Rare Variant in the SLC6A2 Encoding a Norepinephrine Transporter Is Associated with Elite Athletic Performance in the Polish Population.
Ontology highlight
ABSTRACT:
SUBMITTER: Fichna JP
PROVIDER: S-EPMC8232774 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The human norepinephrine transporter (NET) is an established drug target for a wide range of psychiatric disorders. Conventional methods that are used to functionally characterize NET inhibitors are based on the use of radiolabeled or fluorescent substrates. These methods are highly informative, but pose limitations to either high-throughput screening (HTS) adaptation or physiologically accurate representation of the endogenous uptake events. Recently, we developed a label-free functional assay based on the activation of G protein-coupled receptors by a transported substrate, termed the TRACT assay. In this study, the TRACT assay technology was applied to NET expressed in a doxycycline-inducible HEK 293 JumpIn cell line. Three endogenous substrates of NET-norepinephrine (NE), dopamine (DA) and epinephrine (EP)-were compared in the characterization of the reference NET inhibitor nisoxetine. The resulting assay, using NE as a substrate, was validated in a manual HTS set-up with a Z' = 0.55. The inhibitory potencies of several reported NET inhibitors from the TRACT assay showed positive correlation with those from an established fluorescent substrate uptake assay. These findings demonstrate the suitability of the TRACT assay for HTS characterization and screening of NET inhibitors and provide a basis for investigation of other solute carrier transporters with label-free biosensors.
| S-EPMC8192900 | biostudies-literature
Project description:There is increasing evidence for strong genetic influences on athletic performance and for an evolutionary "trade-off" between performance traits for speed and endurance activities. We have recently demonstrated that the skeletal-muscle actin-binding protein alpha-actinin-3 is absent in 18% of healthy white individuals because of homozygosity for a common stop-codon polymorphism in the ACTN3 gene, R577X. alpha-Actinin-3 is specifically expressed in fast-twitch myofibers responsible for generating force at high velocity. The absence of a disease phenotype secondary to alpha-actinin-3 deficiency is likely due to compensation by the homologous protein, alpha-actinin-2. However, the high degree of evolutionary conservation of ACTN3 suggests function(s) independent of ACTN2. Here, we demonstrate highly significant associations between ACTN3 genotype and athletic performance. Both male and female elite sprint athletes have significantly higher frequencies of the 577R allele than do controls. This suggests that the presence of alpha-actinin-3 has a beneficial effect on the function of skeletal muscle in generating forceful contractions at high velocity, and provides an evolutionary advantage because of increased sprint performance. There is also a genotype effect in female sprint and endurance athletes, with higher than expected numbers of 577RX heterozygotes among sprint athletes and lower than expected numbers among endurance athletes. The lack of a similar effect in males suggests that the ACTN3 genotype affects athletic performance differently in males and females. The differential effects in sprint and endurance athletes suggests that the R577X polymorphism may have been maintained in the human population by balancing natural selection.
| S-EPMC1180686 | biostudies-literature
Project description:ObjectiveDespite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.MethodsChildren (6-12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families.ResultsA highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z=3.74, P=0.0002), behavioral assessments by parents (CBCL, P=0.00008), as well as restless-impulsive subscale scores on Conners'-teachers (P=0.006) and parents (P=0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z=3.28, P=0.001), parents (Z=2.62, P=0.009), as well as evaluation in the simulated academic environment (Z=3.58, P=0.0003).ConclusionsBy using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information - Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD); www.clinicaltrials.gov; NCT00483106.
| S-EPMC3502190 | biostudies-literature
Project description: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.
| S-EPMC6934758 | biostudies-literature
Project description:Oral pathologies can cause athletic underperformance. The aim of this study was to determine the effect of malocclusion on maximal aerobic capacity in young athletes with the same anthropometric data, diet, training mode, and intensity from the same athletics training center. Sub-elite track and field athletes (middle-distance runners) with malocclusion (experimental group (EG); n = 37; 21 girls; age: 15.1 ± 1.5 years) and without malocclusion (control group (CG); n = 13; 5 girls; age: 14.7 ± 1.9 years) volunteered to participate in this study. Participants received an oral diagnosis to examine malocclusion, which was defined as an overlapping of teeth that resulted in impaired contact between the teeth of the mandible and the teeth of the upper jaw. Maximal aerobic capacity was assessed using the VAMEVAL test (calculated MAS and estimated VO2max). The test consisted of baseline values that included the following parameters: maximum aerobic speed (MAS), maximal oxygen uptake (VO2max), heart rate frequency, systolic (SAP) and diastolic arterial pressure (DAP), blood lactate concentration (LBP), and post-exercise blood lactate assessment (LAP) after the performance of the VAMEVAL test. There were no statistically significant differences between the two study groups related to either anthropometric data (age: EG = 15.1 ± 1.5 vs. CC = 14.7 ± 1.9 years (p = 0.46); BMI: EG = 19.25 ± 1.9 vs. CC = 19.42 ± 1.7 kg/m2 (p = 0.76)) or for the following physical fitness parameters and biomarkers: MAS: EG = 15.5 (14.5-16.5) vs. CG = 15.5 (15-17) km/h (p = 0.47); VO2max: EG = 54.2 (52.5-58.6) vs. CG = 54.2 (53.4-59.5) mL/kg/min (p = 0.62) (IQR (Q1-Q3)); heart rate before the physical test: EG = 77.1 ± 9.9 vs. CG = 74.3 ± 14.0 bpm (p = 0.43); SAP: EG = 106.6 ± 13.4 vs. CG = 106.2 ± 14.8 mmHg (p = 0.91); DAP: EG = 66.7 ± 9.1 vs. CG = 63.9 ± 10.2 mmHg (p = 0.36); LBP: EG = 1.5 ± 0.4 vs. CG = 1.3 ± 0.4 mmol/L (p = 0.12); and LAP: EG = 4.5 ± 2.36 vs. CG = 4.06 ± 3.04 mmol/L (p = 0.60). Our study suggests that dental malocclusion does not impede maximal aerobic capacity and the athletic performance of young track and field athletes.
| S-EPMC10051721 | biostudies-literature
Project description:The FTO A/T polymorphism (rs9939609) is a strong candidate to influence obesity-related traits. Elite athletes from many different sporting disciplines are characterized by low body fat. Therefore, the aim of this study was to assess whether athletic status is associated with the FTO A/T polymorphism.A large cohort of European Caucasians from Poland, Russia and Spain were tested to examine the association between FTO A/T polymorphism (rs9939609) and athletic status. A total of 551 athletes were divided by type of sport (endurance athletes, n = 266 vs. sprint/power athletes, n = 285) as well as by level of competition (elite-level vs. national-level). The control group consisted of 1,416 ethnically-matched, non-athletic participants, all Europeans. Multinomial logistic regression analyses were conducted to assess the association between FTO A/T genotypes and athletic status/competition level.There were no significantly greater/lesser odds of harbouring any type of genotype when comparing across athletic status (endurance athletes, sprint/power athletes or control participants). These effects were observed after controlling for sex and nationality. Furthermore, no significantly greater/lesser odds ratios were observed for any of the genotypes in respect to the level of competition (elite-level vs. national-level).The FTO A/T polymorphism is not associated with elite athletic status in the largest group of elite athletes studied to date. Large collaborations and data sharing between researchers, as presented here, are strongly recommended to enhance the research in the field of exercise genomics.
| S-EPMC3616005 | biostudies-literature
Project description:Gene variation linked to physiological functions is recognised to affect elite athletic performance by modulating training and competition-enabling behaviour. The fatty acid amide hydrolase (FAAH) has been investigated as a good candidate for drug targeting, and recently, its single-nucleotide polymorphism (SNP) rs324420 was reported to be associated with athletic performance. Given the implications, the biological pathways of this genetic polymorphism linked to elite athletic performance, considering sport type, psychological traits and sports injuries, need to be dissected. Thus, a narrative review of the literature concerning the biological mechanisms of this SNP was undertaken. In addition to its role in athletic performance, FAAH rs324420 is also involved in important mechanisms underlying human psychopathologies, including substance abuse and neural dysfunctions. However, cumulative evidence concerning the C385A variant is inconsistent. Therefore, validation studies considering homogeneous sports modalities are required to better define the role of this SNP in elite athletic performance and its impact on stress coping, pain regulation and inflammation control.
| S-EPMC10606937 | biostudies-literature
Project description:Background: The goal of this study was to determine the transcriptional consequences of norepinephrine transporter (NET) gene deletion in noradrenergic neuron differentiation. The norepinephrine transporter (NET) is the target of powerful mind-altering substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET function in adult noradrenergic neurons of the peripheral and central nervous systems is that of a scavenger that internalizes norepinephrine from the synaptic cleft. By contrast, norepinephrine (NE) transport has a different role in embryogenesis. It promotes differentiation of neural crest cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors, such as the tricyclic antidepressant desipramine and the drug of abuse, cocaine, inhibit noradrenergic differentiation. While NET structure und regulation of NET function is well described, little is known about downstream targets of NE transport. Results: We have determined by long serial analysis of gene expression (LongSAGE) the gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) neural crest derivatives. Comparison analyses with the wild type library (GSM 105765) have identified a number of important differentially expressed genes, including genes relevant to noradrenergic neuron differentiation and to the phenotype of NETKO mice. Furthermore we have identified novel differentially expressed genes. Conclusions: Loss of NET function during embryonic development deregulates signaling pathways that are critically involved in neural crest formation and noradrenergic neuron differentiation.
2008-06-23 | GSE11788 | GEO
Project description:Background: The goal of this study was to determine the transcriptional consequences of norepinephrine transporter (NET) gene deletion in noradrenergic neuron differentiation. The norepinephrine transporter (NET) is the target of powerful mind-altering substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET function in adult noradrenergic neurons of the peripheral and central nervous systems is that of a scavenger that internalizes norepinephrine from the synaptic cleft. By contrast, norepinephrine (NE) transport has a different role in embryogenesis. It promotes differentiation of neural crest cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors, such as the tricyclic antidepressant desipramine and the drug of abuse, cocaine, inhibit noradrenergic differentiation. While NET structure und regulation of NET function is well described, little is known about downstream targets of NE transport. Results: We have determined by long serial analysis of gene expression (LongSAGE) the gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) neural crest derivatives. Comparison analyses with the wild type library (GSM 105765) have identified a number of important differentially expressed genes, including genes relevant to noradrenergic neuron differentiation and to the phenotype of NETKO mice. Furthermore we have identified novel differentially expressed genes. Conclusions: Loss of NET function during embryonic development deregulates signaling pathways that are critically involved in neural crest formation and noradrenergic neuron differentiation. The library was constructed from total RNA of 60 neural crest culture at culture day 7. The neural tubes were dissected from E9.5 embryos that lack the norepinephrine transporter gene.
2008-06-23 | E-GEOD-11788 | biostudies-arrayexpress
Project description:The aims of the present study were 2-fold: (1) to measure interlimb asymmetries from a battery of fitness tests in youth soccer players and (2) to determine the association between asymmetry and measures of athletic performance. Sixteen elite youth soccer players (14.7 ± 0.2 years) performed a single-leg Abalakov test (ABK), change of direction (COD) test over 10 m (5 + 5) and 20 m (10 + 10), and an iso-inertial power test. Subjects also performed 10-, 20-, and 30-m sprints and a bilateral countermovement jump, which were correlated with all ABK, COD, and iso-inertial asymmetry scores. A one-way repeated-measures analysis of variance showed significant differences between interlimb asymmetry scores across multiple tests (p < 0.05), with the iso-inertial power test presenting the greatest magnitude of asymmetry, whereas individual data highlighted substantially greater interindividual differences in each test. Pearson r correlations showed no significant relationships (p > 0.05) between the different interlimb asymmetry scores, and between asymmetry scores and athletic performance. These findings show the test-specific nature of asymmetries in youth soccer players, with the iso-inertial power test being the most sensitive in detecting asymmetry. Moreover, the results obtained suggest that inherent asymmetry in young soccer players did not negatively impact their performance.
| S-EPMC7063114 | biostudies-literature