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- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)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.
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- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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- Soderholm, M., et al.
(författare)
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Genome-wide association meta-analysis of functional outcome after ischemic stroke
- 2019
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 92:12
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Tidskriftsartikel (refereegranskat)abstract
- Objective To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. Methods The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 x 10(-8). Results We identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 x 10(-9)). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10(-5)), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1). Conclusions In this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.
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- Escaned, Javier, et al.
(författare)
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Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes
- 2018
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Ingår i: JACC. - : Elsevier. - 1936-8798 .- 1876-7605. ; 11:15, s. 1437-1449
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS). BACKGROUND Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization. METHODS The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. RESULTS Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p < 0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04). CONCLUSIONS Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year. (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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- Neovius, M., et al.
(författare)
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Drug survival on TNF inhibitors in patients with rheumatoid arthritis comparison of adalimumab, etanercept and infliximab
- 2015
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 74:2, s. 354-360
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Tidskriftsartikel (refereegranskat)abstract
- Objective To compare drug survival on adalimumab, etanercept and infliximab in patients with rheumatoid arthritis (RA). Methods Patients with RA (n=9139; 76% women; mean age 56 years) starting their first tumour necrosis factor (TNF) inhibitor between 2003 and 2011 were identified in the Swedish Biologics Register (ARTIS). Data were collected through 31 December 2011. Drug survival over up to 5 years of follow-up was compared overall and by period of treatment start (2003-2005/2006-2009; n=3168/4184) with adjustment for age, sex, education, period, health assessment questionnaire (HAQ), disease duration, concomitant disease modifying antirheumatic drug (DMARD) treatment and general frailty (using hospitalisation history as proxy). Results During 20 198 person-years (mean/median 2.2/1.7 years) of follow-up, 3782 patients discontinued their first biological (19/100 person-years; 51% due to inefficacy, 36% due to adverse events). Compared with etanercept, infliximab (adjusted HR 1.63, 95% CI 1.51 to 1.77) and adalimumab initiators had higher discontinuation rates (1.26, 95% CI 1.16 to 1.37), and infliximab had a higher discontinuation rate than adalimumab (1.28, 95% CI 1.18 to 1.40). These findings were consistent across periods, but were modified by time for adalimumab versus etanercept (p<0.001; between-drug difference highest the 1st year in both periods). The discontinuation rate was higher for starters in 2006-2009 than 2003-2005 (adjusted HR 1.12, 95% CI 1.04 to 1.20). The composition of 1-year discontinuations also changed from 2003-2005 vs 2006-2009: adverse events decreased from 45% to 35%, while inefficacy increased from 43% to 53% (p<0.001). Conclusions Discontinuation rates were higher for infliximab compared with adalimumab and etanercept initiators, and for adalimumab versus etanercept during the 1st year. Discontinuation rates increased with calendar period, as did the percentage discontinuations due to inefficacy.
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- Collins, Peter J., et al.
(författare)
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The Bi-directional Relationship Between Source Characteristics and Message Content
- 2018
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Ingår i: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Much of what we believe we know, we know through the testimony of others (Coady, 1992). While there has been long-standing evidence that people are sensitive to the characteristics of the sources of testimony, for example in the context of persuasion, researchers have only recently begun to explore the wider implications of source reliability considerations for the nature of our beliefs. Likewise, much remains to be established concerning what factors influence source reliability. In this paper, we examine, both theoretically and empirically, the implications of using message content as a cue to source reliability. We present a set of experiments examining the relationship between source information and message content in people's responses to simple communications. The results show that people spontaneously revise their beliefs in the reliability of the source on the basis of the expectedness of a source's claim and, conversely, adjust message impact by perceived reliability; hence source reliability and message content have a bi-directional relationship. The implications are discussed for a variety of psychological, philosophical and political issues such as belief polarization and dual-route models of persuasion.
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| 10. |
- Olsson, Maja, 1975, et al.
(författare)
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Genome-wide analysis of genetic determinants of circulating factorVII-activating protease (FSAP) activity
- 2018
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 16:10, s. 2024-2034
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Tidskriftsartikel (refereegranskat)abstract
- Background FactorVII-activating protease (FSAP) has roles in both coagulation and fibrinolysis. Recent data indicate its involvement in several other processes, such as vascular remodeling and inflammation. Plasma FSAP activity is highly variable among healthy individuals and, apart from the low-frequency missense variant Marburg-I (rs7080536) in the FSAP-encoding gene HABP2, determinants of this variation are unclear. Objectives To identify novel genetic variants within and outside of the HABP2 locus that influence circulating FSAP activity. Patients/Methods We performed an exploratory genome-wide association study (GWAS) on plasma FSAP activity amongst 3230 Swedish subjects. Directly genotyped rare variants were also analyzed with gene-based tests. Using GWAS, we confirmed the strong association between the Marburg-I variant and FSAP activity. HABP2 was also significant in the gene-based analysis, and remained significant after exclusion of Marburg-I carriers. This was attributable to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant showed a similar reduction in FSAP activity as Marburg-I carriers, and this finding was replicated. A secondary genome-wide significant locus was identified at a 5p15 locus (rs35510613), and this finding requires future replication. This common variant is located upstream of ADCY2, which encodes a protein catalyzing the formation of cAMP. Results and Conclusions This study verified the Marburg-I variant to be a strong regulator of FSAP activity, and identified an HABP2 stop variant with a similar impact on FSAP activity. A novel locus near ADCY2 was identified as a potential additional regulator of FSAP activity.
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