Association between MAPT polymorphism but not APOE promoter and elite rugby athlete status

INTRODUCTION: Incidence and outcomes of concussions have been hypothesised to be genetically influenced. The APOE Promoter G219T (rs405509) polymorphism has been associated with differential promoter activity and unfavourable outcomes after traumatic brain injury. The TT genotype is associated with a 3-fold greater risk of multiple concussions. The TT genotype of MAPT (rs10445337) has also been associated with poorer outcomes after concussion. Rugby has one of the highest incidences of concussion in sport, so it was hypothesised that APOE Promoter TT and MAPT TT genotypes would be less prevalent in elite rugby athletes because those genotypes, previously associated with increased risk, would be less compatible with achieving elite athlete status. METHODS: Participants were from the RugbyGene project, comprising elite Caucasian male rugby athletes (n = 528; mean (standard deviation) height 1.85 (0.07) m, mass 101 (14) kg, age 29 (7) yr), including 420 rugby union (RU) athletes that for some analyses were divided into forwards and backs and 108 rugby league (RL) athletes. Non-athletes were 592 Caucasian men and women (57% male, height 1.72 (0.10) m, mass 74 (14) kg, age 31 (7) yr). PCR of genomic DNA was used to determine genotypes using TaqMan probes, then groups were compared using χ2 and odds ratio (OR) statistics. RESULTS: All genotype data were in Hardy-Weinberg equilibrium. For MAPT (rs10445337), the risk genotype (TT) was underrepresented in rugby athletes (60%) compared to non-athletes (66%), CT more common in rugby athletes (34%) than non-athletes (29%) and little difference in CC genotype frequencies (χ2 = 7.092, P = 0.029; TT genotype frequency OR = 0.80, 95% confidence intervals (CI) = 0.62-1.02). There were no differences in MAPT (rs10445337) genotype frequencies between RU forwards and backs. For APOE Promoter G219T (rs405509), there were no differences in genotype frequencies between all athletes (RU and RL) and non-athletes (27% TT genotype in players and non-athletes), nor between RU forwards and backs. CONCLUSION: The MAPT (rs10445337) TT genotype is 6% less common in elite rugby athletes than non-athletes. Therefore, carrying at least one rs10445337 C allele appears to increase the probability of sustained career success in the high-risk concussion environment of elite rugby, perhaps via a greater ability to recover from concussions.Peer reviewe

Association of MMP3 but not TIMP2 gene variants with elite rugby player status and rugby code

Introduction: Achilles tendon pathology and anterior cruciate ligament rupture are multifactorial conditions for which genetic risk factors have been identified. Single nucleotide polymorphisms (SNPs) within the MMP3 (rs591058, rs679620, rs650108) and TIMP2 (rs4789932) genes have previously been associated with tendon and ligament pathologies. Although not entirely clear, prior literature indicates the risk alleles for Achilles tendon pathology as T (rs591058), G (rs679620) and A (rs650108) for MMP3. However, prior evidence regarding TIMP2 is equivocal. MMP3 is considered an essential regulator of matrix degradation and remodelling within diseased and normal musculoskeletal soft tissues. TIMP2 maintains homeostasis in the extracellular matrix in part by inhibiting MMP function. Given the high incidence and severity of tendon and ligament injuries in elite rugby athletes, we hypothesised that the aforementioned SNPs would be associated with career success. Methods: Participants from the RugbyGene project were elite Caucasian male rugby athletes (n = 566; mean (standard deviation) height 1.85 (0.07) m, mass 101 (14) kg, age 29 (7) yr), including 420 rugby union (RU) athletes that for some analyses were divided into forwards and backs and 120 rugby league (RL) athletes. Non-athletes were 589 Caucasian men and women (n = 589, 57% male, height 1.72 (0.10) m, mass 74 (14) kg, age 31 (7) yr). PCR of genomic DNA was used to determine genotypes using TaqMan probes, then groups were compared using Χ2 and odds ratio (OR) statistics. Results: As hypothesized, the MMP3 rs591058 risk genotype (TT) was less frequent in rugby athletes (28%) compared to non-athletes (33%) (Χ2 = 7.265, P = 0.026; OR = 1.18, 95% confidence intervals (CI) = 0.86-1.63). No differences were found for MMP3 rs679620, rs650108 or TIMP2 rs4789932 between rugby athletes and non-athletes. When RL athletes were compared to non-athletes, the risk genotype (TT) of MMP3 rs591058 was underrepresented in RL athletes (19%) compared to non-athletes (33%). The MMP3 rs679620 ‘protective’ allele (C) was more frequent in RL athletes (55%) compared to non-athletes (48%) (OR = 1.3, 95% CI = 0.98-1.74). However, for MMP3 rs650108 the ‘risk’ allele (A) was overrepresented in RL athletes (32%) compared to non-athletes (26%). There were no genotype differences for any gene variant between RU athletes and non-athletes. The ‘risk’ allele (T) of the MMP3 rs679629 polymorphism and the ‘protective’ allele (G) of the MMP3 rs650108 polymorphism were less common in RL (45%, 68%, respectively) than RU athletes (54%, 76%, respectively). Conclusion: We provide evidence for elite rugby athletes possessing a protective genetic profile regarding tendon and ligament injury risk. Notably, a less frequent rs591058 TT genotype in athletes suggests a lower risk of injury could therefore enhance career success in rugby. Furthermore, RL players appear to have differing genetic characteristics compared to their RU counterparts, which might reflect some differences in physiological demands between codes.Peer reviewedFinal Published versio

An Investigation into Genetic Associations with Musculoskeletal Soft Tissue Injuries in Elite Rugby – Preliminary Findings

Peer reviewe

Bone Mineral Density and Associated Genetic Variants in High-level Caucasian Marathon Runners

INTRODUCTION:Endurance runners (except those who may have low energy availability) tend to have higher total and/or loading site-specific bone mineral density (BMD) in comparison with non-athletes, most likely due to the larger volume of exercise completed. A large genetic component also contributes to BMD, although little is known about which specific genes are involved, whether particular genotypes are sensitive to mechanical loading and the impact of such an interaction on BMD. This study investigated if high-level endurance runners possess enhanced BMD associated with an “advantageous” genetic predisposition, via a potential gene-physical activity interaction.METHODS:Age- and weight-adjusted total BMD (TBMD) and leg BMD (LBMD) measured via Dual-energy X-ray absorptiometry of 67 high-level Caucasian marathon runners (males < 2 h 45 min, n = 37; females < 3 15 min, n = 30) was compared with 40 male and 26 female non-athletes. LRP5 rs3736228, TNFRSF11B rs4355801, VDR rs2228570, WNT16 rs3801387 and AXIN1 rs9921222 variants were then investigated singularly, and collectively, as a total genotype score (TGS) via multivariate analysis of variance in a subgroup of this cohort (male runners n = 19, controls n = 26; female runners n = 17, controls n = 14). RESULTS:Male runners had higher TBMD (1.34 vs 1.28 g/cm2; P=0.02) and LBMD (1.53 vs 1.42 g/cm2; P=<0.01) than non-athletes. Female runners had higher LBMD than non-athletes (1.30 vs 1.22 g/cm2; P=0.02) but not TBMD (1.23 vs 1.18 g/cm2; P=0.22). An interaction (P=0.047) was observed between VDR rs2228570 genotype and group regarding LBMD in males: ff genotype runners had 0.02 g/cm2 higher LBMD than FF or Ff runners, but the FF genotype had the highest LBMD (1.45 g/cm2) amongst non-athletes. LBMD was also 0.12 g/cm2 higher in ff runners compared to ff non-athletes, whereas FF and Ff runners had 0.09 g/cm2 higher LBMD compared to their genotype-matched controls. No other interactions or variants, individually or collectively as part of a TGS, were associated with BMD (P≥0.11). CONCLUSION:High-level female runners possess higher LBMD but not TBMD in comparison with non-athletes whereas male runners possess both higher TBMD and LBMD than non-athletes. Consistent with prior literature, we observed higher BMD in VDR rs2228570 FF genotype in non-athletes, which may be due to increased biological activity associated with the F variant. However, our preliminary data suggest that the ff genotype may be associated with enhanced LBMD in male runners via a gene-environment interaction.Peer reviewedFinal Published versio

The Impact of Depression, Anxiety and Personality Disorders on the Outcome of Patients with Functional Limb Weakness – Individual Patient Data Meta-Analysis

Objective: Psychiatric comorbidities such as depression, anxiety, and personality disorders are common in patients with functional limb weakness/paresis (FND-par). The impact of these conditions on the prognosis of FND-par has not been systematically reviewed. The aim of this study was to identify a potential prognostic effect of comorbid depression, anxiety, and/or personality disorder on prognosis in patients with FND-par. Methods: A systematic review was performed to identify studies that reported measures of baseline depression, anxiety, and/or personality disorder, and physical disability. An individual patient data meta-analysis was subsequently performed. Results: Eight studies comprising 348 individuals were included (7 prospective cohorts; 1 case-control study). There was heterogeneity in sample size, follow-up duration, and treatment modality. Depression and anxiety were present in 51.4% and 53.0% of FND-par patients, respectively. In individuals whose FND-par improved, there was no significant difference between those with versus without depression (52.6% vs 47.4%, p = 0.69) or those with versus without anxiety (50.3% vs 49.7%, p = 0.38). Meta-analysis showed no clear impact of baseline depression or anxiety per se [pooled OR for depression 0.85 (95%CI 0.50–1.45; p = 0.40) and anxiety 0.84 (95%CI 0.51–1.38; p = 0.91)]; and of depression or anxiety severity [pooled OR for depression 1.23 (95%CI 0.63–2.39; p = 0.91) and anxiety 1.40 (95%CI 0.70–2.78; p = 0.58)] on FND-par outcome. Insufficient data were available to assess the impact of personality disorders. Conclusion: We found no evidence that depression or anxiety influenced outcome in FND-par. Large-scale, prospective studies in FND-par, and other FND subtypes, are needed to fully contextualize the impact of concurrent mental health concerns on outcomes.</p

Bose-Einstein Condensation of Light in a Semiconductor Quantum Well Microcavity

When particles with integer spin accumulate at low temperature and high density they undergo Bose-Einstein condensation (BEC). Atoms, solid-state excitons and excitons coupled to light all exhibit BEC, which results in high coherence due to massive occupation of the respective system's ground state. Surprisingly, photons were shown to exhibit BEC much more recently in organic dye-filled optical microcavities, which, owing to the photon's low mass, occurs at room temperature. Here we demonstrate that photons within an inorganic semiconductor microcavity also thermalise and undergo BEC. Although semiconductor lasers are understood to operate out of thermal equilibrium, we identify a region of good thermalisation in our system where we can clearly distinguish laser action from BEC. Based on well-developed technology, semiconductor microcavities are a robust system for exploring the physics and applications of quantum statistical photon condensates. Notably, photon BEC is an alternative to exciton-based BECs, which dissociate under high excitation and often require cryogenic operating conditions. In practical terms, photon BECs offer their critical behaviour at lower thresholds than lasers. Our study shows two further advantages of photon BEC in semiconductor materials: the lack of dark electronic states allows these BECs to be sustained continuously; and semiconductor quantum wells offer strong photon-photon scattering. We measure an unoptimised interaction parameter, $\tilde{g}=0.0023\pm0.0003$, which is large enough to access the rich physics of interactions within BECs, such as superfluid light or vortex formation.Comment: 15 pages, 4 figure

Purcell-Enhanced Single Photons at Telecom Wavelengths from a Quantum Dot in a Photonic Crystal Cavity

Quantum dots are promising candidates for telecom single photon sources due to their tunable emission across the different low-loss telecommunications bands, making them compatible with existing fiber networks. Their suitability for integration into photonic structures allows for enhanced brightness through the Purcell effect, supporting efficient quantum communication technologies. Our work focuses on InAs/InP QDs created via droplet epitaxy MOVPE to operate within the telecoms C-band. We observe a short radiative lifetime of 340 ps, arising from a Purcell factor of 5, owing to interaction of the QD within a low-mode-volume photonic crystal cavity. Through in-situ control of the sample temperature, we show both temperature tuning of the QD's emission wavelength and a preserved single photon emission purity at temperatures up to 25K. These findings suggest the viability of QD-based, cryogen-free, C-band single photon sources, supporting applicability in quantum communication technologies

Tendon and ligament-associated gene variants and history of soft tissue injury in elite male rugby athletes

There is a genetic component to tendon and ligament injuries which is highly likely to be polygenic in nature (1). Elite rugby has one of the highest reported injury incidences of any professional sport with some of the most severe injuries affecting tendons and ligaments (1). Thus, this study investigated if suspected tendon and ligament injury-associated polygenic profiles of elite rugby athletes (RA) with a history of prior tendon and ligament injury differed from RA with no history of injury. We hypothesised that tendon and ligament injury-associated genotypes and polygenic profiles would be overrepresented in RA with a history of soft tissue injury compared to RA with no history of injury. Participants were from the RugbyGene project, comprising elite male RA (185 white males; mean (standard deviation) height 1.86 (0.07) m, mass 102 (12.6) kg, age 26.4 (5.1) yr) competing at an elite level in rugby union (n = 165) and league (n = 20) in the UK, Ireland, Italy and South Africa. Soft-tissue injury history was collected using a self-reported injury history questionnaire. PCR of genomic DNA was used to determine genotypes using TaqMan probes, and total genotype scores (TGS) from 13 polymorphisms were calculated, then groups were compared using χ2 and odds ratio (OR) statistics. In addition, multifactor dimensionality reduction (MDR) and inferred haplotype analysis were used to identify genetic interactions. For MMP3 rs679620, the C allele was more common in the tendinopathy group (TD) compared to the non-injured tendon group (NIT) (63.5% vs 50.0%, P = 0.02, OR = 1.62, 95% CI = 01.00-2.60). However, the C allele was more common in the non-injured ligament group (NIL) compared to the ligament rupture (LR) group (63.7% v 47.9%, P = 0.02, OR = 1.91, 95% CI = 1.09-3.35). For COL5A1 rs12722 the TT genotype was more common in NIT compared to the tendon rupture group (TR) (25.0% vs. 3.8%, P = 0.006, OR 4.35, 95% CI = 0.49-37.01). TGS differed between NIL and the ligament sprain group (LS) (U=1868.50;P = 0.02). Receiver operating characteristic curve (ROC) and area under the curve (AUC) analysis confirmed the TGS algorithm could identify LS (AUC = 0.61; 95% CI = 0.52-0.72; P = 0.02) . The T-C inferred haplotype frequency of COL5A1 rs12722 and COL5A1 rs3196378 respectively, was higher in TR, LS and the all-injured athlete groups compared to NIT, NIL and the all-non-injured group (P < 0.01) (Fig. 3). MDR could not identify a model to predict any of the injury groups with a sufficiently powerful cross-validation statistic. The current data suggests musculoskeletal soft-tissue injury could be influenced by an athlete’s genetic predisposition. This study provides further insight into the detailed aetiology of musculoskeletal soft tissue injuries within elite rugby and may, in future, be worthy of consideration for managing the interindividual variability of injury risk in rugbyPeer reviewe

Tendon and Ligament Injuries in Elite Rugby: The Potential Genetic Influence

This article reviews tendon and ligament injury incidence and severity within elite rugby union and rugby league. Furthermore, it discusses the biological makeup of tendons and ligaments and how genetic variation may influence this and predisposition to injury. Elite rugby has one of the highest reported injury incidences of any professional sport. This is likely due to a combination of well-established injury surveillance systems and the characteristics of the game, whereby high-impact body contact frequently occurs, in addition to the high intensity, multispeed and multidirectional nature of play. Some of the most severe of all these injuries are tendon and ligament/joint (non-bone), and therefore, potentially the most debilitating to a player and playing squad across a season or World Cup competition. The aetiology of these injuries is highly multi-factorial, with a growing body of evidence suggesting that some of the inter-individual variability in injury susceptibility may be due to genetic variation. However, little effort has been devoted to the study of genetic injury traits within rugby athletes. Due to a growing understanding of the molecular characteristics underpinning the aetiology of injury, investigating genetic variation within elite rugby is a viable and worthy proposition. Therefore, we propose several single nucleotide polymorphisms within candidate genes of interest; COL1A1, COL3A1, COL5A1, MIR608, MMP3, TIMP2, VEGFA, NID1 and COLGALT1 warrant further study within elite rugby and other invasion sports