Investigating the role of ELN rs2071307 gene variant as a risk factor for Achilles Tendon Pathologies in a British Cohort

Injuries to the Achilles tendon (tendinopathies or ruptures) are considered as ones of the most severe musculoskeletal traumas in sports with an incidence rate of 50% in athletes and 10% in the general population. A number of gene variants coding for tendon structural proteins such as COL5A11 and FBN22 have previously been associated with Achilles tendon pathologies (ATP). These protein along with others maintain a harmonious interaction with elastin to allow tendons to respond to tensile load by stretching and returning to their original lengths. The ELN rs2071307 variant has been associated with soft tissue pathologies and is believed to be a good candidate gene as it results in the substitution of the hydrophobic amino acid glycine with the hydrophilic serine. However, in a previous study this variant was not associated with either Achilles tendinopathy or ACL rupture in populations from Australia and South Africa2. As recent evidence suggests that genetic risk factors for tendinopathy may depend, to some extent, on geographic location 3, the aim of this study was to determine whether the ELN rs2071307 variant was associated with the risk of ATP in a British cohort

Variants within the MMP3 gene are associated with achilles tendinopathy: possible interaction with the COL5A1 gene

Objectives: Sequence variation within the COL5A1 and TNC genes are known to associate with Achilles tendinopathy. The primary aim of this case-control genetic association study was to investigate whether variants within the matrix metalloproteinase 3 (MMP3) gene also contributed to both Achilles tendinopathy and Achilles tendon rupture in a Caucasian population. A secondary aim was to establish whether variants within the MMP3 gene interacted with the COL5A1 rs12722 variant to raise risk of these pathologies. Methods: 114 subjects with symptoms of Achilles tendon pathology and 98 healthy controls were genotyped for MMP3 variants rs679620, rs591058 and rs650108. Results: As single markers, significant associations were found between the GG genotype of rs679620 (OR = 2.5, 95% CI 1.2 to 4.90, p = 0.010), the CC genotype of rs591058 (OR = 2.3, 95% CI 1.1 to 4.50, p = 0.023) and the AA genotype of rs650108 (OR = 4.9, 95% CI 1.0 to 24.1, p = 0.043) and risk of Achilles tendinopathy. The ATG haplotype (rs679620, rs591058, and rs650108) was under-represented in the tendinopathy group when compared to the control group (41% vs 53%, p = 0.038). Finally, the G allele of rs679620 and the T allele of COL5A1 rs12722 significantly interacted to raise risk of AT (p = 0.006). No associations were found between any of the MMP3 markers and Achilles tendon rupture. Conclusion: Variants within the MMP3 gene are associated with Achilles tendinopathy. Furthermore, the MMP3 gene variant rs679620 and the COL5A1 marker rs12722 interact to modify the risk of tendinopathy. These data further support a genetic contribution to a common sports related injur

Sarcopenia as a Risk Factor for Alzheimer’s Disease: Genetic and Epigenetic Perspectives

Sarcopenia, defined as the age-associated loss of muscle mass and increased fragility with age, is increasing worldwide. The condition often precedes the development of Alzheimer’s disease, thereby decreasing the levels of mobility and physical activity in those affected. Indeed, the loss of muscle mass has, in some studies, been associated with an increased risk of Alzheimer’s disease and other dementias. However, a detailed understanding of the interplay between both conditions is not available and needs to be thoroughly addressed. In the following review, we focus on several genes, specifically APOE, BDNF, ACE, FTO, and FNDC5, that have been associated with both conditions. We also discuss the epigenetic regulation of each of these genes along with non-coding RNAs (ncRNAs) that may have a role in the development of both the sarcopenic and Alzheimer’s disease phenotypes. Finally, we assert that the application of systems biology will unravel the relationship between sarcopenia and Alzheimer’s disease and believe that the prevention of muscle loss in older age will reduce the incidence of debilitating cognitive decline

TIMP2 and GDF-5 gene variants and achilles tendon pathology: replication study in a British case-control population

Introduction: Achilles tendon pathology (ATP) encompasses a range of tendon overuse injuries that can be sub-classified into separate pathologies [Weinfeld, 2014]. To date, a number of single nucleotide polymorphisms (SNPs) have been associated with ATP [Raleigh and Collins, 2012] but, with the exception of the COL5A1 rs12722 variant, limited work has been published on attempting to replicate these findings in cohorts other than those recruited from either South Africa or Australia. We selected variants within the TIMP2 (rs4789932) and GDF-5 (rs143383) genes, that have previously been shown to associate with ATP [El Khoury et al, 2013 and Posthumus et al, 2010], and attempted to replicate previous associations in a newly recruited British-based, case-control, Caucasian cohort. Methods: We recruited 133 ATP Caucasian patients from the County Clinic in Northampton along with 131 physically active controls from various sports clubs within the East Midlands region. DNA samples were collected from saliva (DNA genotek Ltd) and Taqman technology, using allele specific probes and primers, was used to genotype all DNA samples. Reactions were run on a StepOne Plus real-time PCR instrument (ABI). Genotypes were called according to post run cluster profiles and data were analysed using Chi-squared (c2) analysis or Fisher’s exact test. Significance was accepted at p < 0.05. All procedures were approved by the University of Northampton Research Ethics Committee. Results: For the TIMP2 rs4789932 variant we found no association between genotype and case or control status in the entire cohort (p = 0.279). However, in sex specific analysis we did find that the CC genotype was associated (p = 0.043) with male ATP cases compared to controls (Table 1). For the GDF-5 rs143383 variant, we found no association between genotype and case or control status in the entire cohort (p = 0.538) or in either male (p = 0.319) or female (p = 0.737) specific analysis (data not shown). Genotypes did not associate with any other potential confounding variables. Conclusions: The TIMP2 rs478992 CC genotype was associated with male cases of ATP. Although this locus was previously associated with ATP in cohorts recruited from the Southern Hemisphere it was the CT genotype that was the risk factor and the association was not sex specific [El Khoury et al, 2013]. This result might be related to differences in unknown environmental exposures between the cohorts investigated that may modify the effect of the genotype. We found no evidence of an association between ATP and the GDF-5 variant. These data should be viewed as preliminary findings and will need to be repeated in a larger cohort

MMP3 and TIMP2 gene variants as predisposing factors for Achilles tendon pathologies: attempted replication study in a British case–control cohort

Variants within the MMP3 (rs679620) and TIMP2 (rs4789932) genes have been associated with the risk of Achilles tendon pathology (ATP) in populations from South Africa and Australia. This study aimed to determine whether these variants were associated with the risk of ATP in British Caucasians. We recruited 118 cases with ATP, including a subset of 25 individuals with Achilles tendon rupture (RUP) and 131 controls. DNA samples were isolated from saliva and genotyped using qPCR. For the TIMP2 rs4789932 variant we found a significant (p = 0.038) difference in the genotype distribution frequency between males with ATP (CC, 39.4%; CT, 43.7%; TT, 16.9%) compared to male controls (CC, 20.7%; CT, 59.8%; TT, 19.5%). We also observed a difference in the TIMP2 rs4789932 genotype distribution between males with rupture compared to male controls (p = 0.038). The MMP3 rs679620 GG genotype was found to be overrepresented in the Achilles tendon rupture (RUP) group (AA, 24.0%; AG, 32.0%; GG, 44.0%) compared to controls (AA, 26.7%; AG, 54.2%; GG, 19.1%). In conclusion, the CT genotype of the TIMP2 rs4789932 variant was associated with lower risk of ATP in males. Furthermore, while we revealed differences for both variants in genotype distribution between the RUP and control groups, the sample size of the RUP group was small and confirmation would be required in additional cohorts. Finally, although both the TIMP2 rs4789932 and MMP3 rs679620 variants tentatively associated with ATP, there were differences in the direction of association compared to earlier work