62 Etiopathogenesis of Cruciate Ligament Rupture
for the transcription factor Sp1, in relation to
ACL injury (Khoschnauet al.2008; Posthumus
et al.2009). Although the TT genotype was rare,
both studies concluded that the homozygous
TT genotype seemed to have a protective effect
on the development of ACL rupture. It is pro-
posed that the increased binding of the Sp1
transcription factor increases the expression of
the alpha 1 chain, but it is unknown how this
protects against ACL injury. In another study,
female participants with an ACL injury were
2.4-fold more likely to have the AA homozy-
gous genotype for the SNP (rs970547, S3058G)
in exon 65 ofCollagen Type 12 alpha 1(COL12A1)
(Posthumuset al. 2010). This finding was con-
firmed in a separate cohort (O’Connellet al.
2015). This study also reported an interaction
between the COL5A1 rs12722 and COL12A1
rs970547, such that individuals with the T+A–
pseudo-haplotype were at greater risk of expe-
riencing ACL rupture (O’Connellet al. 2015).
Another candidate gene study identified an
association between matrix metalloproteinase
genes and ACL rupture, particularlyMMP12
rs2276109, where the AA genotype is sig-
nificantly more prevalent among individuals
with confirmed non-contact cruciate rupture
(Posthumuset al. 2012). Angiogenesis signal-
ing may also play a role in ACL rupture risk,
as theVEGFArs699947 CC genotype is also
significantly over-represented among individu-
als with non-contact ACL rupture (Rahimet al.
2014). Proteoglycans have also been identified
as a potential factor influencing the risk of ACL
rupture in human beings. Proteoglycans play
important roles in fibrillogenesis and ECM col-
lagen. A candidate gene study identified loci in
ACAN(aggrecan) andDCN(decorin) that were
associated with ACL injury susceptibility (Man-
nionet al. 2014). A separate study evaluated
gene expression in biopsies taken from rup-
tured ACL ligament, and noted that the expres-
sion ofACANwas significantly upregulated in
female compared to male patients. This sug-
gests that aggrecan may be playing a role in the
observed sex-related differences regarding sus-
ceptibility to ACL rupture (Johnsonet al. 2015).
Summary and future recommendations
The combined results of these studies sug-
gest that canine CR is a moderately heritable
(Nielenet al. 2001; Wilkeet al. 2006; Baker
et al. 2017), highly polygenic complex trait dis-
ease. Biological networks that control collagen
genes (Wilkeet al. 2005; Bairdet al. 2014b),
neurologic pathways (Bairdet al. 2014a), innate
immune mechanisms (Bakeret al. 2017), and
aggrecan signaling (Wilkeet al. 2009; Wilke
2010; Bakeret al. 2017) may all play a role in
CR pathogenesis and warrant further investiga-
tion. The overlap between the results of canine,
equine, and human discovery research impli-
cating aggrecan in susceptibility to ACLrupture
makesACANa particularly interesting target
for further genetic investigation. Given the com-
plex nature of this condition, further investiga-
tion of mutations with larger effects will likely
require a combination of high-powered GWAS
with large sample sizes and next-generation
sequencing.
A genetic test for CR is possible and should
remain a goal of current research efforts. Geno-
typing dogs at individual loci is not likely to
be predictive, as individual genetic mutations
most likely contribute small amounts to pheno-
typic variance. A predictive test for CR is more
likely to resemble genomic prediction methods
commonly employed in animal and dairy sci-
ence (Vazquezet al. 2012). These approaches
consider the additive effect of all non-null-effect
SNPs, which may be used to develop a genetic
risk assessment tool.
The comparative value of the canine model
for complex trait disease has received much
attention during recent years (Karlsson &
Lindblad-Toh 2008; Shearin & Ostrander 2010;
Haywardet al. 2016; van Steenbeeket al. 2016).
There are many similarities between canine CR
and human ACL rupture. It is very likely that
advances made in understanding how genetic
variants may affect biological pathways that
influence disease risk in the dog will lead to
similar advancements in the understanding and
treatment of ACL rupture in human beings.References
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