Genetic variants within the COL5A1 gene are associated with ligament injuries in physically active populations from Australia, South Africa, and Japan

Abstract

Previous small-scale studies have shown an association between the COL5A1 gene and anterior cruciate ligament (ACL) injury risk. In this larger study, the genotype and allele frequency distributions of the COL5A1 rs12722 C/T and rs10628678 AGGG/deletion (AGGG/-) indel variants were compared between participants: (i) with ACL injury in independent and combined cohorts from South-Africa (SA) and Australia (AUS) vs controls (CON), and (ii) with any ligament (ALL) or only ACL injury in a Japanese (JPN) cohort vs CON. Samples were collected from SA (235 cases; 232 controls), AUS (362 cases; 80 controls) and JPN (500 cases; 1,403 controls). Genomic DNA was extracted and genotyped. Distributions were compared, and inferred haplotype analyses performed. No independent associations were noted for rs12722 or rs10628678 when the combined SA + AUS cohort was analysed. However, the C-deletion (rs12722-rs10628678) inferred haplotype was under-represented (p = 0.040, OR = 0.15, CI = 0.04-0.56), while the Tdeletion inferred haplotype was over-represented in the female SA + AUS ACL participants versus controls (p < 0.001, OR = 4.74, CI = 1.66-13.55). Additionally, the rs12722 C/C genotype was under-represented in JPN CON vs ACL (p = 0.039, OR = 0.52, 0.27-1.00), while the rs10628678 −/− genotype was associated with increased risk of any ligament injuries (p = 0.035, OR = 1.31, CI = 1.02-1.68) in the JPN cohort. Collectively, these results highlight that a region within the COL5A1 3'-UTR is associated with ligament injury risk. This must be evaluated in larger cohorts and its functional relevance to the structure and capacity of ligaments and joint biomechanics be explored. Highlights. The COL5A1 T-deletion inferred haplotype (rs12722-rs10628678) was associated with an increased risk of ACL rupture in the combined SA and AUS female participants. . The COL5A1 C-deletion inferred haplotype (rs12722-rs10628678) was associated with a decreased risk of ACL rupture in the combined SA and AUS female participants. . The COL5A1 rs12722 C/C and rs10628678 −/− genotypes were associated with increased risk of ACL rupture and of ligament injuries in JPN, respectively. . A region within the COL5A1 3'-UTR is associated with risk of ligament injury, including ACL rupture, and therefore the functional significance of this region on ligament capacity and joint biomechanics requires further exploration.

Association between Total Genotype Score and Muscle Injuries in Top-level Football Players: a pilot study

“…Regarding the COL5A1 polymorphism, the present study supports previous ndings that showed the protective effect of the C-allele against severe muscle injuries [6] and ligament rupture [30]. The COL5A1 rs12722-TT genotype has recently been linked to a greater estimated number of total muscle-related injuries per game than the CC and CT genotypes (p = 0.028), according to research on 44 professional Australian football players [31].…”

Are commercial genetic injury tests premature?

“… 25,29,57–60 Similarly, no associations were observed in all, as well as male and female, participants when all the published studies investigating European populations (South African, Australian, Swedish, Polish, Norwegian, and Finnish) were combined and analyzed (Table S4). 60 …”

“…Although initial reports suggested that the rs12722 CC genotype was associated with reduced risk of ACL injuries in females, 55,56 subsequent studies have not reported an independent association of rs12722 with ACL rupture (Table S4). 25,29,57–60 Similarly, no associations were observed in all, as well as male and female, participants when all the published studies investigating European populations (South African, Australian, Swedish, Polish, Norwegian, and Finnish) were combined and analyzed (Table S4). 60 …”

Tendon and Ligament Genetics: How Do They Contribute to Disease and Injury? A Narrative Review

“…As in AT research, variants within the 3’-UTR of the COL5A1 gene have been associated with ACL rupture susceptibility, specifically in females [ 152 , 153 , 154 ], and more recently with ligament injuries [ 155 ]. Laguette explored the intron 4-exon 5 region of COL5A1 , which was previously implicated with ligament injuries in a canine model but found no significant associations in a South African ACL cohort [ 156 ].…”