Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

New genetic loci link adipose and insulin biology to body fat distribution.

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

The picture superiority effect in a cross-modality recognition task

Words and pictures were studied, and recognition tests were given in which each studied object was to be recognized in both word and picture format. The main dependent variable was the latency of the recognition decision. The purpose was to investigate the effects of study modality (word or picture), of congruence between study and test modalities, and of priming resulting from repeated testing. Experiments 1 and 2 used the same basic design, but the latter also varied retention interval. Exp. 3 added a manipulation of instructions to name studied objects, and Exp. 4 deviated from the others by presenting both picture and word referring to the same object together for study. The results showed that congruence between study and test modalities consistently facilitated recognition. Furthermore, items studied as pictures were more rapidly recognized than items studied as words. With repeated testing, the second instance was affected by its predecessor, but the facilitating effect of picture-to-word priming exceeded that of word-to-picture priming. The findings suggest a two-stage recognition process, in which the first is based on perceptual familiarity, and the second uses semantic links for a retrieval search. Common-code theories which grant privileged access to the semantic code for pictures are supported by the findings, or alternatively dual-code theories which assume mnemonic superiority for the image code. Explanations of the picture superiority effect as resulting from dual encoding of pictures are not supported by the data

All professions can benefit — a mixed-methods study on simulation-based teamwork training for operating room teams

Background: Operating rooms have become more technically complex due to new advanced procedures, which has increased demands on teamwork in the operating room. In response, team training has been proposed to improve team performance, workplace culture, and patient safety. We developed and delivered a simulation-based team training course for entire professional surgical teams. This type of intervention has been proposed by researchers but has not been widely published. The aims of this intervention study were to examine participants’ reactions to the course in terms of their motivation for the training and their self-efficacy in relation to their performance, as well as their views on transferring the lessons learned in the course to their workplace. Methods: In a prospective mixed-methods intervention study, operating room professionals participated in a full-day simulation-based teamwork training course. Learning objectives were nontechnical skills, specifically communication and collaboration across the team. Seventy-one staff members representing 5 operating room professions were included, and the average work experience of participants was 6 years. Quantitative data on self-efficacy and situational motivation were collected by questionnaires before and after training. Qualitative data were collected through 5 focus group interviews that took place in direct relation to the courses and included a total of 31 participants. Transcripts were coded and analyzed using thematic analysis. Results: All occupations showed a similar pattern in terms of increases in self-efficacy and intrinsic motivation after the training. Analysis of the qualitative data showed that training in one’s profession and in authentic multiprofessional teams was important factors for motivation. Participating staff described an awareness of undesirable communication barriers in surgical teams that can lead to risks for patients. Systematic training was definitely perceived as a means to reduce barriers and improve communication and collaboration. Conclusion: Simulation-based training was equally well received by all professional groups. Our results confirm the feasibility of this type of training for professional teams and promising opportunities for improving teamwork skills. The qualitative data reveal both opportunities and limitations for transferring the learning experiences to the workplace

Shared ambiguity but different experiences and demands among dental students : a gender perspective

This study explores how dental students experience their clinical semesters from a gender perspective. Twelve students (seven women and five men) and three teachers (two women and one man) at the Umeå dentistry programme participated in semi-structured interviews that were analysed with Grounded Theory methodology. The model we propose consists of the core category Experiencing ambiguity and the three categories Experiencing pressure and stress, Assessing your own performance, and Passing through the eye of the needle and also includes four subcategories. At the core of our findings lies ambiguity, captured in the student dilemmas What’s enough/When’s enough. The answers to these dilemmas are further complicated by the gendered dimension and the dimension of unequal treatment, which provide students with different and contradicting sets of rules and roles. A comparison with recent findings from the U.S. shows that their experiences are not unique. Our Experiencing ambiguity model constitutes a platform for future research on how students experience clinical education, as well as potential predictors and consequences in relation to performance and well-being

Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland.

Andrew Hattersley and T Frayling were collaborators on this journal article/project.Finnish samples have been extensively utilized in studying single-gene disorders, where the founder effect has clearly aided in discovery, and more recently in genome-wide association studies of complex traits, where the founder effect has had less obvious impacts. As the field starts to explore rare variants' contribution to polygenic traits, it is of great importance to characterize and confirm the Finnish founder effect in sequencing data and to assess its implications for rare-variant association studies. Here, we employ forward simulation, guided by empirical deep resequencing data, to model the genetic architecture of quantitative polygenic traits in both the general European and the Finnish populations simultaneously. We demonstrate that power of rare-variant association tests is higher in the Finnish population, especially when variants' phenotypic effects are tightly coupled with fitness effects and therefore reflect a greater contribution of rarer variants. SKAT-O, variable-threshold tests, and single-variant tests are more powerful than other rare-variant methods in the Finnish population across a range of genetic models. We also compare the relative power and efficiency of exome array genotyping to those of high-coverage exome sequencing. At a fixed cost, less expensive genotyping strategies have far greater power than sequencing; in a fixed number of samples, however, genotyping arrays miss a substantial portion of genetic signals detected in sequencing, even in the Finnish founder population. As genetic studies probe sequence variation at greater depth in more diverse populations, our simulation approach provides a framework for evaluating various study designs for gene discovery.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full text via the publisher's site

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageTo further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475info:eu-repo/grantAgreement/EC/FP7/20141