The sense and nonsense of direct-to-consumer genetic testing for cardiovascular disease

Expectations are high that increasing knowledge of the genetic basis of cardiovascular disease will eventually lead to personalised medicine—to preventive and therapeutic interventions that are targeted to at-risk individuals on the basis of their genetic profiles. Most cardiovascular diseases are caused by a complex interplay of many genetic variants interacting with many non-genetic risk factors such as diet, exercise, smoking and alcohol consumption. Since several years, genetic susceptibility testing for cardiovascular diseases is being offered via the internet directly to consumers. We discuss five reasons why these tests are not useful, namely: (1) the predictive ability is still limited; (2) the risk models used by the companies are based on assumptions that have not been verified; (3) the predicted risks keep changing when new variants are discovered and added to the test; (4) the tests do not consider non-genetic factors in the prediction of cardiovascular disease risk; and (5) the test results will not change recommendations of preventive interventions. Predictive genetic testing for multifactorial forms of cardiovascular disease clearly lacks benefits for the public. Prevention of disease should therefore remain focused on family history and on non-genetic risk factors as diet and physical activity that can have the strongest impact on disease risk, regardless of genetic susceptibility

The current role of next-generation DNA sequencing in routine care of patients with hereditary cardiovascular conditions: a viewpoint paper of the European Society of Cardiology working group on myocardial and pericardial diseases and members of the European Society of Human Genetics

Cardiomyopathies, arrhythmic syndromes, aortopathies, and other cardiovascular diseases with Mendelian inheritance are relatively frequent conditions for which genetic testing is recommended in various guidelines.1,2 The most widely recognized indication for genetic testing in patients with these conditions is to identify a causative mutation and subsequently provide pre-symptomatic or predictive testing of relatives who are at risk of developing the same disease at a later stage. This process of cascade screening of family members ensures adequate clinical surveillance of mutation carriers and allows non-carriers to be discharged from clinical follow-up. A number of studies have reported a greater cost-effectiveness combining molecular screening with clinical screening compared with isolated clinical investigations.3 Previously, genetic testing was based on conventional techniques like Sanger sequencing analysing genes one by one, but recent advances in DNA sequencing technologies have made it possible to investigate large numbers of disease genes simultaneously, making mutation analysis much faster and cheaper. These new methods are known as next-generation sequencing (NGS) and represent a major advance in the ability to identify causative mutations in families affected by genetic diseases (see Supplementary material online, Figure S1).4,5 However, analysis of large numbers of genes may identify a number of sequence variants of uncertain clinical significance (VUS). As a result, cardiologists and clinical geneticists who counsel and manage families with inherited cardiovascular disorders are facing a major challenge in determining the clinical relevance of NGS results.6,7 This paper gives a brief overview of the principles of NGS, discusses the general strategies for the interpretation of sequencing results, and reviews the implications of NGS for cardio-genetic services. In addition, issues related to genetic counselling and ethical considerations are discussed. A summary of viewpoints is given in Table 1

Greenland ice sheet surface mass loss: recent developments in observation and modeling

Surface processes currently dominate Greenland ice sheet (GrIS) mass loss. We review recent developments in the observation and modelling of GrIS surface mass balance (SMB), published after the July 2012 deadline for the Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC AR5). Since IPCC AR5 our understanding of GrIS SMB has further improved, but new observational and model studies have also revealed that temporal and spatial variability of many processes are still poorly quantified and understood, e.g. bio-albedo, the formation of ice lenses and their impact on lateral meltwater transport, heterogeneous vertical meltwater transport (‘piping’), the impact of atmospheric circulation changes and mixed-phase clouds on the surface energy balance and the magnitude of turbulent heat exchange over rough ice surfaces. As a result, these processes are only schematically or not at all included in models that are currently used to assess and predict future GrIS surface mass loss

Changes in Channel Trafficking and Protein Stability Caused by LQT2 Mutations in the PAS Domain of the HERG Channel

Inherited human long-QT2 syndrome (LQTS) results from mutations in the gene encoding the HERG channel. Several LQT2-associated mutations have been mapped to the amino terminal cytoplasmic Per-Arnt-Sim (PAS) domain of the HERG1a channel subunit. Here we have characterized the trafficking properties of some LQT2-associated PAS domain mutants and analyzed rescue of the trafficking mutants by low temperature (27°C) or by the pore blocker drug E4031. We show that the LQT2-associated mutations in the PAS domain of the HERG channel display molecular properties that are distinct from the properties of LQT2-associated mutations in the trans-membrane region. Unlike the latter, many of the tested PAS domain LQT2-associated mutations do not result in trafficking deficiency of the channel. Moreover, the majority of the PAS domain mutations that cause trafficking deficiencies are not rescued by a pore blocking drug. We have also explored the in vitro folding stability properties of isolated mutant PAS domain proteins using a thermal unfolding fluorescence assay and a chemical unfolding assay

Real-time prostate motion assessment: image-guidance and the temporal dependence of intra-fraction motion

BACKGROUND: The rapid adoption of image-guidance in prostate intensity-modulated radiotherapy (IMRT) results in longer treatment times, which may result in larger intrafraction motion, thereby negating the advantage of image-guidance. This study aims to qualify and quantify the contribution of image-guidance to the temporal dependence of intrafraction motion during prostate IMRT. METHODS: One-hundred and forty-three patients who underwent conventional IMRT (n=67) or intensity-modulated arc therapy (IMAT/RapidArc, n=76) for localized prostate cancer were evaluated. Intrafraction motion assessment was based on continuous RL (lateral), SI (longitudinal), and AP (vertical) positional detection of electromagnetic transponders at 10 Hz. Daily motion amplitudes were reported as session mean, median, and root-mean-square (RMS) displacements. Temporal effect was evaluated by categorizing treatment sessions into 4 different classes: IMRT(c) (transponder only localization), IMRT(cc) (transponder + CBCT localization), IMAT(c) (transponder only localization), or IMAT(cc) (transponder + CBCT localization). RESULTS: Mean/median session times were 4.15/3.99 min (IMAT(c)), 12.74/12.19 min (IMAT(cc)), 5.99/5.77 min (IMRT(c)), and 12.98/12.39 min (IMRT(cc)), with significant pair-wise difference (p<0.0001) between all category combinations except for IMRT(cc) vs. IMAT(cc) (p>0.05). Median intrafraction motion difference between CBCT and non-CBCT categories strongly correlated with time for RMS (t-value=17.29; p<0.0001), SI (t-value=−4.25; p<0.0001), and AP (t-value=2.76; p<0.0066), with a weak correlation for RL (t-value=1.67; p=0.0971). Treatment time reduction with non-CBCT treatment categories showed reductions in the observed intrafraction motion: systematic error (Σ)<0.6 mm and random error (σ)<1.2 mm compared with ≤0.8 mm and <1.6 mm, respectively, for CBCT-involved treatment categories. CONCLUSIONS: For treatment durations >4-6 minutes, and without any intrafraction motion mitigation protocol in place, patient repositioning is recommended, with at least the acquisition of the lateral component of an orthogonal image pair in the absence of volumetric imaging

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference