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- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- 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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- Hoppe, Torborg, et al.
(författare)
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Moisturizing treatment of patients with atopic dermatitis and ichthyosis vulgaris improves dry skin, but has a modest effect on gene expression regardless of FLG genotype
- 2015
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Ingår i: Journal of the European Academy of Dermatology and Venereology. - : Wiley. - 0926-9959 .- 1468-3083. ; 29:1, s. 174-177
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundLoss-of-function mutations in FLG (encoding filaggrin) are a predisposing factor for atopic dermatitis (AD) and cause ichthyosis vulgaris (IV). Patients with AD and IV display impaired skin barrier and dry skin, and altered epidermal expression of genes in pro-inflammatory and lipid metabolic pathways are often evident.ObjectivesTo evaluate the effect of three different moisturizers on skin barrier function and epidermal gene expression in patients with AD/IV in relation to FLG mutation status.MethodsPatients (n = 43) were classified according to their FLG status: AD with FLG+/+ (n = 14), AD with FLG+/− (n = 14), and AD/IV with FLG−/− (n = 15). Dryness score and transepidermal water loss (TEWL) were monitored on volar forearms, and punch biopsies were taken for analysis of gene expression. Measurements were repeated after 4 weeks of treatment with either of two moisturizers on each forearm.ResultsTreatment with any of the three moisturizers significantly reduced dryness score and TEWL in the group as a whole. FLG−/− patients displayed the largest reduction in dryness score. Only minute changes occurred in the mRNA expression of 15 selected epidermal genes.ConclusionsMoisturizing treatment improves dry skin and certain aspects of abnormal skin barrier function, especially in patients with AD/IV and dual FLG mutations, but does not normalize the epidermal gene expression profile.
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- Lindberg, Anne, et al.
(författare)
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Low nicotine dependence and high self-efficacy can predict smoking cessation independent of the presence of chronic obstructive pulmonary disease: a three year follow up of a population-based study
- 2015
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Ingår i: Tobacco Induced Diseases. - : E.U. European Publishing. - 1617-9625. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD), and smoking cessation is the only intervention that slows disease progression. It is important to know whether current factors related to smoking and smoking cessation are different among subjects with and without COPD in order to support smoking cessation. The aim of this study was to evaluate factors related to smoking cessation and to compare characteristics and nicotine dependence among smokers with and without COPD. Methods: In 2005, 1614 subjects in a population-based longitudinal study of subjects with COPD and controls were examined. The Fagerstrom Test for Nicotine Dependence (FTND) and motivation for smoking cessation were assessed for current smokers (n = 299 total, 194 with COPD). Data on smoking cessation were collected in a follow-up in 2008 (n = 240). Results: Smokers with COPD had more pack-years and respiratory symptoms than smokers without COPD, whereas higher FTND scores were associated with anxiety/depression and respiratory symptoms in both groups. Nineteen percent of the smokers had quit smoking by the follow-up 3 years later, and they had significantly lower FTND scores (2.54 vs. 3.75, p < 0.001) and higher self-efficacy scores (10.0 vs. 6.0, p = 0.020) at baseline than the sustained smokers. Smoking cessation was related to low FTND scores and high self-efficacy independent of the presence of COPD, respiratory symptoms, anxiety/depression, and heart disease. Conclusions: The FTND score and a simple visual analog scale for assessing self-efficacy seem to be valuable instruments for predicting smoking cessation over several years, independent of COPD, respiratory symptoms, presence of anxiety/depression, and heart disease.
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- Perisic, L., et al.
(författare)
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Gene expression signatures, pathways and networks in carotid atherosclerosis
- 2016
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Ingår i: Journal of Internal Medicine. - : Wiley-Blackwell. - 0954-6820 .- 1365-2796. ; 279:3, s. 293-308
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundEmbolism from unstable atheromas in the carotid bifurcation is a major cause of stroke. Here, we analysed gene expression in endarterectomies from patients with symptomatic (S) and asymptomatic (AS) carotid stenosis to identify pathways linked to plaque instability. MethodsMicroarrays were prepared from plaques (n = 127) and peripheral blood samples (n = 96) of S and AS patients. Gene set enrichment, pathway mapping and network analyses of differentially expressed genes were performed. ResultsThese studies revealed upregulation of haemoglobin metabolism (P = 2.20E-05) and bone resorption (P = 9.63E-04) in S patients. Analysis of subgroups of patients indicated enrichment of calcification and osteoblast differentiation in S patients on statins, as well as inflammation and apoptosis in plaques removed >1 month compared to <2 weeks after symptom. By prediction profiling, a panel of 30 genes, mostly transcription factors, discriminated between plaques from S versus AS patients with 78% accuracy. By meta-analysis, common gene networks associated with atherosclerosis mapped to hypoxia, chemokines, calcification, actin cytoskeleton and extracellular matrix. A set of dysregulated genes (LMOD1, SYNPO2, PLIN2 and PPBP) previously not described in atherosclerosis were identified from microarrays and validated by quantitative PCR and immunohistochemistry. ConclusionsOur findings confirmed a central role for inflammation and proteases in plaque instability, and highlighted haemoglobin metabolism and bone resorption as important pathways. Subgroup analysis suggested prolonged inflammation following the symptoms of plaque instability and calcification as a possible stabilizing mechanism by statins. In addition, transcriptional regulation may play an important role in the determination of plaque phenotype. The results from this study will serve as a basis for further exploration of molecular signatures in carotid atherosclerosis.
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