1,181 research outputs found
Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
No full textGenome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer
Height and body mass index as Modifiers of breast cancer risk in BRCA1/2 mutation carriers: A Mendelian randomization study
No full textBackground: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants.We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P=1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P=.47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P=.007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P=.02). BMI was primarily associated with premenopausal breast cancer. Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management
Types of Scientific Collaborators: A Perspective of Author Contribution Network
No full textThe purpose of this study is to investigate interaction between collaborators within individual studies by measuring how they made contributions to their studies. Author contribution network is constructed based on the author contribution statements of 140,000 full-text articles in PloS by viewing every collaborator as a node and a shared contribution as an edge. Three types of contributors are identified: general team-players, factotums, and mavericks. The preliminary result suggests that division of labor widely exists in scientific re-search and the latter two types of collaborators are common in small teams.Made available in DSpace on 2018-07-12T15:28:19Z (GMT). No. of bitstreams: 2
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Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers
No full textBACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m 2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P interaction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population
Transcriptome-wide association study of breast cancer risk by estrogen-receptor status. [Elektronisk resurs]
No full textPrevious transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer
Hospital-based caregiver intervention for people following hip fracture surgery (HIP HELPER) : multicentre randomised controlled feasibility trial with embedded qualitative study in England
No full textObjectives: To assess the feasibility of conducting a pragmatic, multi-centre randomised controlled trial (RCT) to test the clinical and cost-effectiveness of an informal caregiver training programme to support the recovery of people following hip fracture surgery.
Design: Two-arm, multi-centre, pragmatic, open, feasibility RCT with embedded qualitative study.
Setting: National Health Service (NHS) providers in five English hospitals.
Participants: Community-dwelling adults, aged 60 years and over, who undergo hip fracture surgery and their informal caregivers.
Intervention: Usual care: usual NHS care.
Experimental: usual NHS care plus a caregiver-patient dyad training programme (HIP HELPER). This programme comprised of three, one-hour, one-to-one training sessions for a patient and caregiver, delivered by a nurse, physiotherapist or occupational therapist in the hospital setting pre-discharge. After discharge, patients and caregivers were supported through three telephone coaching sessions. Randomisation and blinding: Central randomisation was computer generated (1:1), stratified by hospital and level of patient cognitive impairment. There was no blinding.
Main outcome measures: Data collected at baseline and four months post-randomisation included: screening logs, intervention logs, fidelity checklists, acceptability data and clinical outcomes. Interviews were conducted with a subset of participants and health professionals.
Results: 102 participants were enrolled (51 patients; 51 caregivers). Thirty-nine percent (515/1311) of patients screened were eligible. Eleven percent (56/515) of eligible patients consented to be randomised. Forty-eight percent (12/25) of the intervention group reached compliance to their allocated intervention. There was no evidence of treatment contamination. Qualitative data demonstrated the trial and HIP HELPER programme was acceptable.
Conclusions: The HIP HELPER programme was acceptable to patient-caregiver dyads and health professionals. The COVID-19 pandemic impacting on site’s ability to deliver the research. Modifications are necessary to the design for a viable definitive RCT.
Trial registration number: ISRCTN13270387 Data availability statement: The data that support the findings of this study are available from the corresponding author (TS) upon reasonable request. This includes access to the full protocol, anonymised participant-level dataset and statistical code.
STRENGTHS AND LIMITATIONS OF THIS STUDY
• Mixed-method approach provided useful feasibility and acceptability data.
• Assessment of diverse measures allowed evaluation of data collection for key outcome domains.
• Participant experiences and acceptability data suggest perceived value in the HIP HELPER programme. • 10% of the cohort were living with cognitive impairment; none were recruited to the qualitative sub-study. • COVID-19 pandemic affected NHS services, which impacted on study delivery
A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
No full textBreast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers
Publisher Correction: Global estimates on the number of people blind or visually impaired by cataract: a meta-analysis from 2000 to 2020
No full textFully disaggregated data is not available publicly due to data sharing agreements with some principal investigators yet requests for summary data can be made to the corresponding author.” Furthermore, the information in the “Funding” section was incomplete. The following information was added: “This study was funded by Brien Holden Vision Institute, Fondation Thea, Fred Hollows Foundation, Bill & Melinda Gates Foundation, Lions Clubs International Foundation (LCIF), Sightsavers International, and University of Heidelberg.” The “Competing interests” section has been corrected from “The authors declare no competing interests” to the following detailed information: GBD 2019 Blindness and Vision Impairment Collaborators Declarations N S Bayileyegn reports participation on a Data Safety Monitoring Board or Advisory Board with Jimma University, and leadership or fiduciary roles in board, society, committee or advocacy groups, paid or unpaid with Jimma University as a discipline committee member; outside the submitted work. S Bhaskar reports grants or contracts from the Japan Society for the Promotion of Science (JSPS), JSPS International Fellowship, Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Australian Academy of Science, Grant-in-Aid for Scientific Research (KAKENHI); leadership or fiduciary roles in board, society, committee or advocacy groups, paid or unpaid with Rotary District 9675 as the District Chair of Diversity, Equity, and Inclusion; the Global Health & Migration Hub Community and the Global Health Hub Germany (Berlin, Germany) as the Chair and Manager; PLOS One, BMC Neurology, Frontiers In Neurology, Frontiers in Stroke, Frontiers in Public Health and BMC Medical Research Methodology as an Editorial Board Member; and with the College of Reviewers, Canadian Institutes of Health Research (CIHR), and the Government of Canada as a Member; outside the submitted work. X Dai reports support for the present manuscript from the Institute for Health Metrics and Evaluation and the University of Washington. M Cenderadewi reports grants or contracts from James Cook University (International Research Training Program Scholarship for doctoral study), and support for attending meetings and travel from James Cook University; all outside the submitted work. M Foschi reports consulting fees from Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sanofi, Merck, and Novartis; support for attending meetings and travel from Novartis and Roche; leadership or fiduciary roles in board, society, committee or advocacy groups, paid or unpaid with MSBase as a scientific leadership board member, and Cochrane Review Group for Multiple Sclerosis and other rate diseases of the CNS as a member; all outside the submitted work. F Ghassemi reports support for the present manuscript from medical writing. B N G Goulart reports stock or stock options with Bristo Myers-Squibb and Pfizer; outside the submitted work. V B Gupta reports grants or contracts from the National Health and Medical Research Council (NHMRC); outside the submitted work. S Hallaj reports support for the present manuscript from the National Institute of Health, Bridge to AI common fund (grant number: OT2 OD032644). I M Ilic reports support for the present manuscript from the Ministry of Education, Science and Technological development, Republic of Serbia (project No 175042, 2011-2023). S Islam reports support for the present manuscript from the National Health and Medical Research Council (NHMRC) Investigator Grant and the Heart Foundation Vanguard Grant. J H Kempen reports support for the present manuscript from Sight for Souls and Mass Eye and Ear Global Surgery Program; and leadership or fiduciary roles in board, society, committee or advocacy groups, paid or unpaid with Sight for Souls as the President. K Krishan reports other non-financial support from the UGC Centre of Advanced Study, CAS II, awarded to the Department of Anthropology, Panjab University (Chandigarh, India); outside the submitted work. O P Kurmi reports grants or contracts from the British Council India paid to Coventry University; outside the submitted work. V C Lansingh reports consulting fees from HelpMeSee, and financial support for attending meetings and travel from HelpMeSee; outside the submitted work. J L Leasher leadership or fiduciary roles in board, society, committee or advocacy groups, unpaid with the National Eye Institute as a member and the National Eye Health Education Program as a planning committee member; outside the submitted work. M Lee reports support for the present manuscript from the Ministry of Education of the Republic of Korea, and the National Research Foundation of Korea (NRF-2021R1I1A4A01057428) and Bio-convergence Technology Education Program through the Korea Institute for Advancement Technology (KIAT) funded by the Ministry of Trade, Industry and Energy (No. P0017805). C McAlinden reports grants or contracts from the Welsh Government on the following study: Feasibility of an alternative pathway for hospital referrals from Diabetic Eye Screening Wales (DESW) for people suspected with sight-threatening diabetic eye disease (diabetic maculopathy). No funds will be received from the author’s institution or personally related to this study. Any work conducted as part of this study is as an unpaid collaborator; consulting fees from Acufocus (Irvine, California, USA), Atia Vision (Campbell, California, USA), Bausch and Lomb (Bridgewater, New Jersey, USA), BVI / PhysIOL (Liège, Belgium), Coopervision (Pleasanton, California, USA), Cutting Edge (Labége, France), Fudan University (Fudan, China), Hoya (Frankfurt, Germany), Knowledge Gate Group (Copenhagen, Denmark), Johnson & Johnson Surgical Vision (Santa Ana, California, USA), Keio University (Tokyo, Japan), Ludwig-Maximilians-University (München, Germany), Medevise Consulting SAS (Strasbourg, France), Novartis (Basel, Switzerland), Ophtec BV (Groningen, The Netherlands), Sun Yat-sen University (Guangzhou, China), SightGlass vision (Menlo Park, California, USA), Science in Vision (Bend, Oregan, USA), SpyGlass (Aliso Viejo, California, USA), Targomed GmbH (Bruchsal, Germany), University of São Paulo (São Paulo, Brazil), and Vold Vision (Arkansas, USA); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Scope (Crawley, UK), Bausch and Lomb (Bridgewater, New Jersey, USA), and Thea pharmaceuticals (Clemont-Ferrand, France); support for attending meetings and/or travel from Royal College of Ophthalmologists (London, UK), Scope (Crawley, UK), Portuguese Society of Ophthalmology (Portugal), British Society of Refractive surgery (BSRS), Thea pharmaceuticals (Clemont-Ferrand, France), Bausch and Lomb (Bridgewater, New Jersey, USA); leadership or fiduciary roles in board, society, committee or advocacy groups, paid or unpaid with the British Society of Refractive Surgery (BSRS) as an unpaid council member, and the Royal College of Ophthalmologists (London, UK) as an unpaid PROM advisor; other financial interests from the Quality of Vision (QoV) Questionnaire tool, the Orthokeratology and Contact Lens Quality of Life Questionnaire (OCL-QoL), and paid peer reviews for Research Square; outside of the submitted work. Finally, the section “Author Contributions” has been added and an Appendix with more detailed information for individual author contributions has been included in the form of electronic supplementary material. The original article has been corrected
Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021
No full textBackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378-521), affecting 3·40 billion (3·20-3·62) individuals (43·1%, 40·5-45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7-26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6-38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5-32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7-2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed.FundingBill & Melinda Gates Foundation
Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers
No full textGenome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy- number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies
only confirmed 40% of predicted common (41% allele frequency) variants. These include four loci that were associated (unadjusted Po0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk = 0.50, P = 0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers
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