The apoptosis pathway and the genetic predisposition to Achilles tendinopathy

Abstract

Achilles tendinopathy (AT) is a degenerative condition for which several risk factors have been implicated including components of the inflammatory pathway. The aim was to assess functional variants within genes encoding components of the apoptosis signaling cascade and the effectiveness of a polygenic apoptosis profile to capture tendinopathy (TEN) risk. A total of 358 unaffected control (CON) participants [159 South Africa (SA CON) and 199 Australia (AUS CON)] and 166 affected AT (TEN) participants (87 SA TEN and 79 AUS TEN) were genotyped for four variants [CASP8 (rs384129), CASP8 (rs1045485), NOS3 (rs1799983), and NOS2 (rs2779249)]. Logistic regression was used to derive risk models for AT. A receiver operator characteristic (ROC) curve was plotted to determine the effectiveness of a model to capture AT risk. This study indicates the independent association of CASP8_rs1045485 and CASP8_rs3834129 as well as their haplotype with AT risk and the identification of an optimal model which included genetic loci CASP8_rs384129 and CASP8_rs1045485 together with sex to capture AT risk in both SA and AUS. Collectively, these results further implicate the apoptosis signaling cascade as one of the biological pathways involved in the development of AT. ß

Polymorphisms within the COL5A1 3′‐UTR That Alters mRNA Structure and the MIR608 Gene are Associated with Achilles Tendinopathy

“…Polymorphisms within several other genes such as TNC (Mokone et al, 2005), MMP3 , GDF5 (Posthumus et al, 2010) and CASP8 (Nell et al, 2012) have therefore also been shown to independently associate with chronic Achilles tendinopathy.…”

The Achilles Tendinopathy: Pathogenesis Review

“…The results of the increased levels of VEGF in tendons are mainly two: on the one hand the alteration of the tendon matrix which leads to a weakening of the tendon structure; on the other hand the following nervous ingrowth that causes pain symptoms. It was recently shown that human tendon increase in proliferation (as well as gene expression and type I collagen production) in a stretching magnitude-dependent manner [112] ; overload, on the opposite, can decrease proliferation and collagen production in human tendon fibroblasts, changing the extracellular matrix composition and even resulting in tenocytes apoptosis (programmed cell death) [113][114][115] . Since tenocytes are required to maintain homeostasis of the extracellular matrix (ECM) by regulating the balance between its synthesis and degradation [116] , tenocyte apoptosis may compromise the ability of the tendon to regulate repair processes.…”

Variation within three apoptosis associated genes as potential risk factors for Achilles tendinopathy in a British based case–control cohort

“…In contrast, the functional effect of altered CN at 255 the CASP8 locus we investigated is presently unknown. Secondly, the association of this 256 region of the CASP8 gene with ATP might be a population specific effect, as association with 257 the CASP8 rs1045485 SNP was reported in South African and Australian cohorts 10 and our 258 data were obtained from British Caucasians. With this in mind, we would envisage further 259 studies on this British cohort using the SNPs investigated by Nell et al (2012) to establish 260 whether they specifically associate with ATP.…”

“…Previous work in this area has been limited to variants within the CASP8 (rs384129, 70 rs1045485), NOS2 (rs2779249) and NOS3 (rs1799983) genes in two cohorts from the 71 Southern Hemisphere (South Africa and Australia) 10 .…”

“…Additionally, this was the first 285 study to investigate whether genomic CNV (in this case within the CASP8 locus) was a 286 possible predisposing factor for ATP. To date, studies on the genetics of ATP have been 287 conducted predominantly in South African and Australian cohorts 10,[29][30][31] Our study was the 288 first to investigate the effect of these variants in British-based individuals. 289…”