Coding and regulatory variants are associated with serum protein levels and disease.

Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases

Impairments in hearing and vision impact on mortality in older people: the AGES-Reykjavik Study.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.to examine the relationships between impairments in hearing and vision and mortality from all-causes and cardiovascular disease (CVD) among older people.population-based cohort study.the study population included 4,926 Icelandic individuals, aged ≥67 years, 43.4% male, who completed vision and hearing examinations between 2002 and 2006 in the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-RS) and were followed prospectively for mortality through 2009.participants were classified as having 'moderate or greater' degree of impairment for vision only (VI), hearing only (HI), and both vision and hearing (dual sensory impairment, DSI). Cox proportional hazard regression, with age as the time scale, was used to calculate hazard ratios (HR) associated with impairment and mortality due to all-causes and specifically CVD after a median follow-up of 5.3 years.the prevalence of HI, VI and DSI were 25.4, 9.2 and 7.0%, respectively. After adjusting for age, significantly (P < 0.01) increased mortality from all causes, and CVD was observed for HI and DSI, especially among men. After further adjustment for established mortality risk factors, people with HI remained at higher risk for CVD mortality [HR: 1.70 (1.27-2.27)], whereas people with DSI remained at higher risk of all-cause mortality [HR: 1.43 (1.11-1.85)] and CVD mortality [HR: 1.78 (1.18-2.69)]. Mortality rates were significantly higher in men with HI and DSI and were elevated, although not significantly, among women with HI.older men with HI or DSI had a greater risk of dying from any cause and particularly cardiovascular causes within a median 5-year follow-up. Women with hearing impairment had a non-significantly elevated risk. Vision impairment alone was not associated with increased mortality.National Institutes of Health, National Institute on Aging (NIA) N01-AG-12100 NIA Z01-AG007380 National Eye Institute (NEI) ZIAEY000401 National Institute on Deafness and Other Communication Disorders (NIDCD) Division of Scientific Programs/IAA Y2-DC-1004-02 Hjartavernd (Icelandic Heart Association) Althingi (Icelandic Parliament

Pseudoscalar Glueball Mass: QCD vs. Lattice Gauge Theory Prediction

We study whether the pseudoscalar glueball mass in full QCD can differ from the prediction of quenched lattice calculations. Using properties of the correlator of the vacuum topological susceptibility we derive an expression for the upper bound on the QCD glueball mass. We show that the QCD pseudoscalar glueball is lighter than the pure Yang-Mills theory glueball studied in quenched lattice calculations. The mass difference between those two states is of order of $1/N_c$. The value calculated for the $0^{-+}$ QCD glueball mass can not be reconciled with any physical state observed so far in the corresponding channel. The glueball decay constant and its production rate in $J/\psi$ radiative decays are calculated. The production rate is large enough to be studied experimentally.Comment: 18 pages, LaTex fil

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Functional outcome after perineal stapled prolapse resection for external rectal prolapse

<p>Abstract</p> <p>Background</p> <p>A new surgical technique, the Perineal Stapled Prolapse resection (PSP) for external rectal prolapse was introduced in a feasibility study in 2008. This study now presents the first results of a larger patient group with functional outcome in a mid-term follow-up.</p> <p>Methods</p> <p>From December 2007 to April 2009 PSP was performed by the same surgeon team on patients with external rectal prolapse. The prolapse was completely pulled out and then axially cut open with a linear stapler at three and nine o'clock in lithotomy position. Finally, the prolapse was resected stepwise with the curved Contour^®Transtar™ stapler at the prolapse's uptake. Perioperative morbidity and functional outcome were prospectively measured by appropriate scores.</p> <p>Results</p> <p>32 patients participated in the study; median age was 80 years (range 26-93). No intraoperative complications and 6.3% minor postoperative complications occurred. Median operation time was 30 minutes (15-65), hospital stay 5 days (2-19). Functional outcome data were available in 31 of the patients after a median follow-up of 6 months (4-22). Preoperative severe faecal incontinence disappeared postoperatively in 90% of patients with a reduction of the median Wexner score from 16 (4-20) to 1 (0-14) (<it>P </it>< 0.0001). No new incidence of constipation was reported.</p> <p>Conclusions</p> <p>The PSP is an elegant, fast and safe procedure, with good functional results.</p> <p>Trial registration</p> <p>ISRCTN68491191</p

Hyperphosphorylated tau in young and middle-aged subjects

The brain tissue obtained from ninety-five cognitively unimpaired subjects, with ages ranging from 22 to 50 years upon death, were immunohistochemically assessed for neurodegenerative changes, i.e., hyperphosphorylated tau (HPτ) and β-amyloid (Aβ) pathology in predilection neuroanatomical areas. HPτ pathology was observed in the transentorhinal cortex and/or the locus coeruleus (LC) in 33% of the subjects, without any obvious risk factors known to alter the microtubule-associated protein. HPτ pathology was noted in the LC in 25 out of 83 subjects (30%), lacking concomitant cortical Aβ or transentorhinal HPτ pathology. This observation was present even when assessing only one routine section of 7 μm thickness. The recent suggestion of prion-like propagation of neurodegeneration and the finding of neurodegeneration being quite common in middle-aged persons is alarming. It is noteworthy, however, that a substantial number of neurologically unimpaired subjects even at a very old age display only sparse to modest extent of neurodegenerative pathology. Thus, only a subset of subjects with neurodegenerative changes early in life seem to progress to a symptomatic disease with ageing. This observation brings forth the notion that other, yet unknown modifying factors influence the progression of degeneration that leads to a symptomatic disorder. The known association between alterations in the LC and mood disorders, and the finding of the LC being frequently affected with HPτ pathology suggest that clinicopathological studies on young subjects both with or without mood disorders are warranted

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.