ELN and FBN2 Gene Variants as Risk Factors for Two Sports-related Musculoskeletal Injuries

Abstract

The proteins ELN and FBN2 are important in extracellular matrix function. The ELN rs2071307 and FBN2 rs331079 gene variants have been associated with soft tissue pathologies. We aimed to determine whether these variants were predisposing factors for both Achilles tendinopathy (AT) and anterior cruciate ligament (ACL) ruptures. For the AT study, 135 cases (TEN group) and 239 asymptomatic controls were recruited. For the ACL rupture study our cohort consisted of 141 cases (ACL group) and 219 controls. Samples were genotyped for both the ELN rs2071307 and FBN2 rs331079 variants using TaqMan assays. Analysis of variance and chi-squared tests were used to determine whether either variant was associated with AT or ACL rupture with significance set at p<0.05. The GG genotype of the FBN2 variant was significantly over-represented within the TEN group (p=0.035; OR=1.83; 95% CI 1.04–3.25) compared to the CON group. We also found that the frequency of the G allele was significantly different between the TEN (p=0.017; OR=1.90; 95% CI 1.11–3.27) and ACL groups (p=0.047; OR=1.76; 95% CI 1.00–3.10) compared to controls. The ELN rs207137 variant was not associated with either AT or ACL rupture. In conclusion, DNA sequence variation within the FBN2 gene is associated with both AT and ACL rupture.

Key words

gene - achilles tendinopathy - tendon rupture - ligament rupture - injury prevention

• References

• 1 Berget S, Moore C, Sharp P. Spliced Segments at 5′ Terminus of Adenovirus 2 Late Messenger-RNA. Proc Natl Acad Sci USA 1977; 74: 3171-3175
• 2 Charbonneau NL, Ono RN, Corson GM, Keene DR, Sakai LY. Fine tuning of growth factor signals depends on fibrillin microfibril networks. Birth Defects Res C Embryo Today 2004; 72: 37-50
• 3 Collins M, Raleigh SM. Genetic Risk Factors for Musculoskeletal Soft Tissue Injuries. Med Sport Sci 2009; 54: 136-149
• 4 Cook C, McDonagh M. Measurement of muscle and tendon stiffness in man. Eur J Appl Physiol 1996; 72: 380-382
• 5 El Khoury L, Posthumus M, Collins M, Handley CJ, Cook J, Raleigh SM. Polymorphic variation within the ADAMTS2, ADAMTS14, ADAMTS5, ADAM12 and TIMP2 genes and the risk of Achilles tendon pathology: A genetic association study. J Sci Med Sport 2013; 16: 493-498
• 6 Ellis SG, Dushman-Ellis S, Luke MM, Murugesan G, Kottke-Marchant K, Ellis GM, Griffin B, Tuzcu EM, Hazen S. Pilot Candidate Gene Analysis of Patients ≥60 Years Old With Aortic Stenosis Involving a Tricuspid Aortic Valve. Am J Cardiol 2012; 110: 88-92
• 7 Gianotti SM, Marshall SW, Hume PA, Bunt L. Incidence of anterior cruciate ligament injury and other knee ligament injuries: A national population-based study. J Sci Med Sport 2009; 12: 622-627
• 8 Gosline J, Lillie M, Carrington E, Guerette P, Ortlepp C, Savage K. Elastic proteins: biological roles and mechanical properties. Philos Trans R Soc Lond B Biol Sci 2002; 357: 121-132
• 9 Gupta PA, Putnam EA, Carmical SG, Kaitila I, Steinmann B, Child A, Danesino C, Metcalfe K, Berry SA, Chen E, Delorme CV, Thong M, Adès LC, Milewicz DM. Ten novel FBN2 mutations in congenital contractural arachnodactyly: Delineation of the molecular pathogenesis and clinical phenotype. Hum Mutat 2002; 19: 39-48
• 10 Harriss D, Atkinson G. Ethical Standards in Sport and Exercise Science Research: 2014 Update·. Int J Sports Med 2013; 34: 1025-1028
• 11 Harriss D, Atkinson G. Update-ethical standards in sport and exercise science research. Int J Sports Med 2011; 32: 819-821
• 12 Jarvinen TAH, Kannus P, Maffulli N, Khan KM. Achilles tendon disorders: etiology and epidemiology. Foot Ankle Clin 2005; 10: 255-266
• 13 Jelinsky SA, Li L, Ellis D, Archambault J, Li St J, Andre M, Morris C, Seeherman H. Treatment with rhBMP12 or rhBMP13 increase the rate and the quality of rat Achilles tendon repair. J Orthop Res 2011; 29: 1604-1612
• 14 Lahiri D, Nurnberger J. A Rapid Nonenzymatic Method for the Preparation of HMW DNA from Blood for RFLP Studies. Nucleic Acids Res 1991; 19: 5444
• 15 Ljungqvist A, Schwellnus MP, Bachl N, Collins M, Cook J, Khan KM, Maffulli N, Pitsiladis Y, Riley G, Golspink G, Venter D, Derman EW, Engebretsen L, Volpi P. International Olympic Committee . Consensus Statement: Molecular Basis of Connective Tissue and Muscle Injuries in Sport. Clin Sports Med 2008; 27: 231-239
• 16 Mokone GG, Schwellnus MP, Noakes TD, Collins M. The COL5A1 gene and Achilles tendon pathology. Scand J Med Sci Sports 2006; 16: 19-26
• 17 Mokone GG, Gajjar M, September AV, Schwellnus MP, Greenberg J, Noakes TD, Collins M. The Guanine-Thymine Dinucleotide Repeat Polymorphism Within the Tenascin-C Gene Is Associated With Achilles Tendon Injuries. Am J Sports Med 2005; 33: 1016-1021
• 18 Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 2003; 31: 3812-3814
• 19 Parkkari J, Pasanen K, Mattila VM, Kannus P, Rimpelä A. The risk for a cruciate ligament injury of the knee in adolescents and young adults: a population-based cohort study of 46 500 people with a 9 year follow-up. Br J Sport Med 2008; 42: 422-426
• 20 Perneger TV. What’s wrong with Bonferroni adjustments. BMJ 1998; 316: 1236
• 21 Posthumus M, Collins M, van der Merwe L, O’Cuinneagain D, van der Merwe W, Ribbans WJ, Schwellnus MP, Raleigh SM. Matrix metalloproteinase genes on chromosome 11q22 and the risk of anterior cruciate ligament (ACL) rupture. Scand J Med Sci Sports 2011; 321
• 22 Posthumus M, September AV, Keegan M, Cuinneagain D, Van der Merwe W, Schwellnus MP, Collins M. Genetic risk factors for anterior cruciate ligament ruptures: COL1A1 gene variant. Br J Sport Med 2009; 43: 352-356
• 23 Posthumus M, Collins M, Cook J, Handley CJ, Ribbans WJ, Smith RKW, Schwellnus MP, Raleigh SM. Components of the transforming growth factor-β family and the pathogenesis of human Achilles tendon pathology – a genetic association study. Rheumatology 2010; 49: 2090-2097
• 24 Posthumus M, September AV, O’Cuinneagain D, van der Merwe W, Schwellnus MP, Collins M. The association between the COL12A1 gene and anterior cruciate ligament ruptures. Br J Sport Med 2009; 44: 1160-1165
• 25 Posthumus M, September AV, O’Cuinneagain D, van der Merwe W, Schwellnus MP, Collins M. The COL5A1 Gene Is Associated With Increased Risk of Anterior Cruciate Ligament Ruptures in Female Participants. Am J Sport Med 2009; 37: 2234-2240
• 26 Pruna R, Ribas J, Montoro JB, Artells R. The impact of single nucleotide polymorphisms on patterns of non-contact musculoskeletal soft tissue injuries in a football player population according to ethnicity. Med Clin (Barc). 2013 Dec13. pii: S0025-7753(13)00735-5
• 27 Puddu G, Ippolito E, Postacchini F. A classification of Achilles tendon disease. Am J Sport Med 1976; 4: 145-150
• 28 Radermecker MA, Limet R, Lapiere CM, Nusgens B. Increased mRNA expression of decorin in the prolapsing posterior leaflet of the mitral valve. Interact CardioVasc Thorac Surg 2003; 2: 389-394
• 29 Raleigh SM, Posthumus M, O’Cuinneagain D, van der Merwe W, Collins M. The GDF5 Gene and Anterior Cruciate Ligament Rupture. Int J Sports Med 2013; 34: 364-367
• 30 Raleigh SM, van der Merwe L, Ribbans WJ, Smith RKW, Schwellnus MP, Collins M. Variants within the MMP3 gene are associated with Achilles tendinopathy: possible interaction with the COL5A1 gene. Br J Sports Med 2009; 43: 514-520
• 31 Robinson PN, Godfrey M. The molecular genetics of Marfan syndrome and related microfibrillopathies. J Med Genet 2000; 37: 9-25
• 32 Rosenbloom J, Abrams WR, Mecham R. Extracellular matrix 4: the elastic fiber. FASEB J 1993; 7: 1208-1218
• 33 Ruigrok YM, Rinkel GJE, van’t Slot R, Wolfs M, Tang S, Wijmenga C. Evidence in favor of the contribution of genes involved in the maintenance of the extracellular matrix of the arterial wall to the development of intracranial aneurysms. Hum Mol Genet 2006; 15: 3361-3368
• 34 Saracini C, Bolli P, Sticchi E, Pratesi G, Pulli R, Sofi F, Pratesi C, Gensini GF, Abbate R, Giusti B. Polymorphisms of genes involved in extracellular matrix remodeling and abdominal aortic aneurysm. J Vasc Surg 2012; 55: 171.e2-179.e2
• 35 September AV, Cook J, Handley CJ, van der Merwe L, Schwellnus MP, Collins M. Variants within the COL5A1 gene are associated with Achilles tendinopathy in two populations. Br J Sports Med 2009; 43: 357-365
• 36 Zhang H, Hu W, Ramirez F. Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J Cell Biol 1995; 129: 1165-1176