PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations.

Aims: Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition.

Methods And Results: In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)].

bubbleHeatmap: an R package for visualization of nightingale health metabolomics datasets.

Summary: We present bubbleHeatmap, an R plotting package which combines elements of a bubble plot and heatmap to conveniently display two numerical variables for each data point across a categorical two dimensional grid. This has particular advantages for visualizing the 251 metabolomic measures produced by the automated, high-throughput, H-NMR-based platform provided by Nightingale Health, which includes 12 measures repeated across each of 14 lipoprotein subclasses. As these metabolomic profiles are currently available for large biobanks, we provide a figure template to aid the use of in displaying results from analyses using these data.

Response to comment on "Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics".

Triangulation of evidence from clinical trials and human genetics suggests a potential excess risk of cardiovascular disease events arising from therapeutic inhibition of sclerostin.

Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics.

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease.

Author Correction: New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations.

Lipids, Lipoproteins, and Metabolites and Risk of Myocardial Infarction and Stroke.

Background: Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles, and circulating metabolites for MI and stroke subtypes.

Objectives: This study sought to investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS), and intracerebral hemorrhage (ICH).

Methods: In a nested case-control study (912 MI, 1,146 IS, and 1,138 ICH cases, and 1,466 common control subjects) 30 to 79 years of age in China Kadoorie Biobank, nuclear magnetic resonance spectroscopy measured 225 metabolic markers in baseline plasma samples.

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults.

Importance: Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD).

Objective: To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes.

Design, Setting, And Participants: This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008.

Preliminary investigation of miRNA expression in individuals at high familial risk of bipolar disorder.

Bipolar disorder (BD) is a highly heritable psychiatric disorder characterised by recurrent episodes of mania and depression. Many studies have reported altered gene expression in BD, some of which may be attributable to the dysregulated expression of miRNAs. Studies carried out to date have largely studied medicated patients, so it is possible that observed changes in miRNA expression might be a consequence of clinical illness or of its treatment.

Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

Background: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

Methods: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years.

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests.

DISC1 and Huntington's disease--overlapping pathways of vulnerability to neurological disorder?

We re-annotated the interacting partners of the neuronal scaffold protein DISC1 using a knowledge-based approach that incorporated recent protein interaction data and published literature to. This revealed two highly connected networks. These networks feature cellular function and maintenance, and cell signaling.

Short term bioassay of cigarettes containing Cytrel tobacco supplement.

The toxicity of smoke from cigarettes containing tobacco, Cytrel tobacco supplement, or mixtures of the 2 materials, was investigated using 6 short term test methods. The tests used were rat trachea organ culture and mouse skin thickening tests, which may provide information on carcinogenicity, a ciliatoxicity test, an alveolar macrophage viability test, a haemolysis assay and a thiol inactivation test to provide measures of irritant and cytotoxic effects. In each case a response to the smoke from cigarettes containing tobacco alone was detected, while the magnitude of this response declined as the proportion of tobacco supplement in the blend increased.

Permeability of membranes of dead fetus.

Membranes of dead fetuses showed a three-fold increase in permeability to the haemoglobin molecule when compared with normal and stored membranes. The friability of some of these membranes was markedly increased and their strength and elasticity diminished. These findings may be significant in the aetiology of the hypofibrinogenaemia and the increased incidence of amniotic fluid embolism with intrauterine death of the fetus.