Genetics and metabolomics of elite athletes: Genome-wide association study and Metabolomics profiling of elite athletes

AIM: The outstanding performance of elite athletes is a product of a complex interaction between genetic and environmental factors. The aims of this study was to compare differences in genetic and metabolic profiles among different classes of elite athletes and to identify genetically-influenced metabolic profiles (metabotypes) underlying these differences. METHODS: Genome-wide association study (GWAS) was conducted in 1259 elite athlete samples using Drug core BeadChip arrays, followed by non-targeted metabolomics of 692 serum samples. Genotype distribution, differences in metabolic levels and genetically-influenced metabotypes were compared between high and moderate endurance and power sports as well as among sports with different cardiovascular demands (CVD). RESULTS: Out of 341385 SNPs, two novel associations are reported for endurance status including rs56330321 in ATP2B2 (p=1.47E-7) and rs2635438 in SYNE1 (p=2.54E-7). A meta-analysis confirmed the association of rs56330321 and rs2635438 with endurance athlete status at GWAS level of significance. Metabolomics analysis of 740 metabolites was performed in in 191 (discovery cohort) and 500 (replication cohort) elite athletes. These studies revealed changes in various metabolites involved in steroid biosynthesis, fatty acid oxidation, oxidative stress response, xenobiotics and various mediators of cell signaling among different groups of endurance, power and CVD athletes. By combining GWAS with metabolomics profiling data (mGWAS), 19 common variant metabolic quantitative trait loci (mQTLs) were identified, of which 5 were novel. When focusing on metabolites associated with endurance, power and CVD, 4 common variant mQTLs were found, of which one novel mQTL linking 4-androsten-3alpha,17alpha-diol monosulfate and SULT2A1 involved in steroid sulfation was identified in association with endurance. CONCLUSIONS: GWAS, metabolomics and mGWAS of elite athletes identified novel markers associated with elite athletic performance with a potential application in biomarker discovery in relation to elite athletic performance

Phylogenetic Diversity of Cyanobacteria from Qatar Coastal Waters

Cyanobacteria represent the major microorganism phyla, being diverse and widespread group inhabiting most of the earth's environments. The recent increase of occurrence of toxic cyanobacterial strains in the marine environment attracts attention of the scientific community and environmental managers. The deterministic factors leading to such events are under scrutiny and are closely linked to our understanding of the diversity and environmental response of these strains to environmental conditions. The extreme environment witnessed in the Arabian Gulf is likely to nurture the occurence of such harmful events. In recent times advanced molecular methodologies for the detection and genetic characterization of cyanobacteria were developed based on DNA amplification techniques. We aim in this work to better understand the diversity of the cyanobacterial natural communities found in Qatar marine environment through a genotypic characterization (phylogenetic analysis) with the objective to i. assess the local diversity, and ii. provide consistent reference for future comparative analysis, biotechnological applications and monitoring. In this study, QUCCCM strains from Qatar coastal were used to amplify fragments of the 16S rRNA gene followed by phylogenetic analysis. This methodology showed to produce accurate identification of the considered strains and analyze their evolutionary relationship. 28 taxa were identified among them 21.4% belong to the genus Geitlerinem, 25% Chroococcidiopsis, 10.7% Synechococcus, 10.7% Stanieria, 7.1% Euhalothece, 7.1% Geminocystis, 3.6% Leptolyngbya, 3.6% Oscillatoria, and 3.6% Dermocarpella. The biogeographic distribution of the strains and their potential toxicity is discussed

Metabolic Signature of Leukocyte Telomere Length in Elite Male Soccer Players

Introduction: Biological aging is associated with changes in the metabolic pathways. Leukocyte telomere length (LTL) is a predictive marker of biological aging; however, the underlying metabolic pathways remain largely unknown. The aim of this study was to investigate the metabolic alterations and identify the metabolic predictors of LTL in elite male soccer players. Methods: Levels of 837 blood metabolites and LTL were measured in 126 young elite male soccer players who tested negative for doping abuse at anti-doping laboratory in Italy. Multivariate analysis using orthogonal partial least squares (OPLS), univariate linear models and enrichment analyses were conducted to identify metabolites and metabolic pathways associated with LTL. Generalized linear model followed by receiver operating characteristic (ROC) analysis were conducted to identify top metabolites predictive of LTL. Results: Sixty-seven metabolites and seven metabolic pathways showed significant associations with LTL. Among enriched pathways, lysophospholipids, benzoate metabolites, and glycine/serine/threonine metabolites were elevated with longer LTL. Conversely, monoacylglycerols, sphingolipid metabolites, long chain fatty acids and polyunsaturated fatty acids were enriched with shorter telomeres. ROC analysis revealed eight metabolites that best predict LTL, including glutamine, N-acetylglutamine, xanthine, beta-sitosterol, N2-acetyllysine, stearoyl-arachidonoyl-glycerol (18:0/20:4), N-acetylserine and 3-7-dimethylurate with AUC of 0.75 (0.64–0.87, p &lt; 0.0001). Conclusion: This study characterized the metabolic activity in relation to telomere length in elite soccer players. Investigating the functional relevance of these associations could provide a better understanding of exercise physiology and pathophysiology of elite athletes.</p

Metabolic GWAS of elite athletes reveals novel genetically-influenced metabolites associated with athletic performance

Genetic research of elite athletic performance has been hindered by the complex phenotype and the relatively small effect size of the identified genetic variants. The aims of this study were to identify genetic predisposition to elite athletic performance by investigating genetically-influenced metabolites that discriminate elite athletes from non-elite athletes and to identify those associated with endurance sports. By conducting a genome wide association study with high-resolution metabolomics profiling in 490 elite athletes, common variant metabolic quantitative trait loci (mQTLs) were identified and compared with previously identified mQTLs in non-elite athletes. Among the identified mQTLs, those associated with endurance metabolites were determined. Two novel genetic loci in FOLH1 and VNN1 are reported in association with N-acetyl-aspartyl-glutamate and Linoleoyl ethanolamide, respectively. When focusing on endurance metabolites, one novel mQTL linking androstenediol (3alpha, 17alpha) monosulfate and SULT2A1 was identified. Potential interactions between the novel identified mQTLs and exercise are highlighted. This is the first report of common variant mQTLs linked to elite athletic performance and endurance sports with potential applications in biomarker discovery in elite athletic candidates, non-conventional anti-doping analytical approaches and therapeutic strategies

Genome-Wide Association Study Reveals a Novel Association Between MYBPC3 Gene Polymorphism, Endurance Athlete Status, Aerobic Capacity and Steroid Metabolism.

The genetic predisposition to elite athletic performance has been a controversial subject due to the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis. The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high ( = 662) and low/moderate ( = 134) aerobic component. Replication of results was performed by comparing the frequencies of the most significant SNPs between 242 and 168 elite Russian high and low/moderate aerobic athletes, respectively, and between 60 elite Japanese endurance athletes and 406 controls. A meta-analysis has identified rs1052373 (GG homozygotes) in Myosin Binding Protein (; implicated in cardiac hypertrophic myopathy) gene to be associated with endurance athlete status ( = 1.43 × 10, odd ratio 2.2). Homozygotes carriers of rs1052373 G allele in Russian athletes had significantly greater VO than carriers of the AA + AG ( = 0.005). Subsequent metabolomics analysis revealed several amino acids and lipids associated with rs1052373 G allele (1.82 × 10) including the testosterone precursor androstenediol (3beta,17beta) disulfate. This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warranted

Genome-wide association study identifies a novel association between a cardiovascular gene polymorphism and superior athletic performance

Background: Research into the genetic predisposition to superior athletic performance has been a hindered by the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis. Results: The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high (n=662) and low/moderate (n=134) aerobic component. Validation of results was performed by comparing the frequencies of the most significant SNPs between 242 and 168 elite Russian high and low/moderate aerobic athletes, respectively, and between 60 elite Japanese endurance athletes and 406 controls. A meta-analysis has identified rs1052373 (GG homozygotes) in Myosin Binding Protein (MYBPC3; implicated in cardiac hypertrophic myopathy) gene to be associated with endurance athlete status (P=1.43E-08, odd ratio 2.2). Homozygotes carriers of rs1052373 G allele in Russian athletes had significantly greater VO2max than carriers of the AA+AG (P = 0.005). Subsequent metabolomics analysis revealed several amino acids and lipids associated with rs1052373 G allele (1.82x10-05) including the testosterone precursor androstenediol (3beta,17beta) disulfate. Conclusions: This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warrante

Combined metformin and insulin treatment reverses metabolically impaired omental adipogenesis and accumulation of 4-hydroxynonenal in obese diabetic patients

OBJECTIVE: Obesity-associated impaired fat accumulation in the visceral adipose tissue can lead to ectopic fat deposition and increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). This study investigated whether impaired adipogenesis of omental (OM) adipose tissues and elevated 4-hydroxynonenal (4-HNE) accumulation contribute to this process, and if combined metformin and insulin treatment in T2DM patients could rescue this phenotype. ----- METHODS: OM adipose tissues were obtained from forty clinically well characterized obese individuals during weight reduction surgery. Levels of 4-HNE protein adducts, adipocyte size and number of macrophages were determined within these tissues by immunohistochemistry. Adipogenic capacity and gene expression profiles were assessed in preadipocytes derived from these tissues in relation to insulin resistance and in response to 4-HNE, metformin or combined metformin and insulin treatment. ----- RESULTS: Preadipocytes isolated from insulin resistant (IR) and T2DM individuals exhibited lower adipogenesis, marked by upregulation of anti-adipogenic genes, compared to preadipocytes derived from insulin sensitive (IS) individuals. Impaired adipogenesis was also associated with increased 4-HNE levels, smaller adipocytes and greater macrophage presence in the adipose tissues. Within the T2DM group, preadipocytes from combined metformin and insulin treated subset showed better in vitro adipogenesis compared to metformin alone, which was associated with less presence of macrophages and 4-HNE in the adipose tissues. Treatment of preadipocytes in vitro with 4-HNE reduced their adipogenesis and increased proliferation, even in the presence of metformin, which was partially rescued by the presence of insulin. ----- CONCLUSION: This study reveals involvement of 4-HNE in the impaired OM adipogenesis-associated with insulin resistance and T2DM and provides a proof of concept that this impairment can be reversed by the synergistic action of insulin and metformin. Further studies are needed to evaluate involvement of 4-HNE in metabolically impaired abdominal adipogenesis and to confirm benefits of combined metformin-insulin therapy in T2DM patients