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971.
Gjesing AP Vestmar MA Jørgensen T Heni M Holst JJ Witte DR Hansen T Pedersen O 《PloS one》2011,6(9):e23907
Background
We aimed to evaluate the effects of the G-allele of rs6232 and the C-allele of rs6235 within PCSK1 on measures of body fat and glucose homeostasis in Danish individuals and to assess interactions of genotypes with age, sex and glucose tolerance status. Data were included in meta-analyses of additional Europeans.Methodology/Principal Findings
Rs6232 and rs6235 were genotyped in 6,164 Danes from the Inter99 study of middle-aged people. Results from these analyses were combined with previously published studies in meta-analyses of a total of 27,786 individuals. The impact of the variants was also investigated in a subset of 62 glucose-tolerant men during a meal challenge including measures of serum incretins. In men we found an effect on body composition in sex-stratified analyses where the rs6235 C-allele conferred an increased waist circumference of 0.8 cm per allele (0.2–1.5, p = 0.008) and increased waist-to-hip ratio of 0.004 (0.0005–0.008, p = 0.027). In the meta-analyses where men and women were combined, the rs6232 G-allele associated with increased waist-to-hip ratio (p = 0.02) and the rs6235 C-allele associated with increased waist circumference (p = 0.01). Furthermore, the rs6235 C-allele was associated nominally with a 0.6% (0.1–1%, p = 0.01) reduction in fasting glucose, it interacted with glucose tolerance status for traits related to glucose metabolism and analysis among individuals having abnormal glucose tolerance revealed a 5% (−0.7–9%, p = 0.02) elevated level of acute insulin response for this variant. Finally, we found that the rs6232 G-allele associated with higher levels of GLP-1, GLP-2 and glucagon and that the rs6235 C-allele associated with higher levels of GIP and glucagon during a meal-test.Conclusions/Significance
PCSK1 rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex, whereas the effect of rs6235 C-allele on fasting and stimulated circulating plasma glucose and hormone levels may be influenced by glucose tolerance status. 相似文献972.
Banasik K Justesen JM Hornbak M Krarup NT Gjesing AP Sandholt CH Jensen TS Grarup N Andersson A Jørgensen T Witte DR Sandbæk A Lauritzen T Thorens B Brunak S Sørensen TI Pedersen O Hansen T 《PloS one》2011,6(1):e16542
Objective
Candidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes.Research Design and Methods
By integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs) which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D), central obesity, and WHO-defined metabolic syndrome (MetS).Results
273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P<0.05) to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations.Conclusions
Using a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS. 相似文献973.
Inference of the Genetic Architecture Underlying BMI and Height with the Use of 20,240 Sibling Pairs
Gibran Hemani Jian Yang Anna Vinkhuyzen Joseph?E. Powell Gonneke Willemsen Jouke-Jan Hottenga Abdel Abdellaoui Massimo Mangino Ana?M. Valdes Sarah?E. Medland Pamela?A. Madden Andrew?C. Heath Anjali?K. Henders Dale?R. Nyholt Eco?J.C. de?Geus Patrik?K.E. Magnusson Erik Ingelsson Grant?W. Montgomery Timothy?D. Spector Dorret?I. Boomsma Nancy?L. Pedersen Nicholas?G. Martin Peter?M. Visscher 《American journal of human genetics》2013,93(5):865-875
Evidence that complex traits are highly polygenic has been presented by population-based genome-wide association studies (GWASs) through the identification of many significant variants, as well as by family-based de novo sequencing studies indicating that several traits have a large mutational target size. Here, using a third study design, we show results consistent with extreme polygenicity for body mass index (BMI) and height. On a sample of 20,240 siblings (from 9,570 nuclear families), we used a within-family method to obtain narrow-sense heritability estimates of 0.42 (SE = 0.17, p = 0.01) and 0.69 (SE = 0.14, p = 6 × 10−7) for BMI and height, respectively, after adjusting for covariates. The genomic inflation factors from locus-specific linkage analysis were 1.69 (SE = 0.21, p = 0.04) for BMI and 2.18 (SE = 0.21, p = 2 × 10−10) for height. This inflation is free of confounding and congruent with polygenicity, consistent with observations of ever-increasing genomic-inflation factors from GWASs with large sample sizes, implying that those signals are due to true genetic signals across the genome rather than population stratification. We also demonstrate that the distribution of the observed test statistics is consistent with both rare and common variants underlying a polygenic architecture and that previous reports of linkage signals in complex traits are probably a consequence of polygenic architecture rather than the segregation of variants with large effects. The convergent empirical evidence from GWASs, de novo studies, and within-family segregation implies that family-based sequencing studies for complex traits require very large sample sizes because the effects of causal variants are small on average. 相似文献
974.
In the high-arctic archipelago of Svalbard, the pink-footed goose (Anser brachyrhynchus) population has increased dramatically over the last decades. The population increase and the corresponding range expansion suggest a substantial increase in the potential for disturbance of the tundra caused by goose herbivory. In this study, we used surveys of pink-footed goose grubbing from two separate years (2007 and 2012) to examine the temporal changes in the prevalence of grubbing in central Spitsbergen. During this time period, the Svalbard-breeding pink-footed goose population had increased from 56,400 to 80,000 individuals. We compared grubbing prevalence between the 2 years, standardising the comparison by using a published model of habitat suitability for grubbing (Speed et al. in Ecosystems 12:349-359, 2009) as a covariate. Habitat suitability was a significant predictor of grubbing prevalence across both years, with higher grubbing probability in habitats predicted to be more suitable for grubbing. The probability of grubbing was on average 4 times higher in 2012 than in 2007. In 2007, all tundra habitats had a probability of <27 % of being grubbed whilst in 2012, there was a probability for being grubbed of more than 34 % in the least suitable habitat and around 59 % in the most suitable habitat. The increase in grubbing prevalence demonstrates a great need for monitoring the expanding pink-footed goose population and its impact on the tundra landscape. 相似文献
975.
976.
Kristin I. L?ken-Amsrud Kjell-Morten Myhr S?ren J. Bakke Antonie G. Beiske Kristian S. Bjerve B?rd T. Bj?rnar? Harald Hovdal Finn Lille?s Rune Midgard Tom Pedersen Jūrat? ?altyt? Benth ?ivind Torkildsen Stig Wergeland Trygve Holm?y 《PloS one》2013,8(1)
Objective
Alpha-tocopherol is the main vitamin E compound in humans, and has important antioxidative and immunomodulatory properties. The aim of this study was to study alpha-tocopherol concentrations and their relationship to disease activity in Norwegian multiple sclerosis (MS) patients.Methods
Prospective cohort study in 88 relapsing-remitting MS (RRMS) patients, originally included in a randomised placebo-controlled trial of omega-3 fatty acids (the OFAMS study), before and during treatment with interferon beta. The patients were followed for two years with repeated 12 magnetic resonance imaging (MRI) scans and nine serum measurements of alpha-tocopherol.Results
During interferon beta (IFNB) treatment, each 10 µmol/L increase in alpha-tocopherol reduced the odds (CI 95%) for simultaneous new T2 lesions by 36.8 (0.5–59.8) %, p = 0.048, and for combined unique activity by 35.4 (1.6–57.7) %, p = 0.042, in a hierarchical regression model. These associations were not significant prior to IFNB treatment, and were not noticeably changed by gender, age, body mass index, HLA-DRB1*15, treatment group, compliance, or the concentrations of 25-hydroxyvitamin D, retinol, neutralising antibodies against IFNB, or the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. The corresponding odds for having new T1 gadolinium enhancing lesions two months later was reduced by 65.4 (16.5–85.7) %, p = 0.019, and for new T2 lesions by 61.0 (12.4–82.6) %, p = 0.023.Conclusion
During treatment with IFNB, increasing serum concentrations of alpha-tocopherol were associated with reduced odds for simultaneous and subsequent MRI disease activity in RRMS patients. 相似文献977.
Objective
In a large population-based cohort in Denmark to examine if maternal use of antibiotics during pregnancy, as a marker of infection, increases the risk of febrile seizures in childhood in a large population-based cohort in Denmark.Methods
All live-born singletons born in Denmark between January 1, 1996 and September 25, 2004 and who were alive on the 90th day of life were identified from the Danish National Birth Registry. Diagnoses of febrile seizures were obtained from the Danish National Hospital Register and maternal use of antibiotics was obtained from the National Register of Medicinal Product Statistics. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazard regression models.Results
We followed 551,518 singletons for up to 5 years and identified a total of 21,779 children with a diagnosis of febrile seizures. Slightly increased hazard ratios were observed among most exposure groups when compared to the unexposed group, ex. HR 1.08 95% CI: 1.05–1.11 for use of any systemic antibiotic during pregnancy.Conclusion
We found weak associations between the use of pharmacologically different antibiotics during pregnancy and febrile seizures in early childhood which may indicate that some infections, or causes or effects of infections, during pregnancy could affect the fetal brain and induce susceptibility to febrile seizures. 相似文献978.
David J. Pedersen Barbara Diakanastasis Jacqueline St?ckli Carsten Schmitz-Peiffer 《PloS one》2013,8(3)
We have previously shown that deletion of protein kinase C epsilon (PKCε) in mice results in protection against glucose intolerance caused by a high fat diet. This was in part due to reduced insulin uptake by hepatocytes and insulin clearance, which enhanced insulin availability. Here we employed mouse embryonic fibroblasts (MEFs) derived from wildtype (WT) and PKCε-deficient (PKCε−/−) mice to examine this mechanistically. PKCε−/− MEFs exhibited reduced insulin uptake which was associated with decreased insulin receptor phosphorylation, while downstream signalling through IRS-1 and Akt was unaffected. Cellular fractionation demonstrated that PKCε deletion changed the localization of the insulin receptor, a greater proportion of which co-fractionated with flotillin-1, a marker of membrane microdomains. Insulin stimulation resulted in redistribution of the receptor in WT cells, while this was markedly reduced in PKCε−/− cells. These alterations in insulin receptor trafficking were associated with reduced expression of CEACAM1, a receptor substrate previously shown to modulate insulin clearance. Virally-mediated reconstitution of PKCε in MEFs increased CEACAM1 expression and partly restored the sensitivity of the receptor to insulin-stimulated redistribution. These data indicate that PKCε can affect insulin uptake in MEFs through promotion of receptor-mediated endocytosis, and that this may be mediated by regulation of CEACAM1 expression. 相似文献
979.
980.
Anne Louise Bischoff Nilofar Vahman F?lsgaard Charlotte Giwercman Carson Jakob Stokholm Louise Pedersen Maria Holmberg Amalie Bisgaard Sune Birch Theodore F. Tsai Hans Bisgaard 《PloS one》2013,8(4)