Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Review: Avoiding restenosis: is there a role for glucocorticoids in the drug-eluting stent era?

Restenosis is an important limitation of percutaneous coronary interventions (PCI). In-stent restenosis is mainly due to neointimal hyperplasia, a proliferative process modulated by inflammatory mechanisms. Numerous technical and pharmacological means have been tested to reduce restenosis rates, with frequently disappointing clinical results. Drug-eluting stents (DES) have demonstrated a high efficacy in reducing restenosis, but there are some associated problems that limit its generalized utilization. Glucocorticoids (GC), as potent anti-inflammatory agents, may exert beneficial effects on neointimal proliferation. Clinical studies with oral and intracoronary GC therapy have demonstrated reduction in restenosis rates in selected patients. Although further investigations are warranted, GC might have a potential role for restenosis prevention in selected cases.Depto. de MedicinaFac. de MedicinaTRUEpu

Trehalose induces autophagy and activates autophagic flux in CHIP-mutant fibroblasts.

<p>The cells were treated for 24 h with o without trehalose 50 mM in the presence or absence of 10 µM chloroquine (CQ), a lysosomotropic agent widely used to block lysosomal degradation. <b>A</b>) Fluorescence microscopy images showing autophagosome marker LC-3 (green), lysosomal marker Lamp-2A (red) and LC3-LAMP-2A colocalization (yellow). (Scale bar  = 20 µm). <b>B</b>) Integrated optical density (IOD) quantification of LC3 expression. <b>C</b>) The lysosomal degradation was measured by IOD quantification of colocalization LC-3-LAMP-2A (yellow). <b>D</b>) Western blot showing LC3-II accumulation. Data of the control and CHIP-mutant groups were analyzed independently, no inter-group statistical analysis was performed. Data are expressed as the mean ± SEM. In 7B and 7C values are the mean ± S.E.M. of six independent coverslips (each value represents the mean of 20 field for coverslip). Three individuals with the mean of 2 independent coverslips (n = 3) in the control group and in the CHIP-mutant group 6 independent coverslips of the only patient (pseudo-replicates, n = 6). In 7D values represents the mean of 2 independent dishes of cells of 2 controls (n = 2) and for the CHIP-mutant group one patient with four independent dishes (pseudo-replicates, n = 4). Statistical analysis was performed by Student's t-test. *p<0.05, **p<0.01, ***p<0.001 <i>vs</i> solvents without chloroquine; δδp<0.01, δδδp<0.001 trehalose -CQ <i>vs</i> trehalose + CQ treated cultures.</p