Genomic Prediction of Tendinopathy Risk in Elite Team Sports

The authors investigated the association between risk of tendinopathies and genetic markers in professional team sports. Methods: The authors studied 363 (mean [SD]; 25 [6] y, 89% male) elite players (soccer, futsal, basketball, handball, and roller hockey) from a top-level European team (FC Barcelona, Spain). Of 363, 55% (cases) had experienced 1+ episodes of tendinopathy during 2008–2018 and 45% (controls) remained injury free. The authors first examined the association between single-nucleotide polymorphisms (SNPs) and tendinopathy risk in a hypothesis-free case-control genome-wide association study (495,837 SNPs) with additional target analysis of 58 SNPs that are potential candidates to influence tendinopathy risk based on the literature. Thereafter, the authors augmented the SNP set by performing synthetic variant imputation (1,419,369 SNPs) and then used machine learning-based multivariate modeling (support vector machine and random forest) to build a reliable predictive model. Results: Suggestive association (P < 10−5) was found for rs11154027 (gap junction alpha 1), rs4362400 (vesicle amine transport 1-like), and rs10263021 (contactin-associated protein-like 2). Carriage of 1+ variant alleles for rs11154027 (odds ratio = 2.11; 95% confidence interval, 1.07–4.19, P = 1.01 × 10−6) or rs4362400 (odds ratio = 1.98; 95% confidence interval, 1.05–3.73, P = 9.6 × 10−6) was associated with a higher risk of tendinopathy, whereas an opposite effect was found for rs10263021 (odds ratio = 0.42; 95% confidence interval, 0.20–0.91], P = 4.5 × 10−6). In the modeling approach, one of the most robust SNPs was rs10477683 in the fibrillin 2 gene encoding fibrillin 2, a component of connective tissue microfibrils involved in elastic fiber assembly. Conclusions: The authors have identified previously undescribed genetic predictors of tendinopathy in elite team sports athletes, notably rs11154027, rs4362400, and rs10263021.Sin financiación4.010 JCR (2020) Q1, 22/88 Sport Sciences2.278 SJR (2020) Q1, 8/288 Orthopedics and Sports MedicineNo data IDR 2019UE

Preservation of 5'-end integrity of a potyvirus genomic RNA is not dependent on template specificity

Full-length in vitro transcripts of plum pox potyvirus (PPV) genomic RNA with mutations altering the number of 5'-terminal adenosine residues were able to infect Nicotiana clevelandii plants, whereas a mutant with a substitution of adenosine in position 2 by guanosine failed to infect. The genomic 5' end was template-independently repaired during in vivo RNA synthesis producing wild-type viral progeny. Putative models of replication initiation are discussed. (C) 2000 Academic Press.This work was supported by Grants BIO98-0769 from CICYT, 06G/ 021/96 from Comunidad de Madrid, and BIO4-CT96-0304 and BIO4- CT97-2300 from the Biotechnology Program of the European Union.Peer Reviewe

Alpha-Actinin-3 Deficiency Might Affect Recovery from Non-Contact Muscle Injuries: Preliminary Findings in a Top-Level Soccer Team

There are recent data suggesting an association between the R577X polymorphism (rs1815739) in the gene encoding α-actinin-3 (ACTN3) and the risk of musculoskeletal injuries. The purpose of this study was to analyze the association of rs1815739 with risk of, and recovery time from non-contact soft-tissue muscle injuries in professional soccer players. Forty-six (22 male and 24 female) players from a top-level professional soccer team were assessed during five consecutive seasons: the genotype distribution was: RR, 41.3%; RX, 47.8%; and XX, 10.9%. There was a trend towards a higher risk of muscle injury associated with the XX genotype (p = 0.092, with no injury-free XX player during the 5-year study period) and a significant genotype effect for the time needed to return to play (p = 0.044, with the highest value shown for the XX genotype, i.e., 36 ± 26 days, vs. 20 ± 10 and 17 ± 12 days for RR and RX, respectively). In conclusion, the XX genotype might be associated not only with a higher risk of non-contact muscle injuries, but also of recovery time from these conditions. However, more research in larger cohorts is needed to confirm this preliminary hypothesis.Sin financiación4.096 JCR (2020) Q2, 65/175 Genetics & Heredity1.337 SJR (2020) Q2, 99/340 GeneticsNo data IDR 2019UE

Sex Differences in the Association between Risk of Anterior Cruciate Ligament Rupture and COL5A1 Polymorphisms in Elite Footballers

Background: Single-nucleotide polymorphisms (SNPs) in collagen genes are predisposing factors for anterior cruciate ligament (ACL) rupture. Although these events are more frequent in females, the sex-specific risk of reported SNPs has not been evaluated. Purpose: We aimed to assess the sex-specific risk of historic non-contact ACL rupture considering candidate SNPs in genes previously associated with muscle, tendon, ligament and ACL injury in elite footballers. Study Design: This was a cohort genetic association study. Methods: Forty-six (twenty-four females) footballers playing for the first team of FC Barcelona (Spain) during the 2020–21 season were included in the study. We evaluated the association between a history of non-contact ACL rupture before July 2022 and 108 selected SNPs, stratified by sex. SNPs with nominally significant associations in one sex were then tested for their interactions with sex on ACL. Results: Seven female (29%) and one male (4%) participants had experienced non-contact ACL rupture during their professional football career before the last date of observation. We found a significant association between the rs13946 C/C genotype and ACL injury in women footballers (p = 0.017). No significant associations were found in male footballers. The interaction between rs13946 and sex was significant (p = 0.027). We found that the C-allele of rs13946 was exclusive to one haplotype of five SNPs spanning COL5A1. Conclusions: The present study suggests the role of SNPs in genes encoding for collagens as female risk factors for ACL injury in football players. Clinical Relevance: The genetic profiling of athletes at high risk of ACL rupture can contribute to sex-specific strategies for injury prevention in footballers

Gene expression patterns related to osteogenic differentiation of bone marrow-derived mesenchymal stem cells during ex vivo expansion

Bone marrow is commonly used as a source of adult multipotent mesenchymal stem cells (MSCs), defined for their ability to differentiate in vitro into multiple lineages. The ex vivo-expanded MSCs are currently being evaluated as a strategy for the restoration of function in damaged skeletal tissue, both in cell therapy and tissue engineering applications. The aim of this study was to define gene expression patterns underlying the differentiation of MSCs into mature osteoblasts during the expansion in vitro, and to explore a variety of cell functions that cannot be easily evaluated using morphological, cytochemical, and biochemical assays. Cell cultures were obtained from bone marrow samples of six individuals undergoing total hip replacement, and a large-scale transcriptome analysis, using Affymetrix HG-U133A Plus 2.0 array (Affymetrix((R)), Santa Clara, CA), was performed at the occurrence of specific events, including the appearance of MSC surface markers, formation of colonies, and deposition of mineral nodules. We focused our attention on 213 differentially upregulated genes, some belonging to well-known pathways and some having one or more Gene Ontology annotations related to bone cell biology, including angiogenesis, bone-related genes, cell communication, development and morphogenesis, transforming growth factor-beta signaling, and Wnt signaling. Twenty-nine genes, whose role in bone cell pathophysiology has not been described yet, were found. In conclusion, gene expression patterns that characterize the early, intermediate, and late phases of the osteogenic differentiation process of ex vivo-expanded MSCs were defined. These signatures represent a useful tool to monitor the osteogenic process, and to analyze a broad spectrum of functions of MSCs cultured on scaffolds, especially when the constructs are conceived for releasing growth factors or other signals to promote bone regeneration

Antigen-stimulated PBMC transcriptional protective signatures for malaria immunization

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Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis

Alpha1 antitrypsin deficiency; Diagnosis; Dried blood spotsDeficiencia de alfa1 antitripsina; Diagnóstico; Manchas de sangre secaDeficiència d'alfa1 antitripsina; Diagnòstic; Taques de sang secaIntroduction Currently, strategies for improving alpha1 antitrypsin deficiency (AATD) diagnosis are needed. Here we report the performance of a multinational multiplex-based genotyping test on dried blood spots and buccal swabs sent by post or courier and with web registration for subjects with suspected AATD in Argentina, Brazil, Chile, Colombia, Spain, and Turkey. Methods This was an observational, cross-sectional analysis of samples from patients with suspected AATD from March 2018 to January 2022. Samples were coded on a web platform and sent by post or courier to the central laboratory in Northern Spain. Allele-specific genotyping for the 14 most common mutations was carried out with the A1AT Genotyping Test (Progenika-Grifols, Spain). SERPINA1 gene sequencing was performed if none of the mutations were found or one variant was detected in heterozygous status and the AAT serum level was < 60 mg/dl, or if requested by the clinician in charge. Results The study included 30,827 samples: 30,458 (94.7%) with final results after direct genotyping and 369 (1.1%) with additional gene sequencing. Only 0.3% of the samples were not processed due to their poor quality. The prevalence of the most frequent allele combinations was MS 14.7%, MZ 8.6%, SS 1.9%, SZ 1.9%, and ZZ 0.9%. Additionally, 70 cases with new mutations were identified. Family screening was conducted in 2.5% of the samples. Samples from patients with respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also presented AATD mutations. Conclusions Our results confirm the viability of this diagnostic system for genotyping AATD conducted simultaneously in different countries. The system has proved satisfactory and can improve the timely diagnosis of AATD.This project is entirely funded by Grifols

Successful cyclosporin and ustekinumab combination therapy in a patient with severe steroid-refractory ulcerative colitis

The therapeutic management of patients with severe steroid-refractory ulcerative colitis still represents a critical clinical challenge. In this setting, cyclosporin is an effective and rapidly acting induction treatment that is applied in combination with maintenance therapeutic agents like thiopurines or vedolizumab. Here, we present the case of a 33-year-old ulcerative colitis patient with severe steroid-refractory ulcerative colitis who refused surgical intervention and previously demonstrated no long-term benefit to anti-TNF antibody, vedolizumab, cyclosporin, thiopurines or tofacitinib treatment. Intravenous cyclosporin therapy was re-initiated in the patient and, after signs of clinical response, therapy with ustekinumab was additionally applied. After 11 weeks of well tolerated cyclosporin and ustekinumab combination therapy, cyclosporin was discontinued upon clinical and endoscopic remission. Subsequently, ustekinumab treatment has been effective in maintaining remission during the follow-up period of 195 days

CKD273, a new proteomics classifier assessing CKD and its prognosis.

National Kidney Foundation CKD staging has allowed uniformity in studies on CKD. However, early diagnosis and predicting progression to end stage renal disease are yet to be improved. Seventy six patients with different levels of CKD, including outpatients and dialysed patients were studied for transcriptome, metabolome and proteome description. High resolution urinary proteome analysis was blindly performed in the 53 non-anuric out of the 76 CKD patients. In addition to routine clinical parameters, CKD273, a urinary proteomics-based classifier and its peptides were quantified. The baseline values were analyzed with regard to the clinical parameters and the occurrence of death or renal death during follow-up (3.6 years) as the main outcome measurements. None of the patients with CKD273<0.55 required dialysis or died while all fifteen patients that reached an endpoint had a CKD273 score >0.55. Unsupervised clustering analysis of the CKD273 peptides separated the patients into two main groups differing in CKD associated parameters. Among the 273 biomarkers, peptides derived from serum proteins were relatively increased in patients with lower glomerular filtration rate, while collagen-derived peptides were relatively decreased (p<0.05; Spearman). CKD273 was different in the groups with different renal function (p<0.003). The CKD273 classifier separated CKD patients according to their renal function and informed on the likelihood of experiencing adverse outcome. Recently defined in a large population, CKD273 is the first proteomic-based classifier successfully tested for prognosis of CKD progression in an independent cohort

Additional file 1 of Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis

Figure 1S. Evolution over time of genetic study requests in Spain, LATAM and Turkey. Figure 2S. Evolution over time of requests for genetic studies by LATAM countries. Figure 3S. Distribution of sample types by geographical area. Figure 4S. Time elapsed between different steps by geographical area. Figure 5S. Allele distribution according to the different genotyping reasons in different Latin American countries. Table 1S. Description of the allelic variants and associated alleles tested by A1AT Genotyping Test; Information about the activity of the A1AT protein expressed. Table 2S. Cases in which sequencing revealed additional mutation from direct genotyping.Grifols.Peer reviewe