The interaction of polymorphisms in extracellular matrix genes and underlying miRNA motifs that modulate susceptibility to anterior cruciate ligament rupture.

OBJECTIVES: Variants within genes that encode proteins regulating fibrillogenesis such as BGN (rs1126499 C>T, rs1042103 C>T), COL5A1 (rs12722 C>T) and DCN (rs516115 C>T) have been associated with susceptibility to anterior cruciate ligament (ACL) ruptures. A miRNA mediated transcript instability was proposed for the COL5A1 association. The study aims were: (i) to investigate the association of inferred allele combinations across the COL5A1 3'-UTR, BGN and DCN genes with susceptibility to ACL rupture; and (ii) to use an in silico approach to identify miRNA binding sites common to these risk associated allele combinations.

DESIGN: Case-control association study METHODS: Allele combinations were generated from the genotype data of the BGN (rs1126499, rs1042103), COL5A1 (rs12722) and DCN (rs516115) loci for 227 participants with surgically diagnosed ACL ruptures and 234 asymptomatic controls. Statistical analyses between the CON and ACL groups as well as sex-specific interactions were investigated. Significance was accepted at p<0.05. miRNA binding sites within these genes were identified using DIANA tools.

RESULTS: Several sex-specific inferred allele combinations were associated with altered susceptibility and miRNA (miR-22, miR-27b, miR-140, miR-199a, miR-199b, miR-299, miR-338 and miR-484) recognition motifs were identified in range of these susceptibility loci.

CONCLUSIONS: In conclusion, this study has implicated inferred allele combinations across BGN (rs1126499, rs1042103), COL5A1 (rs12722) and DCN (rs516115) as well as eight miRNA recognition sequences in susceptibility to ACL rupture. The biological significance of these genomic signatures needs to be explored to understand their effect on the ligaments functional capacity.