Author(s): SEPTEMBER, A., DLAMINI, S.B., SAUNDERS, C.J., CIESZCZYK, P., FICEK, K., HÄGER, C.K., STATTIN, E., NILSSON, K.G., EYNON, N., FELLER, J., TIROSH, O., BOPE, C.D., CHIMUSA, E.R., COLLINS, M., Institution: UNIVERSITY OF CAPE TOWN, Country: SOUTH AFRICA, Abstract-ID: 1894

INTRODUCTION:
Independently, genetic loci within genes ITGB2 (beta 2 subunit of integrin), COL5A1 (alpha 1 chain of type V collagen) and VEGFA1 (vascular endothelial growth factor A) have been associated with rupture susceptibility of the anterior cruciate ligament (ACL-R). These genes have diverse functions including cell-cell communication, maintaining structural integrity and regulating new blood vessel formation which are all integral to ligament tissue integrity. The aim of the study was to identify key genetic loci which collectively maybe relevant to maintaining extracellular matrix tissue integrity of the ligament.
METHODS:
A genetic association was conducted for a combined cohort recruited from Australia, Poland, Sweden, and South Africa. Participants analysed in this study included uninjured controls CON=584; participants with ACL ruptures ACL-R=731 and a sub-group with non-contact mechanism of ACL ruptures NON=425. Participants were genotyped for ITGB2 (rs2230528 C/T); COL5A1 (rs12722 C/T) and VEGFA (rs699947 C/A, rs2010963 G/C) polymorphisms. Statistical analyses were conducted using the programming environment R. Inferred allele combinations were constructed as a proxy for potential gene-gene interactions using genotype data. Statistical significance was accepted when p < 0.05, and the false discovery rate (FDR) procedure was used to adjust for multiple comparisons.
RESULTS:
Significant distributions were noted for combinations between ITGB2 (rs2230528 C/T); COL5A1 (rs12722 C/T) and VEGFA (rs699947 C/A, rs2010963 G/C). The C-C-A-G combination was overrepresented in the CON (19%) compared to the ACL-R (ACL-14: 5%, p=1.x10-4; OR:0.93; 95% CI: 0.61-1.41) group and ACL-NON (ACL-NON: 14%, p=0.002; OR:0.96; 95% CI: 0.61-1.51) subgroup. The C-T-C-C combination was overrepresented in the CON (13%) compared to the ACL-R (ACL-R:10 %, p=0.023; OR:0.76; 95% CI: 0.46-1.26) group and ACL-NON (ACL-NON: 10%, p=0.003; OR:1.11; 95% CI: 0.63-1.79) subgroup. Similar findings were found when males and females were analysed separately.
CONCLUSION:
The novel associations highlight key genetic loci which in combination are associated with ACL ruptures susceptibility in a large cohort. In addition, the diversity of the gene functions in this risk model highlight the collective contribution towards maintaining tissue integrity.