Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

Dutch juvenile idiopathic arthritis patients, carers and clinicians create a research agenda together following the James Lind Alliance method: A study protocol

Background: Research on Juvenile Idiopathic Arthritis (JIA) should support patients, caregivers/parents (carers) and clinicians to make important decisions in the consulting room and eventually to improve the lives of patients with JIA. Thus far these end-users of JIA-research have rarely been involved in the prioritisation of future research. Main body: Dutch organisations of patients, carers and clinicians will collaboratively develop a research agenda for JIA, following the James Lind Alliance (JLA) methodology. In a 'Priority Setting Partnership' (PSP), they will gradually establish a top 10 list of the most important unanswered research questions for JIA. In this process the input from clinicians, patients and their carers will be equally valued. Additionally, focus groups will be organised to involve young people with JIA. The involvement of all contributors will be monitored and evaluated. In this manner, the project will contribute to the growing body of literature on how to involve young people in agenda setting in a meaningful way. Conclusion: A JIA research agenda established through the JLA method and thus co-created by patients, carers and clinicians will inform researchers and research funders about the most important research questions for JIA. This will lead to research that really matters

Two truncating variants in FANCC and breast cancer risk

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95% CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.Peer reviewe

Kopen op de KLM Open: Zijn sociaal-demografische kenmerken, gedrag en bezoekersmotief en evenementomstandigheden van invloed op de bestedingen van bezoekers?

Steden en landen zetten vaak veel middelen in om sportevenementen naar zich toe te trekken. Vanuit dit oogpunt is het interessant om te analyseren hoeveel bestedingen de bezoekers van een evenement doen en welke factoren hiermee samenhangen. Voor dit onderzoek zijn bezoekers aan de KLM Open in 2016, 2017 en 2018 bevraagd naar hun uitgaven tijdens en rondom dit evenement. Dagbestedingen blijken samen te hangen met het aantal dagen bezoek, of er overnacht wordt, buitenlandse herkomst en leeftijd van de bezoeker. Bovendien blijken de prestaties van Nederlandse deelnemers en de hoeveelheid regenval een rol te spelen in het uitgavenpatroon. Evenementorganisatoren en (horeca-)ondernemers in de regio kunnen deze inzichten gebruiken om te profiteren van de aanwezige geldstromen op en rondom het evenement en daarmee subsidiebijdragen vanuit de overheid beperken

What is the evidence of impaired motor skills and motor control among children with attention deficit hyperactivity disorder (ADHD)? Systematic review of the literature.

This article presents a review of the studies that have analysed the motor skills of ADHD children without medication and the influence of medication on their motor skills. The following two questions guided the study: What is the evidence of impairment of motor skills and aspects of motor control among children with ADHD aged between 6 and 16 years? What are the effects of ADHD medication on motor skills and motor control? The following keywords were introduced in the main databases: attention disorder and/or ADHD, motor skills and/or handwriting, children, medication. Of the 45 articles retrieved, 30 described motor skills of children with ADHD and 15 articles analysed the influence of ADHD medication on motor skills and motor control. More than half of the children with ADHD have difficulties with gross and fine motor skills. The children with ADHD inattentive subtype seem to present more impairment of fine motor skills, slow reaction time, and online motor control during complex tasks. The proportion of children with ADHD who improved their motor skills to the normal range by using medication varied from 28% to 67% between studies. The children who still show motor deficit while on medication might meet the diagnostic criteria of developmental coordination disorder (DCD). It is important to assess motor skills among children with ADHD because of the risk of reduced participation in activities of daily living that require motor coordination and attention

Increased Physical Activity in Preparation for a Women-Only Mass Participation Sport Event: A Framework for Estimating the Health Impact

Mass participation sporting events (MPSEs) are increasing in popularity. However, little research exists into the potential value of these events for improving public health by enhancing physical activity (PA). The aim of this study is to estimate the health impact of increased physical activity as a result of preparing for an MPSE. Participants of a mass participation women-only running event were asked if they performed additional PA in preparation of the event, including the length (weeks) and intensity (min per week). Additionally, self-reported change in health status was evaluated. Based on these results, we have developed a framework for estimating the cumulatively gained quality adjusted life years (QALYs) and monetary value thereof. Of the respondents (N = 468; mean age 42.3 ± 11.9 years), 32% performed additional vigorous PA in preparation of the event, with an average of 63 min per week over 8.8 weeks. Performing additional vigorous PA significantly improved the odds of self-rated health. The estimated total health impact of participants preparing for the Marikenloop was 6.6 QALYs gained with a corresponding monetary value between EUR 133,000 and EUR 532,000. We believe our health impact framework helps to understand that MPSEs can be a notable part of the public health domain

Ervaringen van ouders in Nederland met betrekking tot het verkrijgen van een DCD-diagnose voor hun kind

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Automatische Voertuig Geleiding in het Collectief Openbaar Vervoer: Systematische verkenning van te automatiseren processen in relatie tot de vervoervraag

Automatische Voertuiggeleiding in het Collectieve Openbaar Vervoer is een manier om op kosten, vooral op personeelskosten, te besparen. Er is intussen een groot aanbod aan nieuwe automatische vervoersystemen maar er wordt te weinig aandacht geschonken aan de mogelijkheden bij de bestaande systemen. In deze studie is op basis van technische kenmerken een klasseindeling van openbaar vervoersystemen gemaakt en daarnaast de mogelijkheden voor de automatisering van processen vóór, na en tijdens de dienstuitvoering, en ter controle en bijsturing daarvan. De combinaties van deze systemen met de relevante processen worden AVG-pakketten genoemd. Van deze pakketten is nagegaan welke effecten zij hebben op eisen gesteld door reizigers, exploitanten, overheid en omgeving. Vervolgens is op basis van praktische overwegingen een keuze gemaakt om te bepalen welke van deze pakketten uit technisch oogpunt kansrijk geacht mogen worden. Vooral de automatische stadsbus op een vrije baan en een automatische sneltram op een vrije baan zijn kansrijke AVG-pakketten. De koppeling van deze pakketten aan de vraag naar vervoer rond de studie af. Een onderzoek van een voorbeeldsituatie is nodig om het verkeersvolume preciezer te schatten alsmede de technische en economische haalbaarheid. De ontwikkeling van een geschikte obstakeldetectie voor automatische voertuigen op een vrije baan is hierbij een eerste noodzakelijke stap.Transport and PlanningCivil Engineering and Geoscience