Association between serum cholesterol and bone mineral density

Background: Hypercholesterolaemia has been associated with low bone mineral density (BMD) in some but not all studies. Objectives: To examine the influence of age, menopausal status and hormone replacement therapy (HRT) on the relationship between serum cholesterol and BMD in women. Patients and measurements: 497 female participants (age range 20-81) comprising 224 premenopausal and 273 postmenopausal women (156 on HRT and 117 no HRT) underwent measurements of bone mineral density (BMD) and serum lipid profile. Results: Total serum cholesterol (TC) and low density lipoprotein (LDL) levels were higher and lumbar spine BMD was lower in postmenopausal women not taking HRT compared to those taking HRT. TC and LDL were negatively associated with BMD at all measured sites among postmenopausal women not taking HRT in univariate regression analysis (all p<0.05). High density lipoprotein (HDL) had inverse relationships with BMD at all sites in pre-menopausal women and those who were exposed to HRT (p<0.05). In fully adjusted regression models the relationships between TC and BMD remained significant at the lumbar spine and whole body (p<0.05) and between LDL and lumbar spine BMD only (p<0.05). For subjects in the other groups, no significant associations between TC or LDL and BMD were found. Significant interactions between total cholesterol and LDL levels with HRT were detected among post-menopausal women in the regression analyses (all p<0.05). No such interactions were found between HDL levels and HRT. Conclusion: There is a modest inverse relationship between lumbar spine and whole body BMD and serum TC and LDL levels and in post-menopausal women and HDL in pre-menopausal women. HRT use appears to modify these relationships. The mechanisms of this relationship require further study. (C) 2008 Elsevier Inc. All rights reserved

High osteoporotic fracture risk and CVD risk co-exist in postmenopausal women

Introduction: Osteoporosis related risk factors such as BMD have been associated with cardiovascular endpoints in previous studies but there have been no studies of integrated risk using risk factor algorithms. Methods: A sample of 358 peri- and postmenopausal women, mean age 59.3 (range 45-74) years were studied. Each individual had bone mineral density (BMD) measurements by dual energy X-ray absorptiometiy. Fracture risk was assessed using the WHO FRAX algorithm and cardiovascular disease (CVD) risk using the Framingham Risk Tool. Results: Women with higher 10 year risk of major osteoporotic had significantly higher cardiovascular risk (4.634% vs 8.36%, p=0.001). In multiple regression analysis, 5-year CVD risk was significantly associated with the 10-year risk of having major osteoporotic (beta=0.095, p=0.001) and hip (beta=0.055, p=0.001) fracture. Women with the highest CVD risk were 5.4 times more likely to have higher risk of major osteoporotic fracture. Conclusions: Fracture risk, determined by using a multiple risk factor algorithm such as FRAX, was positively associated with higher cardiovascular risk determined by using the Framingham Risk Tool. Awareness regarding these concurrent risk factors needs to be raised so that appropriate risk reduction can be implemented. (C) 2012 Elsevier Inc. All rights reserved

Serum uric acid plays a protective role for bone loss in peri- and postmenopausal women: A longitudinal study

Objective: Oxidative stress has been linked to osteoporosis. Serum uric acid (UA), a strong endogenous antioxidant, has been associated with higher bone mineral density (BMD), lower bone turnover and lower prevalence of fractures in a large cross-sectional study of men. Whether this relationship is present in women and how UA relates to changes in BMD longitudinally has not been examined. Methods: A sample of 356 peri- and postmenopausal women, mean age 60.5 years was studied. Each individual had baseline BMD and body composition measurements by dual energy x-ray absorptiometry (DXA) and at least one repeat measure, on average 9.7 years later. Annual rate of change in BMD (A%Delta BMD) was calculated. UA was measured at each DXA visit. Calciotropic hormones and bone turnover markers were measured at the final visit only. Results: Cross-sectional data analyses revealed that women with higher UA levels had significantly higher absolute BMD measures at all skeletal sites. These women also had higher measures of body weight and its components such as lean mass (LM) and fat mass (FM). Results of multiple regression analyses showed a positive association between UA and BMD that remained significant even after accounting for possible confounders including LM and FM. Regression analyses of the longitudinal BMD data demonstrated significant associations between serum UA levels and annual rates of change in BMD at all skeletal sites. After adjustment associations remained significant for lumbar spine, forearm and whole body BMD but not for hip BMD. Conclusion: Higher serum UA levels appear to be protective for bone loss in peri- and postmenopausal women and this relationship is not affected by changes in body composition measures

Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

This project was funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215). L.S is funded by the Virtual Brain Cloud from European comission (grant no. H2020-SC1-DTH-2018-1). C.R.B is funded by National Institutes of Health (NIH) research grant R01AG054628. S.R.C is funded by National Institutes of Health (NIH) research grant (R01AG054628), Medical Research Council (MR/R024065/1), Age UK and Economic and Social Research Council. R.E.M. was supported by Alzheimer's Research UK major project grant ARUKPG2017B-10. C.H was supported by an MRC Human Genetics Unit programme grant “Quantitative traits in health and disease” (U.MC_UU_00007/10). H.C.W received funding from Wellcome Trust. J.W is funded by TauRx pharmaceuticals Ltd and received Educational grant from Biogen paid to Alzheimer Scotland/Brain Health Scotland. G.W received GRAMPIAN UNIVERSITY HOSPITALS NHS TRUST, Scottish Government—Chief Scientist Office, ROLAND SUTTON ACADEMIC TRUST, Medical Research Scotland, Sutton Academic Trust and ROLAND SUTTON ACADEMIC TRUST. J.M.W received Wellcome Trust Strategic Award, MRC UK Dementia Research Institute and MRC project grants, Fondation Leducq, Stroke Association, British Heart Foundation, Alzheimer Society, and the European Union H2020 PHC-03-15 SVDs@Target grant (666881). D.S received MRC (MR/S010351/1), MRC (MR/W002388/1) and MRC (MR/W002566/1). A.M is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z, 220857/Z/20/Z) and UKRI MRC (MC_PC_17209, MR/S035818/1). This work is part of a project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776. In addition, A.M has received grant support from The Sackler Trust, outside of the work presented. N.B received grant to institution from GSK as part of GSK/Oxford FxG initiative. A.N.H received John Black Charitable Fund-Rosetrees, H2020 funding from European Comission-Project Virtual Brain Cloud, AI for the Discovery of new therapies in Parkinson's (A2926), Rising Start Initiative—stage 2, Brain-Gut Microbiome (Call: PAR-18-296; Award ID: 1U19AG063744-01), Gut-liver-brain biochemical axis in Alzheimer's disease (5RF1AG057452-01), Virtual Brain Cloud (Call: H2020-SC1-DTH- 2018-1; Grant agreement ID: 826421). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” [STRADL] Reference 104036/Z/14/Z). We are grateful to all the families who took part; the general practitioners and the Scottish School of Primary Care for their help in recruiting them; and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, health-care assistants, and nurses.Peer reviewedPublisher PD

Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection

Background: chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment.Methods: we conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (p&lt;5×10−8) were investigated in additional independent studies, were fine-mapped and putative causal genes identified by gene expression analysis. GWASs of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease among the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWASs).Results: from a GWAS of 9714 cases and 48 471 controls, we identified six novel genome-wide significant signals for chronic sputum production including signals in the human leukocyte antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2203 cases and 17 627 controls. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations including blood cell traits, liver biomarkers, infections, gastrointestinal and thyroid-associated diseases, and respiratory disease.Conclusions: novel signals at the FUT2 and mucin loci suggest that mucin fucosylation may be a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention

Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health

Fulvestrant plus vandetanib versus placebo for the treatment of patients with metastatic breast cancer resistant to aromatase inhibitor therapy (FURVA): a multicentre, Phase 2, randomised controlled trial

Background: FURVA, a randomised, double-blind Phase II trial, investigated whether the addition of vandetanib to fulvestrant improved progression-free survival (PFS) in patients with an aromatase inhibitor(AI)-resistant advanced breast cancer. Methods: Postmenopausal women with oestrogen receptor-positive (ER+ve)/HER2-negative advanced breast cancer, who experienced disease progression on an AI, were randomised (1:1) to fulvestrant 500 mg (Q28) with vandetanib 300 mg od (f + v) or placebo (f + p) until disease progression or discontinuation. The primary endpoint was PFS; secondary endpoints included overall survival (OS) and the influence of REarranged during Transfection (RET) signalling on outcomes. Results: In total, 165 participants were randomised to f + v (n = 80) or f + p (n = 85). Median PFS was 5.5 months (m) for f + v compared to 5.5 m for f + p (hazard ratio (HR) 0.88; 95% CI: 0.62–1.23; P = 0.22). Unexpectedly, high total RET expression was associated with a PFS advantage of 8.87 m vs 3.94 with low RET (HR 0.493: 95% CI 0.32–0.77; P = 0.002) independent of the treatment arm, supported by an OS advantage 21.95 m vs 18.04 (HR 0.584; 95% CI 0.34–1.00; P = 0.051) in the high-RET group. Conclusion: The addition of vandetanib to fulvestrant does not improve PFS. However, high total RET expression was associated with improved PFS, suggesting RET may have a prognostic role in patients treated with fulvestrant. Clinical trial registration: ClinicalTrials.gov, NCT02530411

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN