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Functional polymorphisms within the inflammatory pathway regulate expression of extracellular matrix components in a
Mathijs A M Suijkerbuijk1, Marco Ponzetti2, Masouda Rahim3
1Department of Orthopaedic Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
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>T and 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-1β, IL-6 or tumor necrosis factor (TNF)-α 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-1β stimulation and expressed less COL5A1 (p=0.042) following TNF-α 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-IL6R 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.
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