# 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

## TL;DR

This study finds a genetic combination linked to a higher risk of ACL ruptures, suggesting potential targets for treatment.

## Contribution

A novel combination of genomic loci in ITGB2, COL5A1, and VEGFA is associated with ACL rupture risk.

## Key findings

- The ITGB2 rs2230528 TT genotype is significantly over-represented in ACL rupture cases.
- Specific allele combinations of ITGB2, COL5A1, and VEGFA are associated with reduced ACL risk.
- Integrins with the b2 subunit and related components are potential therapeutic targets for ACL ruptures.

## Abstract

Integrin complexes facilitate cell communication, playing a role in ligament homeostasis. ITGB2 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. ITGB2 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) ITGB2 rs2230528 and (ii) allele-allele combinations of ITGB2’s network partners (COL5A1 rs12722 C/T, VEGFA rs699947 C/A and VEGFA 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. ITGB2 rs2230528-COL5A1 rs12722-VEGFA rs699947-VEGFA 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 ITGB2 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.