Investigation of selected collagen genes in exercise-related musculoskeletal soft tissue phenotypes

Includes bibliographical references.Previous findings have suggested that functional variants within collagen encoding genes are associated with several musculoskeletal soft tissue injuries and other exercise-related phenotypes. Specifically variants within the functional COL5A1 3’- untranslated region (UTR) have previously been associated with (1) chronic Achilles tendinopathy, (2) Anterior Cruciate Ligament (ACL) ruptures in females, (3) endurance running performance and (4) range of motion (ROM). Since this gene encodes for an important structural component of the collagen fibril it has been hypothesised that variants within other collagen fibril encoding genes, such as COL3A1, COL6A1 and COL12A1, will also be associated with these and/or other musculoskeletal soft tissue injuries and exercise-related phenotypes. The COL5A1 rs12722 and COL12A1 rs970547 gene variants have been previously associated with risk of ACL ruptures in females [153;154] and/or chronic Achilles tendinopathy [131;181]. The first aim of this thesis was therefore to investigate the COL3A1 rs1800255 and COL6A1 rs35796750 gene variants as risk factors for these musculoskeletal soft tissue injuries

All Shook Up: A Review of Sport-related Concussions in High School Athletes

Background: Concussions comprise 24.8% of the total injuries in high school athletes, putting developing brains at risk for neurocognitive dysfunction. Recent research has been geared towards finding the most effective process for (a) diagnosing, (b) treating and (c) preventing concussions. The most recent data from the Centers for Disease Control and Prevention (CDC) show that 329,290 children were diagnosed with a sports related concussion or traumatic brain injury (TBI) in 2012. Methods: A systematic review of current literature was performed using the Long Island University online library database and Google Scholar. Search terms included: (a) concussion, (b) sports, (c) high school; (d) screening; (e) risk factors; (f) symptoms; (g) complications, and (h) pathophysiology, including the years 2011 to 2018 and in the English language. Results: A concussion is a form of traumatic brain injury resulting in transient neurologic impairment that can resolve spontaneously or have lingering symptoms without structural changes on routine neuroimaging studies. Concussions are the most common injury among high school student-athletes, rising from 9.1% of all injuries in the 2005-2006 school year to 24.8% in the 2016-2017 school year. The overall prevalence is 2.5 concussions per 10,000 athletic exposures (competition or practice). Football has the highest overall rate of concussion with 6.4 per 10,000 athletic exposures, while soccer has the highest rate among girls’ sports with 3.4 per 10,000 athletic exposures. In gender comparable sports, girls have a higher rate of concussion than boys. In general, concussion rates are higher in competition than in practice. Current protocols center around early recognition of symptoms and removal from the field of play. Several screening tools have been developed, including the Sport Concussion Assessment Tool (SCAT-5) to aid in identifying potential concussions on the sideline and initiating proper treatment. Gradual return-to-school and return-to-play criteria have been developed to allow adequate healing time and prevent re-injury. Concussions, especially repetitive, may have long term effects such as (a) post-concussive syndrome, (b) post-traumatic seizures, (c) chronic traumatic encephalopathy (CTE), and (d) decreased neurocognitive function. The CDC offers recommendations for concussion prevention based on each sport, but in general, strict enforcement of the rules and proper protective equipment are key. Conclusions and Recommendations: Prevention and early recognition of symptoms can help reduce the number of concussions as well as long term effects. Athletes should wear all required protective equipment and the equipment should be fully functional. For contact sports, emphasis should be placed on proper form and safe techniques, as well as a limit on the number of full-contact practices per season. These measures can help to prevent concussions from occurring. In addition, officials should be trained to look for concussion symptoms and not hesitate to remove a player from action if they suspect a concussion. Athletes should not be permitted to return to play unless they are cleared by a medical practitioner and there should be stiff penalties for coaches who pressure players into returning prematurely

Collagen gene sequence variants in exercise-related traits

Collagens are major structural proteins of tendons, ligaments and other components of musculoskeletal tissues. Rare mutations in many of the genes, which encode for the collagen α-chains, result in serious musculoskeletal disorders, highlighting the importance of this protein family in the normal structure an d function of musculoskeletal tissues. Since these rare mutations cause severe disorders, it has been proposed that a lack of biological redundancy exists within the collagen fibril, and that collagen-encoding genes are therefore ideal candidates for association with less severe exercise-related traits. This review identifies a number of collagen gene variants which are associated with various exercise-related traits. Based on the evidence outlined in this review, we propose that a general genetic continuum exists for collagen genes and their associated traits. At one end of this general continuum model, a single mutation within one or more collagen genes will result in severe Mendelian disorders. At the other end of the continuum, functional variants within these collagen genes collectively contribute to the aetiology of anomalous multifactorial connective tissue traits, which arise as a result of the interaction of genetic and non-genetic factors which modulate physiological responses to environmental stimuli

Shared genetic architecture between irritable bowel syndrome and psychiatric disorders reveals molecular pathways of the gut-brain axis

Background: Irritable bowel syndrome (IBS) often co-occurs with psychiatric and gastrointestinal disorders. A recent genome-wide association study (GWAS) identified several genetic risk variants for IBS. However, most of the heritability remains unidentified, and the genetic overlap with psychiatric and somatic disorders is not quantified beyond genome-wide genetic correlations. Here, we characterize the genetic architecture of IBS, further, investigate its genetic overlap with psychiatric and gastrointestinal phenotypes, and identify novel genomic risk loci. Methods: Using GWAS summary statistics of IBS (53,400 cases and 433,201 controls), and psychiatric and gastrointestinal phenotypes, we performed bivariate casual mixture model analysis to characterize the genetic architecture and genetic overlap between these phenotypes. We leveraged identified genetic overlap to boost the discovery of genomic loci associated with IBS, and to identify specific shared loci associated with both IBS and psychiatric and gastrointestinal phenotypes, using the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework. We used functional mapping and gene annotation (FUMA) for functional analyses. Results: IBS was highly polygenic with 12k trait-influencing variants. We found extensive polygenic overlap between IBS and psychiatric disorders and to a lesser extent with gastrointestinal diseases. We identified 132 independent IBS-associated loci (condFDR < 0.05) by conditioning on psychiatric disorders (n = 127) and gastrointestinal diseases (n = 24). Using conjFDR, 70 unique loci were shared between IBS and psychiatric disorders. Functional analyses of shared loci revealed enrichment for biological pathways of the nervous and immune systems. Genetic correlations and shared loci between psychiatric disorders and IBS subtypes were different. Conclusions: We found extensive polygenic overlap of IBS and psychiatric and gastrointestinal phenotypes beyond what was revealed with genetic correlations. Leveraging the overlap, we discovered genetic loci associated with IBS which implicate a wide range of biological pathways beyond the gut-brain axis. Genetic differences may underlie the clinical subtype of IBS. These results increase our understanding of the pathophysiology of IBS which may form the basis for the development of individualized interventions.publishedVersio

Sea, sickness and cautionary tales: a multi-isotope study from a post-mediaeval hospital at the city-port of Gibraltar (AD 1462–1704)

Abstract: During the sixteenth to eighteenth centuries, Spanish ships sailed around the globe connecting Spain to its colonies. While documentary records offer rich details concerning life on board ship, archaeological information is essential to generating a full picture of the past. The cemetery at Old St Bernard’s Hospital, Gibraltar, provides an opportunity to study the skeletal remains of sailors. Following previous osteological research, carbon, nitrogen, oxygen and strontium isotope analyses were undertaken on thirty-three of these individuals. The results show that the, largely male, individuals had various different diets during life and came from several different places. Diets were largely based on C3 food chains; some individuals consumed C3 foods with low δ13C values; others consumed some marine foods, and a few individuals had a high trophic level diet, through the consumption of either freshwater resources or a high proportion of animal protein. The individuals spent their childhoods in several different places, although these homelands do not correlate simply with dietary variation. This variety in diets and homelands is consistent with our expectations for this hospital site given its location in a post-mediaeval entrepôt. The interpretation of these results are greatly helped by the available historical information and this has broader implications for the interpretation of isotope data elsewhere where the historical context of the site and the mobility patterns of the individuals are less well known

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation

Background Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. Methods We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. Results We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. Conclusions Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.publishedVersio