1,721,388 research outputs found
Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles
No full textAims/hypothesis Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals. Methods A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis. Results The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min(-1) m(-2) (mmol/l)(-1), p=1.51 x 10(-6)). The same was seen for the 30 min insulin response (p=4.17 x 10(-7)). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p < 0.001 and p=0.003, respectively). Conclusions/interpretation This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in non-diabetic individuals
A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach
Full text linkGenome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10−7), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05–1.32); meta-analysis p = 2.6×10−8). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10−15; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.Version of Recor
Unraveling the directional link between adiposity and inflammation: a bidirectional mendelian randomization approach
Full text link<b>Context</b>: Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven.
<b>Objective</b>: The aim of the study was to explore the causal direction of the relationship between adiposity and inflammation using a bidirectional Mendelian randomization approach.
<b>Methods</b>: In the PROSPER study of 5804 elderly patients, we related C-reactive protein (CRP) single nucleotide polymorphisms (SNPs) (rs1800947 and rs1205) and adiposity SNPs (FTO and MC4R) to body mass index (BMI) as well as circulating levels of CRP and leptin. We gave each individual two allele scores ranging from zero to 4, counting each pair of alleles related to CRP levels or BMI.
<b>Results</b>: With increasing CRP allele score, there was a stepwise decrease in CRP levels (P for trend < 0.0001) and a 1.98 mg/liter difference between extremes of the allele score distribution, but there was no associated change in BMI or leptin levels (P ≥ 0.89). By contrast, adiposity allele score was associated with 1) an increase in BMI (1.2 kg/m2 difference between extremes; P for trend 0.002); 2) an increase in circulating leptin (5.77 ng/ml difference between extremes; P for trend 0.0027); and 3) increased CRP levels (1.24 mg/liter difference between extremes; P for trend 0.002).
<b>Conclusions</b>: Greater adiposity conferred by FTO and MC4R SNPs led to higher CRP levels, with no evidence for any reverse pathway. Future studies should extend our findings to other circulating inflammatory parameters. This study illustrates the potential power of Mendelian randomization to dissect directions of causality between intercorrelated metabolic factors
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function
No full textOBJECTIVE- Type 2 diabetes is characterized by impaired pancreatic beta-cell function and decreased insulin sensitivity. Genome-wide association studies have identified common, novel type 2 diabetes susceptibility loci within the FTO, CDYAL1, CDKNT2A/CDKNT2B, IGF2BP2, HHEX/IDE, and SLC30A8 gene regions. Our objective was to explore the relationships between the diabetes-associated alleles and measures of beta-cell function and whole-body insulin sensitivity. RESEARCH DESIGN AND METHODS- A total of 1,276 healthy subjects of European ancestry were studied at 19 centers. Indexes of beta-cell function (including 30-min insulin response and glucose sensitivity) were derived from a 75-g oral glucose tolerance test, and whole-body insulin sensitivity (MA) was assessed by hyperinsulinemic-euglycemic clamp. Genotype/phenotype relationships were studied by linear trend analysis correcting for age, sex, and recruitment center. RESULTS- CDYAL1 and HHEX/IDE diabetes-associated alleles were both associated with decreased 30-min insulin response (both P = 0.0002) and decreased pancreatic beta-cell glucose sensitivity (P = 9.86 X 10(-5) and 0.009, respectively), and these relationships remained after correction for M/I. The FTO susceptibility allele showed a weak but consistent association with increased adiposity, which in turn was linked to a decrease in M/I. However, none of the other novel diabetes susceptibility alleles were associated with insulin sensitivity. CONCLUSIONS- CDKAL1 and HHEX/IDF diabetes-associated alleles are associated with decreased pancreatic beta-cell function, including decreased beta-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. We confirmed the association between the FTO allele and increased adiposity, but none of the other novel susceptibility alleles were associated with whole-body insulin sensitivity
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