A Common Variant Associated with Dyslexia Reduces Expression of the KIAA0319 Gene

Numerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s) remains unknown but may modulate gene expression, given that (1) a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2) the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s) responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001), confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits

Gender specific age-related changes in bone density, muscle strength and functional performance in the elderly: a-10 year prospective population-based study

Background:&nbsp;Age-related losses in bone mineral density (BMD), muscle strength, balance, and gait have been linked to&nbsp;an increased risk of falls, fractures and disability, but few prospective studies have compared the timing, rate and pattern&nbsp;of changes in each of these measures in middle-aged and older men and women. This is important so that targeted&nbsp;strategies can be developed to optimise specific musculoskeletal and functional performance measures in older adults.&nbsp;Thus, the aim of this 10-year prospective study was to: 1) characterize and compare age- and gender-specific changes in&nbsp;BMD, grip strength, balance and gait in adults aged 50 years and over, and 2) compare the relative rates of changes&nbsp;between each of these musculoskeletal and functional parameters with ageing.Methods: Men (n = 152) and women (n = 206) aged 50, 60, 70 and 80 years recruited for a population-based study had&nbsp;forearm BMD, grip strength, balance and gait velocity re-assessed after 10-years.Results: The annual loss in BMD was 0.5-0.7% greater in women compared to men aged 60 years and older&nbsp;(p &lt; 0.05- &lt; 0.001), but there were no gender differences in the rate of loss in grip strength, balance or gait. From the age&nbsp;of 50 years there was a consistent pattern of loss in grip strength, while the greatest deterioration in balance and gait&nbsp;occurred from 60 and 70 years onwards, respectively. Comparison of the changes between the different measures&nbsp;revealed that the annual loss in grip strength in men and women aged &lt;70 years was 1-3% greater than the decline in&nbsp;BMD, balance and gait velocity.Conclusion: There were no gender differences in the timing (age) and rate (magnitude) of decline in grip strength,&nbsp;balance or gait in Swedish adults aged 50 years and older, but forearm BMD decreased at a greater rate in women than&nbsp;in men. Furthermore, there was heterogeneity in the rate of loss between the different musculoskeletal and function&nbsp;parameters, especially prior to the age of 70 years, with grip strength deteriorating at a greater rate than BMD,&nbsp;balance and gait.</div

Autoimmunity-Associated LYP-W620 Does Not Impair Thymic Negative Selection of Autoreactive T Cells.

A C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for human autoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays a role in thymic selection. However, the mechanism of action of the R620W variant in autoimmunity remains unclear. One model holds that LYP-W620 is a gain-of-function phosphatase that causes alterations in thymic negative selection and/or thymic output of regulatory T cells (Treg) through inhibition of thymic TCR signaling. To test this model, we generated mice in which the human LYP-W620 variant or its phosphatase-inactive mutant are expressed in developing thymocytes under control of the proximal Lck promoter. We found that LYP-W620 expression results in diminished thymocyte TCR signaling, thus modeling a "gain-of-function" of LYP at the signaling level. However, LYP-W620 transgenic mice display no alterations of thymic negative selection and no anomalies in thymic output of CD4(+)Foxp3(+) Treg were detected in these mice. Lck promoter-directed expression of the human transgene also causes no alteration in thymic repertoire or increase in disease severity in a model of rheumatoid arthritis, which depends on skewed thymic selection of CD4(+) T cells. Our data suggest that a gain-of-function of LYP is unlikely to increase risk of autoimmunity through alterations of thymic selection and that LYP likely acts in the periphery perhaps selectively in regulatory T cells or in another cell type to increase risk of autoimmunity

Deletion of the Human Cytomegalovirus US17 Gene Increases the Ratio of Genomes per Infectious Unit and Alters Regulation of Immune and Endoplasmic Reticulum Stress Response Genes at Early and Late Times after Infection

Human cytomegalovirus (HCMV) employs numerous strategies to combat, subvert, or co-opt host immunity. One evolutionary strategy for this involves capture of a host gene and then its successive duplication and divergence, forming a family of genes, many of which have immunomodulatory activities. The HCMV US12 family consists of 10 tandemly arranged sequence-related genes in the unique short (US) region of the HCMV genome (US12 to US21). Each gene encodes a protein possessing seven predicted transmembrane domains, patches of sequence similarity with cellular G-protein-coupled receptors, and the Bax inhibitor 1 family of antiapoptotic proteins. We show that one member, US17, plays an important role during virion maturation. Microarray analysis of cells infected with a recombinant HCMV isolate with a US17 deletion (the ΔUS17 mutant virus) revealed blunted host innate and interferon responses at early times after infection (12 h postinfection [hpi]), a pattern opposite that previously seen in the absence of the immunomodulatory tegument protein pp65 (pUL83). Although the ΔUS17 mutant virus produced numbers of infectious particles in fibroblasts equal to the numbers produced by the parental virus, it produced \u3e3-fold more genome-containing noninfectious viral particles and delivered increased amounts of pp65 to newly infected cells. These results suggest that US17 has evolved to control virion composition, to elicit an appropriately balanced host immune response. At later time points (96 hpi), ΔUS17 mutant-infected cells displayed aberrant expression of several host endoplasmic reticulum stress response genes and chaperones, some of which are important for the final stages of virion assembly and egress. Our results suggest that US17 modulates host pathways to enable production of virions that elicit an appropriately balanced host immune response

Outcomes after out-of-hospital cardiac arrest in immigrants vs natives in Denmark

Aims: Ethnic disparities subsist in out-of-hospital cardiac arrest (OHCA) outcomes in the US, yet it is unresolved whether similar inequalities exist in European countries. This study compared survival after OHCA and its determinants in immigrants and non-immigrants in Denmark. Methods: Using the nationwide Danish Cardiac Arrest Register, 37,622 OHCAs of presumed cardiac cause between 2001 and 2019 were included, 95% in non-immigrants and 5% in immigrants. Univariate and multiple logistic regression was used to assess disparities in treatments, return of spontaneous circulation (ROSC) at hospital arrival, and 30-day survival. Results: Immigrants were younger at OHCA (median 64 [IQR 53–72] vs 68 [59–74] years; p &lt; 0.05), had more prior myocardial infarction (15% vs 12%, p &lt; 0.05), more diabetes (27% vs 19%, p &lt; 0.05), and were more often witnessed (56% vs 53%; p &lt; 0.05). Immigrants received similar bystander cardiopulmonary resuscitation and defibrillation rates to non-immigrants, but more coronary angiographies (15% vs 13%; p &lt; 0.05) and percutaneous coronary interventions (10% vs 8%, p &lt; 0.05), although this was insignificant after age-adjustment. Immigrants had higher ROSC at hospital arrival (28% vs 26%; p &lt; 0.05) and 30-day survival (18% vs 16%; p &lt; 0.05) compared to non-immigrants, but adjusting for age, sex, witness status, first observed rhythm, diabetes, and heart failure rendered the difference non-significant (odds ratios (OR) 1.03, 95% confidence interval (CI) 0.92–1.16 and OR 1.05, 95% CI 0.91–1.20, respectively). Conclusions: OHCA management was similar between immigrants and non-immigrants, resulting in similar ROSC at hospital arrival and 30-day survival after adjustments.</p

Family history of cardiovascular disease and death in patients with out-of-hospital cardiac arrest

Aim: How a family history of cardiovascular disease (CVD) or death influences the risk of out-of-hospital cardiac arrest (OHCA) is unknown. This study examined the prevalence of family histories of CVD and death in patients with OHCA and if these factors were associated with OHCA. Methods: Patients (&lt;70 years) with OHCA's of presumed cardiac origin and available kinship information were identified from the Danish Cardiac Arrest Register (2001–2014). Patients with OHCA were matched 1:4 (age, sex, and number of identifiable parents) with individuals from the background population (controls) to compare family histories (events in first-degree relatives before OHCA) of CVD, all-cause death, cardiovascular death, and premature death (death &lt;60 years). In conditional multivariable logistic regressions, we examined associations between parental history and offspring OHCA risk. Results: Of 45,293 patients with OHCA 4,994, were eligible for inclusion (median age 50 years at OHCA, 76% male). Of these 47.7% had a family history of CVD (vs. 42.1% of controls), 68.2% of all-cause death (vs. 60.9%), 23% of premature death (vs. 15.8%) and 33.3% of cardiovascular death (vs. 27%) (p &lt; 0.001 for all). A family history of a single parent with CVD (OR: 1.13, 95%CI: 1.05,1.23), all-cause death (OR: 1.42, 95%CI: 1.29,1.56), cardiovascular death (OR: 1.35, 95%CI: 1.24, 1.47), and premature death (OR: 1.45, 95%CI: 1.32,1.59) were all associated with OHCA (p &lt; 0.001 for all). Conclusion: A family history of CVD and death is more common among patients with OHCA compared to a matched background population, as well as being significantly associated with OHCA.</p