A novel combination of genomic loci in ITGB2, COL5A1 and VEGFA associated with anterior cruciate ligament rupture susceptibility: insights from Australian, Polish, Swedish, and South African cohorts

Abstract

Integrin complexes facilitate cell communication, playing a role in ligament homeostasis. <i>ITGB2</i> rs2230528 (C/T) was implicated in anterior cruciate ligament rupture (ACL) risk in a South African cohort. Identifying biologically significant DNA signatures in the predisposition to ACL rupture risk remains important towards understanding mechanisms of ACL ruptures. <i>ITGB2</i> is essential for the activation of important biological pathways regulated by structural components such as collagens and biomechanical components such as vasculo-endothelial growth factors. This study tested the association of (i) <i>ITGB2</i> rs2230528 and (ii) allele-allele combinations of <i>ITGB2's</i> network partners (<i>COL5A1</i> rs12722 C/T, <i>VEGFA</i> rs699947 C/A and <i>VEGFA</i> rs2010963 G/C) with ACL rupture risk. The genetic study was conducted in a combined cohort [n=1279: uninjured controls (CON), n=548; ACL ruptures (ACL), n=731; subgroup with non-contact mechanism of ACL ruptures (NON, n=425)] recruited from Australia, Poland, Sweden and South Africa. The combined cohort, rs2230528 TT (best fit model) was significantly over-represented in the ACL (p=8.00 × 10^-8; OR:3.21; 95% CI:2.10-4.89, AIC=1549) and NON (p=1.59 × 10^-6; OR:3.11; 95% CI:1.97-4.91, AIC=1191) groups compared to CON. <i>ITGB2</i> rs2230528-COL5A1 rs12722-<i>VEGFA</i> rs699947-<i>VEGFA</i> rs2010963, the C-C-A-G and C-T-C-G combinations were significantly associated with reduced ACL risk. This study provided additional evidence highlighting <i>ITGB2</i> as potentially being associated with ACL ruptures even though the gene-gene combinations had a small effect size. Integrins containing the b2 subunit together with its key extracellular matrix components (type V collagen and VEGFA) are potential therapeutic targets for ACL ruptures and potentially other connective tissue-related conditions.