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Functional polymorphisms within the inflammatory pathway regulate expression of extracellular matrix components in a genetic risk dependent model for anterior cruciate ligament injuries
Univ Med Ctr Rotterdam, Dept Orthopaed Surg, Erasmus MC, Rotterdam, Netherlands.
Univ Aquila, Dept Biotechnol & Appl Clin Sci, Laquila, Italy.
Univ Cape Town, Fac Hlth Sci, Dept Human Biol, Div Exercise Sci & Sports Med, Cape Town, South Africa.
Univ Cape Town, Fac Hlth Sci, Dept Human Biol, Div Exercise Sci & Sports Med, Cape Town, South Africa.
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2019 (English)In: Journal of Science and Medicine in Sport, ISSN 1440-2440, E-ISSN 1878-1861, Vol. 22, no 11, p. 1219-1225Article in journal (Refereed) Published
Abstract [en]

Objectives: To investigate the functional effect of genetic polymorphisms of the inflammatory pathway on structural extracellular matrix components (ECM) and the susceptibility to an anterior cruciate ligament (ACL) injury. Design: Laboratory study, case-control study. Methods: Eight healthy participants were genotyped for interleukin (IL)1B rs16944 C> Tand IL6 rs1800795 G >C and classified into genetic risk profile groups. Differences in type I collagen (COL1A1), type V collagen (COL5A1), biglycan (BGN) and decorin (DCN) gene expression were measured in fibroblasts either unstimulated or following IL-1 beta, IL-6 or tumor necrosis factor (TNF)-alpha treatment. Moreover, a genetic association study was conducted in: (i) a Swedish cohort comprised of 116 asymptomatic controls (CON) and 79 ACL ruptures and (ii) a South African cohort of 100 CONs and 98 ACLs. Participants were genotyped for COL5A1 rs12722 C >T, IL1B rs16944 C >T, IL6 rs1800795 G> C and IL6R rs2228145 G >C. Results: IL1B high-risk fibroblasts had decreased BGN (p = 0.020) and COL5A1 (p = 0.012) levels after IL-1 beta stimulation and expressed less COL5A1 (p = 0.042) following TNF-alpha treatment. Similarly, unstimulated IL6 high-risk fibroblasts had lower COL5A1 (p = 0.012) levels than IL6 low-risk fibroblasts. In the genetic association study, the COL5A1-IL1B-IL6 T-C-G (p = 0.034, Haplo-score 2.1) and the COL5A1-IL1B-1L6R T-C-A (p = 0.044, Haplo-score: 2.0) combinations were associated with an increased susceptibility to ACL injury in the Swedish cohort when only male participants were evaluated. Conclusions: This study shows that polymorphisms within genes of the inflammatory pathway modulate the expression of structural and fibril-associated ECM components in a genetic risk depended manner, contributing to an increased susceptibility to ACL injuries. (C) 2019 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2019. Vol. 22, no 11, p. 1219-1225
Keywords [en]
Anterior cruciate ligament injury, Extracellular matrix, Genetics, Polymorphisms, Personalized medicine
National Category
Sport and Fitness Sciences
Identifiers
URN: urn:nbn:se:uu:diva-399088DOI: 10.1016/j.jsams.2019.07.012ISI: 000491303200006PubMedID: 31395468OAI: oai:DiVA.org:uu-399088DiVA, id: diva2:1379162
Funder
Swedish Research Council, K2011-69X-21877-01-6Swedish Research Council, K2014-99X-21876-04-4Västerbotten County Council, ALF VLL548501Västerbotten County Council, VLL-358901;7002795Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2019-12-16Bibliographically approved

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