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The COL1A1 gene and acute soft tissue ruptures
  1. Malcolm Collins1,2,
  2. Michael Posthumus1,
  3. Martin P Schwellnus1
  1. 1South African Medical Research Council, Cape Town, South Africa
  2. 2UCT/MRC Research Unit for Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, Newlands, South Africa
  1. Correspondence to Professor M Collins, UCT/MRC Research Unit for Exercise Science and Sports Medicine, PO Box 115, Newlands 7725, South Africa; malcolm.collins{at}uct.ac.za

Abstract

Three studies have suggested that the rare TT genotype of the functional Sp1 binding site polymorphism within intron 1 of COL1A1 is associated with cruciate ligament ruptures (CL), shoulder dislocations (SD) and/or Achilles tendon ruptures. Similar genotype distributions were reported for the control and the injury groups in all three studies. In this report, the data from these studies were combined and analyzed. The TT genotype, when compared to the control group (4.1%, n=24 of 581), was significantly under-represented in the (1) CL (0.3%, n=1 of 350, OR=15.0, P=0.0002), (2) CL and SD (0.4% TT genotype, n=2 of 476, OR=10.2, P<0.0001), and (3) CL, SD and Achilles tendon ruptures (0.4% TT genotype, n=2 of 517, OR=11.1, P<0.0001) groups. This combined analysis indicates that the TT genotype appears to be protective against acute soft tissue ruptures and should be incorporated into multifactorial models determining risk of acute soft tissue ruptures.

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Acute injuries of soft tissues, including tendons and ligaments, are common in recreational and competitive athletes. Athletes with intrinsic risk factors for these acute injuries, which include a genetic component,1,,4 become injured after exposure to extrinsic factors and an inciting event.5

The main structural component of tendons and ligaments is type I collagen, which is a heterotrimer consisting of two α1 and one α2 chains.6 The α1 chain is encoded for by the COL1A1 gene, which contains a functional Sp1 binding site polymorphism (single nucleotide polymorphism rs1800012) within its first intron.7 This polymorphism, a G to T substitution, has recently been associated with cruciate ligament (CL) ruptures,2 shoulder dislocation (SD),2 anterior cruciate ligament (ACL) ruptures4 and Achilles tendon ruptures8 in two populations. In all these studies the rare TT genotype was shown to be underrepresented in subjects with acute soft tissue ruptures.2 4 8 Khoschnau et al2 only identified one subject each with a TT genotype from 233 (0.4%) and 126 (0.8%) subjects with CL ruptures and SD, respectively. Similarly, studies have reported that the rare TT genotype was absent in 117 subjects with ACL ruptures4 and 41 subjects with Achilles tendon ruptures.8 Two subjects (2.4%) with a TT genotype were identified in a cohort of 85 subjects with chronic Achilles tendinopathy.8

The genotype distribution of this polymorphism was similar within the asymptomatic 256 white South African (4.7% TT genotype)4 8 and 325 Swedish (3.7% TT genotype)2 control populations. The Swedish control population consisted of only female subjects,2 whereas only 36%8 and 25%4 of the South African studies consisted of female subjects. Moreover the genotype distribution within the South African and Swedish control populations were similar to the distributions reported in larger control cohorts consisting of 4175 and 4733 asymptomatic subjects, which reported a TT genotype frequency of 3.8% and 4.4%, respectively.7 9

By combining the similar results that were observed in the independent South African4 8 and Swedish2 studies, the association between acute soft tissue ruptures and a specific genotype could be strengthened. Stronger evidence that the COL1A1 TT genotype potentially protects an athlete from an acute soft tissue rupture would have significant clinical relevance in any injury risk model.

Therefore, the aim of this short communication was to report the combined effect, from the three published studies, of the rare TT genotype of the COL1A1 Sp1 binding site polymorphism on the risk of acute soft tissue ruptures. A Fisher's exact test was used to analyse any differences in the genotype frequencies (TT vs GT and GG) of the 581 combined control and injured groups in the three published studies. The injured groups were analysed as: (1) 350 CL2 4; (2) 476 CL and SD2 4 and (3) all 517 soft tissue ruptures (CL, SD and Achilles tendon).2 4 8

The rare TT genotype was significantly underrepresented in the CL group (0.3% TT genotype, n=1) when compared with the control group (4.1% TT genotype, n=24) of all three published studies (odds ratio (OR) 15.1, 95% CI 2.0 to 111.7, p<0.001). Similar results were obtained when the CL and SD group (0.4% TT genotype, n=2, OR 10.2, 95% CI 2.4 to 43.4, p<0.001) or the all soft tissue ruptures group (0.4% TT genotype, n=2, OR 11.1, 95% CI 2.6 to 47.2, p<0.001) were compared with the control group (figure 1).

Figure 1

The relative genotype frequencies of the functional Sp1 binding site polymorphism within intron 1 of the COL1A1 gene of the combined Swedish2 and South African4 8 studies for the (1) asymptomatic control (CON group); (2) cruciate ligament (CL) ruptures (CL group); (3) CL ruptures and shoulder dislocations (SD)(CL and SD group) and (4) soft tissue ruptures (CL, shoulder dislocations and Achilles tendon) (ALL group). The data from both white South African control populations were from unrelated individuals.

In summary, the combined results from three recently published studies, represented in this report, show that the TT genotype of the COL1A1 Sp1 binding site polymorphism is underrepresented in acute soft tissue ruptures, in particular of the CL. The biological mechanism/s to explain this finding is not known. Furthermore, these data should be interpreted with some caution due to the low frequency of the rare TT genotype.

In conclusion, this COL1A1 gene polymorphism is the first variant to be associated with an increased risk of acute soft tissue rupture when data from three independent studies were combined. The clinical relevance of this finding is that the COL1A1 TT genotype protects an athlete from an acute soft tissue rupture and should be included in future risk models for acute soft tissue ruptures.

References

Footnotes

  • Competing interests None.

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