrogen atoms crossing the reverse shock (RS). For the first time we observe emission from the RS surface well above and below the equatorial. ring (ER), suggesting a bipolar or conical structure perpendicular to the ring plane. Using the H alpha imaging, we measure the mass flux of hydrogen atoms crossing the RS front, in the velocity intervals (-7500 < V-obs < -2800 km s(-1)) and (1000 < V-obs < 7500 km s(-1)), (M)(H) over dot = 1.2 x 10(-3) M-circle dot yr(-1). We also present the first Ly alpha imaging of the whole remnant and new Chandra X-ray observations. Comparing the spatial distribution of the Ly alpha and X-ray emission, we observe that the majority of the high-velocity Ly alpha emission originates interior to the ER. The observed Ly alpha/H alpha photon ratio, < R(L alpha/H alpha)> approximate to 17, is significantly higher than the theoretically predicted ratio of approximate to 5 for neutral atoms crossing the RS front. We attribute this excess to Ly alpha emission produced by X-ray heating of the outer debris. The spatial orientation of the Ly alpha and X-ray emission suggests that X-ray heating of the outer debris is the dominant Ly alpha production mechanism in SN 1987 A at this phase in its evolution.
24.	France, Kevin, et al. (author) MAPPING high-velocity Hα and Lyα emission from supernova 1987A 2015 In: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 801:1 Journal article (peer-reviewed)abstract We present new Hubble Space Telescope images of high-velocity H alpha and Ly alpha emission in the outer debris of SN 1987 A. The Ha images are dominated by emission from hydrogen atoms crossing the reverse shock (RS). For the first time we observe emission from the RS surface well above and below the equatorial. ring (ER), suggesting a bipolar or conical structure perpendicular to the ring plane. Using the H alpha imaging, we measure the mass flux of hydrogen atoms crossing the RS front, in the velocity intervals (-7500 < V-obs < -2800 km s(-1)) and (1000 < V-obs < 7500 km s(-1)), (M)(H) over dot = 1.2 x 10(-3) M-circle dot yr(-1). We also present the first Ly alpha imaging of the whole remnant and new Chandra X-ray observations. Comparing the spatial distribution of the Ly alpha and X-ray emission, we observe that the majority of the high-velocity Ly alpha emission originates interior to the ER. The observed Ly alpha/H alpha photon ratio, < R(L alpha/H alpha)> approximate to 17, is significantly higher than the theoretically predicted ratio of approximate to 5 for neutral atoms crossing the RS front. We attribute this excess to Ly alpha emission produced by X-ray heating of the outer debris. The spatial orientation of the Ly alpha and X-ray emission suggests that X-ray heating of the outer debris is the dominant Ly alpha production mechanism in SN 1987 A at this phase in its evolution.
25.	France, Kevin, et al. (author) Observing Supernova 1987A with the Refurbished Hubble Space Telescope 2010 In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 329:5999, s. 1624-1627 Journal article (peer-reviewed)abstract Observations with the Hubble Space Telescope (HST), conducted since 1990, now offer an unprecedented glimpse into fast astrophysical shocks in the young remnant of supernova 1987A. Comparing observations taken in 2010 with the use of the refurbished instruments on HST with data taken in 2004, just before the Space Telescope Imaging Spectrograph failed, we find that the Ly alpha and H alpha lines from shock emission continue to brighten, whereas their maximum velocities continue to decrease. We observe broad, blueshifted Ly alpha, which we attribute to resonant scattering of photons emitted from hot spots on the equatorial ring. We also detect N v lambda lambda 1239, 1243 angstrom line emission, but only to the red of Ly alpha. The profiles of the N v lines differ markedly from that of H alpha, suggesting that the N4+ ions are scattered and accelerated by turbulent electromagnetic fields that isotropize the ions in the collisionless shock.
26.	Fransson, Claes, et al. (author) Hubble Space Telescope and Ground-based Observations of SN 1993J and SN 1998S : CNO Processing in the Progenitors 2005 In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 622, s. 991-1007 Journal article (peer-reviewed)abstract Ground-based and Hubble Space Telescope observations are presented for SN 1993J and SN 1998S. SN 1998S shows strong, relatively narrow circumstellar emission lines of N III-V and C III-IV, as well as broad lines from the ejecta. Both the broad ultraviolet and optical lines in SN 1998S indicate an expansion velocity of ~7000 km s-1. The broad emission components of Lyα and Mg II are strongly asymmetrical after day 72 past the explosion and differ in shape from Hα. Different models based on dust extinction from dust in the ejecta or shock region, in combination with Hα from a circumstellar torus, are discussed. It is concluded, however, that the double-peaked line profiles are more likely to arise as a result of optical depth effects in the narrow, cool, dense shell behind the reverse shock than in a torus-like region. The ultraviolet lines of SN 1993J are broad, with a boxlike shape, coming from the ejecta and a cool, dense shell. The shapes of the lines are well fitted by a shell with inner velocity ~7000 km s-1 and outer velocity ~10,000 km s-1. For both SN 1993J and SN 1998S a strong nitrogen enrichment is found, with N/C~12.4 in SN 1993J and N/C~6.0 in SN 1998S. From a compilation of all supernovae with determined CNO ratios, we discuss the implications of these observations for the structure of the progenitors of Type II supernovae. Based in part on observations obtained with the Hubble Space Telescope, which is operated by AURA, Inc., under NASA contract NAS 5-26555.
27.	Fransson, Claes, et al. (author) THE DESTRUCTION OF THE CIRCUMSTELLAR RING OF SN 1987A 2015 In: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 806:1 Journal article (peer-reviewed)abstract We present imaging and spectroscopic observations with Hubble Space Telescope and Very Large Telescope of the ring of SN 1987A from 1994 to 2014. After an almost exponential increase of the shocked emission from the hotspots up to day similar to 8000 (similar to 2009), both this and the unshocked emission are now fading. From the radial positions of the hotspots we see an acceleration of these up to 500-1000 km s(-1), consistent with the highest spectroscopic shock velocities from the radiative shocks. In the most recent observations (2013 and 2014), we find several new hotspots outside the inner ring, excited by either X-rays from the shocks or by direct shock interaction. All of these observations indicate that the interaction with the supernova ejecta is now gradually dissolving the hotspots. We predict, based on the observed decay, that the inner ring will be destroyed by similar to 2025.
28.	Fuchsberger, Christian, et al. (author) The genetic architecture of type 2 diabetes 2016 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47 Journal article (peer-reviewed)abstract The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
29.	Furberg, Helena, et al. (author) Genome-wide meta-analyses identify multiple loci associated with smoking behavior 2010 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 134-441 Journal article (peer-reviewed)abstract Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
30.	Graves, Genevieve J. M., et al. (author) Limits from the Hubble Space Telescope on a Point Source in SN 1987A 2005 In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 629, s. 944-959 Journal article (peer-reviewed)abstract We observed supernova 1987A (SN 1987A) with the Space Telescope Imaging Spectrograph (STIS) on the Hubble Space Telescope (HST) in 1999 September and again with the Advanced Camera for Surveys (ACS) on the HST in 2003 November. Our spectral observations cover ultraviolet (UV) and optical wavelengths from 1140 to 10266 Å, and our imaging observations cover UV and optical wavelengths from 2900 to 9650 Å. No point source is observed in the remnant. We obtain a limiting flux of Fopt<=1.6×10-14 ergs s-1 cm-2 in the wavelength range 2900-9650 Å for any continuum emitter at the center of the supernova remnant (SNR). This corresponds to an intrinsic luminosity of Lopt<=5×1033 ergs s-1. It is likely that the SNR contains opaque dust that absorbs UV and optical emission, resulting in an attenuation of ~35% due to dust absorption in the SNR. Correcting for this level of dust absorption would increase our upper limit on the luminosity of a continuum source by a factor of 1.54. Taking into account dust absorption in the remnant, we find a limit of Lopt<=8×1033 ergs s-1. We compare this upper bound with empirical evidence from point sources in other supernova remnants and with theoretical models for possible compact sources. We show that any survivor of a possible binary system must be no more luminous than an F6 main-sequence star. Bright young pulsars such as Kes 75 or the Crab pulsar are excluded by optical and X-ray limits on SN 1987A. Other nonplerionic X-ray point sources have luminosities similar to the limits on a point source in SN 1987A; RCW 103 and Cas A are slightly brighter than the limits on SN 1987A, while Pup A is slightly fainter. Of the young pulsars known to be associated with SNRs, those with ages <=5000 yr are all too bright in X-rays to be compatible with the limits on SN 1987A. Examining theoretical models for accretion onto a compact object, we find that spherical accretion onto a neutron star is firmly ruled out and that spherical accretion onto a black hole is possible only if there is a larger amount of dust absorption in the remnant than predicted. In the case of thin-disk accretion, our flux limit requires a small disk, no larger than 1010 cm, with an accretion rate no more than 0.3 times the Eddington accretion rate. Possible ways to hide a surviving compact object include the removal of all surrounding material at early times by a photon-driven wind, a small accretion disk, or very high levels of dust absorption in the remnant. It will not be easy to improve substantially on our optical-UV limit for a point source in SN 1987A, although we can hope that a better understanding of the thermal infrared emission will provide a more complete picture of the possible energy sources at the center of SN 1987A.
31.	Heng, Kevin, et al. (author) Evolution of the Reverse Shock Emission from SNR 1987A 2006 In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 644, s. 959-970 Journal article (peer-reviewed)abstract We present new (2004 July) G750L and G140L Space Telescope Imaging Spectrograph (STIS) data of the Hα and Lyα emission from supernova remnant (SNR) 1987A. With the aid of earlier data, from 1997 October to 2002 October, we track the local evolution of Lyα emission and both the local and global evolution of Hα emission. The most recent observations allow us to directly compare the Hα and Lyα emission from the same slit position and at the same epoch. Consequently, we find clear evidence that, unlike Hα, Lyα is reflected from the debris by resonant scattering. In addition to emission that we can clearly attribute to the surface of the reverse shock, we also measure comparable emission, in both Hα and Lyα, that appears to emerge from supernova debris interior to the surface. New observations taken through slits positioned slightly eastward and westward of a central slit show a departure from cylindrical symmetry in the Hα surface emission. Using a combination of old and new observations, we construct a light curve of the total Hα flux, F, from the reverse shock, which has increased by a factor of ~4 over about 8 yr. However, due to large systematic uncertainties, we are unable to discern between the two limiting behaviors of the flux: F~t (self-similar expansion) and F~t5 (halting of the reverse shock). Such a determination is important for constraining the rate of hydrogen atoms crossing the shock, which is relevant to the question of whether the reverse shock emission will vanish in <~7 yr. Future deep, low- or moderate-resolution spectra are essential for accomplishing this task.
32.	Kotak, Rubina, et al. (author) Spitzer Measurements of Atomic and Molecular Abundances in the Type IIP SN 2005af 2006 In: The Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 651:2, s. L117-L120 Journal article (peer-reviewed)abstract We present results based on mid-infrared (3.6-30 μm) observations with the Spitzer Space Telescope of the nearby Type IIP supernova 2005af. We report the first ever detection of the SiO molecule in a Type IIP supernova. Together with the detection of the CO fundamental, this is an exciting finding as it may signal the onset of dust condensation in the ejecta. From a wealth of fine-structure lines we provide abundance estimates for stable Ni, Ar, and Ne that, via spectral synthesis, may be used to constrain nucleosynthesis models.
33.	Lawrenson, Kate, et al. (author) Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus 2016 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Journal article (peer-reviewed)abstract A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
34.	Manning, Alisa, et al. (author) A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk 2017 In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032 Journal article (peer-reviewed)abstract To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
35.	Michael, Eli, et al. (author) Hubble Space Telescope Observations of High-Velocity Lyα and Hα Emission from Supernova Remnant 1987A : The Structure and Development of the Reverse Shock 2003 In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 593, s. 809-830 Journal article (peer-reviewed)abstract We present two-dimensional line profiles of high-velocity (~+/-12,000 km s-1) Lyα and Hα emission from supernova remnant 1987A obtained with the Space Telescope Imaging Spectrograph between 1997 September and 2001 September (days 3869-5327 after the explosion). This emission comes from hydrogen in the debris that is excited and ionized as it passes through the remnant's reverse shock. We use these profiles to measure the geometry and development of the reverse-shock surface. The observed emission is confined within ~+/-30° about the remnant's equatorial plane. At the equator, the reverse shock has a radius of ~75% of the distance to the equatorial ring. We detect marginal differences (6%+/-3%) between the location of the reverse-shock front in the northeast and southwest parts of the remnant. The radius of the reverse shock surface increases for latitudes above the equator, a geometry consistent with a model in which the supernova debris expands into a bipolar nebula. Assuming that the outer supernova debris has a power-law density distribution, we can infer from the reverse-shock emission light curve an expansion rate (in the northeast part of the remnant) of 3700+/-900kms-1, consistent with the expansion velocities determined from observations in radio (Manchester et al.) and X-ray (Park et al.; Michael et al.) wavelengths. However, our most recent observation (at day 5327) suggests that the rate of increase of mass flux across the northeast sector of the reverse shock has accelerated, perhaps because of deceleration of the reverse shock caused by the arrival of a reflected shock created when the blast wave struck the inner ring. Resonant scattering within the supernova debris causes Lyα photons created at the reverse shock to be directed preferentially outward, resulting in a factor of ~5 difference in the observed brightness of the reverse shock in Lyα between the near and far sides of the remnant. Accounting for this effect, we compare the observed reverse-shock Lyα and Hα fluxes to infer the amount of interstellar extinction by dust as E(B-V)=0.17+/-0.01 mag. We also notice extinction by dust in the equatorial ring with E(B-V)~0.02-0.08 mag, which implies dust-to-gas ratios similar to that of the LMC. Since Hα photons are optically thin to scattering, the observed asymmetry in brightness of Hα from the near and far sides of the remnant represents a real asymmetry in the mass flux through the reverse shock of ~30%. We discuss future observational strategies that will permit us to further investigate the reverse-shock dynamics and resonant scattering of the Lyα line and to constrain better the extinction by dust within and in front of the remnant.
36.	Patel, Riyaz S., et al. (author) Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data 2019 In: Circulation. - 2574-8300. ; 12:4 Journal article (peer-reviewed)abstract BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
37.	Prasad, Rashmi B., et al. (author) Excess maternal transmission of variants in the THADA gene to offspring with type 2 diabetes 2016 In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:8, s. 1702-1713 Journal article (peer-reviewed)abstract Aims/hypothesis: Genome-wide association studies (GWAS) have identified more than 65 genetic loci associated with risk of type 2 diabetes. However, the contribution of distorted parental transmission of alleles to risk of type 2 diabetes has been mostly unexplored. Our goal was therefore to search for parent-of-origin effects (POE) among type 2 diabetes loci in families. Methods: Families from the Botnia study (n = 4,211, 1,083 families) were genotyped for 72 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes and assessed for POE on type 2 diabetes. The family-based Hungarian Transdanubian Biobank (HTB) (n = 1,463, >135 families) was used to replicate SNPs showing POE. Association of type 2 diabetes loci within families was also tested. Results: Three loci showed nominal POE, including the previously reported variants in KCNQ1, for type 2 diabetes in families from Botnia (rs2237895: pPOE = 0.037), which can be considered positive controls. The strongest POE was seen for rs7578597 SNP in the THADA gene, showing excess transmission of the maternal risk allele T to diabetic offspring (Botnia: pPOE = 0.01; HTB pPOE = 0.045). These data are consistent with previous evidence of allelic imbalance for expression in islets, suggesting that the THADA gene can be imprinted in a POE-specific fashion. Five CpG sites, including those flanking rs7578597, showed differential methylation between diabetic and non-diabetic donor islets. Conclusions/interpretation: Taken together, the data emphasise the need for genetic studies to consider from which parent an offspring has inherited a susceptibility allele.
38.	Wheeler, Eleanor, et al. (author) 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 In: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 14:9 Journal article (peer-reviewed)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.
39.	Yang, Jian, et al. (author) FTO genotype is associated with phenotypic variability of body mass index 2012 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 490:7419, s. 267-272 Journal article (peer-reviewed)abstract There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
40.	Alp, Dennis, et al. (author) The 30 Year Search for the Compact Object in SN 1987A 2018 In: Astrophysical Journal. - : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 864:2 Journal article (peer-reviewed)abstract Despite more than 30 years of searching, the compact object in Supernova (SN) 1987A has not yet been detected. We present new limits on the compact object in SN 1987A using millimeter, near-infrared, optical, ultraviolet, and X-ray observations from ALMA, VLT, HST, and Chandra. The limits are approximately 0.1 mJy (0.1 x 10(-26) erg s(-1) cm(-2) Hz(-1)) at 213 GHz, 1 L-circle dot (6 x 10(-29) erg s(-1) cm(-2) Hz(-1)) in the optical if our line of sight is free of ejecta dust, and 10(36) erg s(-1) (2 x 10(-30) erg s(-1) cm(-2) Hz(-1) ) in 2-10 keV X-rays. Our X-ray limits are an order of magnitude less constraining than previous limits because we use a more realistic ejecta absorption model based on three-dimensional neutrino-driven SN explosion models. The allowed bolometric luminosity of the compact object is 22 L-circle dot if our line of sight is free of ejecta dust, or 138L(circle dot) if dust-obscured. Depending on assumptions, these values limit the effective temperature of a neutron star (NS) to <4-8 MK and do not exclude models, which typically are in the range 3-4 MK. For the simplest accretion model, the accretion rate for an efficiency 77 is limited to <10(-11) eta(-1) M-circle dot yr(-1), which excludes most predictions. For pulsar activity modeled by a rotating magnetic dipole in vacuum, the limit on the magnetic field strength (B) for a given spin period (P) is B less than or similar to 10(14) P-2 G s(-2), which firmly excludes pulsars comparable to the Crab. By combining information about radiation reprocessing and geometry, we infer that the compact object is a dust-obscured thermally emitting NS, which may appear as a region of higher-temperature ejecta dust emission.
41.	Berglund, Lisa, et al. (author) Glucose-Dependent Insulinotropic Polypeptide (GIP) Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB. 2016 In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:1, s. 239-254 Journal article (peer-reviewed)abstract Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the pro-atherogenic cytokine osteopontin (OPN) in mouse arteries, via local release of endothelin-1 (ET-1) and activation of cAMP response element binding protein (CREB). Infusion of GIP increases plasma OPN levels in healthy individuals. Plasma ET-1 and OPN levels are positively correlated in patients with critical limb ischemia. Fasting GIP levels are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared to controls. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients; and expression associates to parameters characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from human, mouse, rat and pig; remarkable up-regulation is observed in endothelial and smooth muscle cells upon culture conditions yielding a "vascular disease-like" phenotype. Moreover, a common variant rs10423928 in the GIPR gene associated with increased risk of stroke in type 2 diabetes patients.
42.	Burman, Peter, et al. (author) Slutrapport: Genomförbarhetsstudie - Lokala nät och lokal spektrumanvändning för industriella radiosystem 2021 Reports (other academic/artistic)abstract I denna rapport sammanfattar vi utfört utredningsarbete för den studie som vi genomfört under perioden november 2020 – mars 2021 avseende lokala 5G-nät för industrin.Medverkande har varit Boliden Mineral AB, Åkerströms i Björbo AB, Post- och Telesturelsen (PTS) samt KTH. Studien har finansierats av det strategiska innovationsprogrammet Smartare elektroniksystem - en gemensam satsning av Vinnova, Formas och Energimyndigheten.Rapporten rymmer två typer av material, dels beskrivning av nuläge dels analys och slutsatser.Nulägesbeskrivningen för 5G innefattar: status för spektrumtilldelning och utbyggnad av nät i några länder samt om forskning och standardisering vad gäller lokala 5G-nät för industrin.Analysdelen består av resonemang och resultat inom fyra olika områden: i) krav och behov, ii) möjliga scenarier och alternativ för systemlösningar, iii) kort summering av centrala tekniska faktorer för lokala nät avsedda för industrin, samt iv) sammanställning av utmaningar för olika aktörer och för spektrumtilldelning.Icke-publika nät (Non-public networks, NPN) är ett globalt fenomen med stort stöd och intresse från existerande ekosystem inom industri och telekom men även från helt nya spelare från tex IT industrin. NPN drivs av industrins behov av säker och tillförlitlig uppkoppling för digitalisering och automatisering av sina processer. Idag är industrins uppkoppling främst trådbunden, alternativt så använder man sig av ”proprietära”- eller WiFi baserade system i icke-licensierade band (alternativt smala frekvensband specifikt dedicerade för olika industriprocesser). Trådbunden uppkoppling är långsiktigt inte önskvärt för industrin då det begränsar rörligheten.För tillverkare av industriell radiostyrning är slutsatsen att man långsiktigt måste förbereda sig på att migrera från punkt-till-punkt kommunikation till användning av cellulära nätverk. För att industriföretag skall kunna ta beslut om investering i cellulär teknik för uppkoppling istället för tex WiFi, krävs långsiktighet både tekniskt och affärsmässigt. Det är därför viktigt att man kan tillhandahålla frekvenser för industriellt bruk. Bandet 3,72-3,80 GHz är i många länder tilldelat för lokala tillstånd. Detta band är definierat för TDD och behöver synkroniseras med operatörernas nät samt även använda samma fördelning av trafik mellan upp-och nedlänk som dessa nät. Industrins kapacitetsbehov är främst i upplänk medan operatörsnäten främst tillhandahåller video i nedlänk. Vidare finns ett antal andra utmaningar för samexistens mellan lokala nät och operatörsnät. Det är i nuläget oklart om man via endast TDD-tillstånd i 3,5 GHz eller högre frekvensband kommer att kunna tillfredsställa alla behov inom området industriell radiostyrning och icke publika nät.Sammanfattningsvis kan vi konstatera att detta projekt har identifierat ett antal osäkerheter och utmaningar avseende lokala 5G-nät för industrin. Vår bedömning är att dessa är så stora att det i nuläget saknas underlag för att definiera ett större utvecklingsprojekt. För att kunna definiera ett relevant projekt för att utveckla och testa 5G baserad system för industriell radiostyrning behöver ytterligare underlag tas fram. Dessutom bör man även invänta beslut från PTS avseende allokering av frekvenser för industrin.
43.	Cashin, Peter, 1984-, et al. (author) Ex vivo assessment of chemotherapy sensitivity of colorectal cancer peritoneal metastases 2023 In: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 110:9, s. 1080-1083 Journal article (peer-reviewed)abstract Patients with peritoneal metastasis from colorectal cancer (PMCRC) may have a chance of cure when treated with cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC)1–5.Choice of chemotherapy for HIPEC has been based on knowledge of its systemic effects, pharmacokinetics, technical feasibility, hyperthermic efficacy enhancement, and tolerance6–8. Selection of cancer drugs for treatment based on phenotypical assessment of patient cancer cell drug sensitivity ex vivo is one approach to personalized cancer treatment. One technique for this is the fluorometric microculture cytotoxicity assay (FMCA) that has been used in drug development and for the development of personalized cancer medicine9–16.This study investigated whether ex vivo assessment of drug sensitivity by the FMCA provides predictive information in terms of peritoneal recurrence-free survival (PRFS) and overall survival (OS) in patients treated with CRS and HIPEC for isolated PMCRC.
44.	Dahlstedt, Sten, et al. (author) Berättelse och kunskap : en samlingsvolym 2006 Reports (other academic/artistic)
45.	den Hoed, Marcel, et al. (author) Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders 2013 In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:6, s. 621- Journal article (peer-reviewed)
46.	Ding, Bo, et al. (author) Human neuropeptide Y signal peptide gain-of-function polymorphism is associated with increased body mass index : possible mode of function. 2005 In: Regul Pept. - : Elsevier BV. - 0167-0115. ; 127:1-3, s. 45-53 Journal article (peer-reviewed)
47.	Erlinge, D., et al. (author) Bivalirudin versus Heparin Monotherapy in Myocardial Infarction 2017 In: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 377:12, s. 1132-1142 Journal article (peer-reviewed)abstract Background The comparative efficacy of various anticoagulation strategies has not been clearly established in patients with acute myocardial infarction who are undergoing percutaneous coronary intervention (PCI) according to current practice, which includes the use of radial-artery access for PCI and administration of potent P2Y12 inhibitors without the planned use of glycoprotein IIb/IIIa inhibitors. Methods In this multicenter, randomized, registry-based, open-label clinical trial, we enrolled patients with either ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) who were undergoing PCI and receiving treatment with a potent P2Y12 inhibitor (ticagrelor, prasugrel, or cangrelor) without the planned use of glycoprotein IIb/IIIa inhibitors. The patients were randomly assigned to receive bivalirudin or heparin during PCI, which was performed predominantly with the use of radial-artery access. The primary end point was a composite of death from any cause, myocardial infarction, or major bleeding during 180 days of follow-up. Results A total of 6006 patients (3005 with STEMI and 3001 with NSTEMI) were enrolled in the trial. At 180 days, a primary end-point event had occurred in 12.3% of the patients (369 of 3004) in the bivalirudin group and in 12.8% (383 of 3002) in the heparin group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.10; P=0.54). The results were consistent between patients with STEMI and those with NSTEMI and across other major subgroups. Myocardial infarction occurred in 2.0% of the patients in the bivalirudin group and in 2.4% in the heparin group (hazard ratio, 0.84; 95% CI, 0.60 to 1.19; P=0.33), major bleeding in 8.6% and 8.6%, respectively (hazard ratio, 1.00; 95% CI, 0.84 to 1.19; P=0.98), definite stent thrombosis in 0.4% and 0.7%, respectively (hazard ratio, 0.54; 95% CI, 0.27 to 1.10; P=0.09), and death in 2.9% and 2.8%, respectively (hazard ratio, 1.05; 95% CI, 0.78 to 1.41; P=0.76). Conclusions Among patients undergoing PCI for myocardial infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received heparin monotherapy. (Funded by the Swedish Heart-Lung Foundation and others; VALIDATE-SWEDEHEART ClinicalTrialsRegister.eu number, 2012-005260-10 ; ClinicalTrials.gov number, NCT02311231 .).
48.	Fadista, Joao, et al. (author) Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. 2014 In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 111:38, s. 13924-13929 Journal article (peer-reviewed)abstract Genetic variation can modulate gene expression, and thereby phenotypic variation and susceptibility to complex diseases such as type 2 diabetes (T2D). Here we harnessed the potential of DNA and RNA sequencing in human pancreatic islets from 89 deceased donors to identify genes of potential importance in the pathogenesis of T2D. We present a catalog of genetic variants regulating gene expression (eQTL) and exon use (sQTL), including many long noncoding RNAs, which are enriched in known T2D-associated loci. Of 35 eQTL genes, whose expression differed between normoglycemic and hyperglycemic individuals, siRNA of tetraspanin 33 (TSPAN33), 5'-nucleotidase, ecto (NT5E), transmembrane emp24 protein transport domain containing 6 (TMED6), and p21 protein activated kinase 7 (PAK7) in INS1 cells resulted in reduced glucose-stimulated insulin secretion. In addition, we provide a genome-wide catalog of allelic expression imbalance, which is also enriched in known T2D-associated loci. Notably, allelic imbalance in paternally expressed gene 3 (PEG3) was associated with its promoter methylation and T2D status. Finally, RNA editing events were less common in islets than previously suggested in other tissues. Taken together, this study provides new insights into the complexity of gene regulation in human pancreatic islets and better understanding of how genetic variation can influence glucose metabolism.
49.	Fransson, Claes, et al. (author) Late spectral evolution of the ejecta and reverse shock in SN 1987a 2013 In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 768:1, s. 88- Journal article (peer-reviewed)abstract We present observations with the Very Large Telescope and Hubble Space Telescope (HST) of the broad emission lines from the inner ejecta and reverse shock of SN 1987A from 1999 February until 2012 January (days 4381-9100 after explosion). We detect broad lines from H alpha, H beta, Mg I], Na I, [O I], [Ca II], and a feature at similar to 9220 angstrom. We identify the latter line with Mg II lambda lambda 9218, 9244, which is most likely pumped by Ly alpha fluorescence. H alpha and H beta both have a centrally peaked component extending to similar to 4500 km s(-1) and a very broad component extending to greater than or similar to 11,000 km s(-1), while the other lines have only the central component. The low-velocity component comes from unshocked ejecta, heated mainly by X-rays from the circumstellar environment, whereas the very broad component comes from faster ejecta passing through the reverse shock, created by the collision with the circumstellar ring. The flux in H alpha from the reverse shock has increased by a factor of four to six from 2000 to 2007. After that there is a tendency of flattening of the light curve, similar to what may be seen in the optical lines from the shocked ring. The core component seen in H alpha, [Ca II], and Mg II has experienced a similar increase, which is consistent with that found from HST photometry. The energy deposition of the external X-rays is calculated using explosion models for SN 1987A and we predict that the outer parts of the unshocked ejecta will continue to brighten because of this. The external X-ray illumination also explains the edge-brightened morphology of the ejecta seen in the HST images. We finally discuss evidence for dust in the ejecta from line asymmetries.
50.	Gallardo, Rodrigo, et al. (author) De novo design of a biologically active amyloid 2016 In: Science. - : AMER ASSOC ADVANCEMENT SCIENCE. - 0036-8075 .- 1095-9203. ; 354:6313, s. 720- Journal article (peer-reviewed)abstract Most human proteins possess amyloidogenic segments, but only about 30 are associated with amyloid-associated pathologies, and it remains unclear what determines amyloid toxicity. We designed vascin, a synthetic amyloid peptide, based on an amyloidogenic fragment of vascular endothelial growth factor receptor 2 (VEGFR2), a protein that is not associated to amyloidosis. Vascin recapitulates key biophysical and biochemical characteristics of natural amyloids, penetrates cells, and seeds the aggregation of VEGFR2 through direct interaction. We found that amyloid toxicity is observed only in cells that both express VEGFR2 and are dependent on VEGFR2 activity for survival. Thus, amyloid toxicity here appears to be both protein-specific and conditional-determined by VEGFR2 loss of function in a biological context in which target protein function is essential.

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