Investigation of the Sp1-binding site polymorphism within the COL1A1 gene in participants with Achilles tendon injuries and controls

Summary

Sequence variants within the type V collagen (COL5A1) and tenascin C (TNC) genes have to date been shown to be associated with chronic Achilles tendinopathies and/or spontaneous Achilles tendon ruptures. Type V collagen and tenascin C are quantitatively minor components of tendon, while type I collagen is the major structural component. There is increased expression of the COL1A1 gene, which encodes for the α1 chain of type I collagen, in the painful Achilles tendon. A functional Sp1-binding site polymorphism (SNP rs1800012; IVS1 + 1023G > T) within this gene has been shown to be associated with several connective tissue disorders. The aim of this study was to determine whether the Sp1-binding site polymorphism within the COL1A1 gene is associated with chronic Achilles tendinopathies and/or spontaneous Achilles tendon ruptures. Achilles tendinopathy (n = 85), Achilles rupture (n = 41) and asymptomatic control (n = 125) participants were genotyped for the COL1A1 Sp1-binding site polymorphism. There were no observed statistical differences in the genotype (p = 0.602) or allele (p = 0.694) distributions between the groups. In conclusion, this study has shown that there is no association between the Sp1-binding site polymorphism within the first intron of COL1A1 and Achilles tendinopathy or Achilles tendon rupture within the population studied.

Introduction

Overuse injuries of the Achilles tendon are common in both competitive and recreational sports.¹ These injuries include acute onset (spontaneous ruptures) and repetitive strain overuse injuries (chronic tendinopathies).² Although the exact mechanisms responsible for these injuries are not yet fully understood, several intrinsic and extrinsic risk factors have been suggested to be associated with Achilles tendon injuries.³ Mokone et al.4, 5 have recently identified polymorphisms within two genes located on the tip of the long arm (q) of chromosome 9 to be associated with chronic tendinopathies and/or spontaneous ruptures of the Achilles tendon in a physically active Caucasian population. One is a BstUI restriction fragment length polymorphism (RFLP) within the 3′-untranslated region of COL5A1 and the other a GT dinucleotide repeat polymorphism within intron 17 of TNC. COL5A1 encodes for a polypeptide component of type V collagen, while the TNC gene encodes for the glycoprotein tenascin C. Type V collagen and Tenascin C are both quantitatively minor components of tendons. Type V collagen intercalates into the core of the heterotypic tendon fibres through a process known as fibrillogenesis.⁶ Tenascin C is able to bind to various cell surface receptors and other components of the extracellular matrix and has been implicated in the regulation of cell–matrix interactions.⁷

Although tendons consist of different types of collagens and non-collagenous proteins, type I collagen constitutes up to 95% of the total collagen content of tendons and 65–80% of its dry mass.⁸ Type I collagen is a heterotrimer consisting of two α1 chains and one α2 chain, which are encoded for by the COL1A1 (17q21.33) and COL1A2 (7q22.1) genes, respectively.9, 10 Type I collagen molecules, together with small amounts of types III and V collagen, assemble into fibrils which in turn are arranged in hierarchical structures consisting of fibrils, fibres and fascicles to produce the mature tendon.¹¹ The expression of the COL1A1 gene was observed to increase significantly in painful Achilles tendons.12, 13

Some studies have shown that the functional Sp1-binding site polymorphism within intron 1 of the COL1A1 gene is associated with various complex disorders including osteoporotic fractures,¹⁴ osteoarthritis,¹⁵ myocardial infarction,¹⁶ lumbar disc disease¹⁷ and stress urinary incontinence.¹⁸ It was proposed that the G > T substitution within the intronic Sp1-binding site increases the affinity for the transcription factor Sp1, resulting in increased COL1A1 gene expression and the production of a weaker type I collagen homotrimer consisting of three α1(I) chains.14, 19

The aim of this study was therefore to determine whether the functional Sp1-binding site polymorphism within intron 1 of the COL1A1 gene is associated with chronic Achilles tendinopathies and/or spontaneous Achilles tendon ruptures.