DOES THE A9285G POLYMORPHISM IN COLLAGEN
TYPE XII α1 GENE ASSOCIATE WITH THE RISK OF
ANTERIOR CRUCIATE LIGAMENT RUPTURES?
Ficek K, Stepien-Slodkowska M, Kaczmarczyk M, Maciejewska-Karlowska A, Sawczuk M,
Cholewinski J, Leonska-Duniec A, Zarebska A, Cieszczyk P, Zmijewski P,
*Corresponding Author: Piotr Zmijewski, Ph.D., Institute of Sport, Department of Physiology, Trylogii 2/16, 01-982
Warsaw, Poland. Tel.: +48-228340812. Fax: +480228350977. E-mail: piotr.zmijewski@insp.waw.pl
page: 41
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DISCUSSION
The role of genetics in sport research increases
with every passing year [20,21]. Knowledge of the
role of individual genes in the processes occurring
in the human body can also be used in sport rehabilitation
and injury prevention [22]. Precise determination
of genotypes at risk for acute or chronic
diseases related to sport will probably enable adjustments
in individual training plans to greatly
minimize the risk of injury.
Approximately two-thirds of ACL tissue consists
of water. The rest is made up of tightly packed
parallel collagen fibril bundles consisting predominately
of type I collagen fibrils (60.0-80.0% dry
mass of ligament) [11].
Collagen XII belongs to the subfamily of fibrilassociated
collagens with interrupted triple helices
(FACIT) [23,24] that are believed to form interfibrillar
connections and mediate fibril interaction
with other extracellular and cell surface molecules
within tendons and other tissues [24,25]. On the basis
of this fact, we suspect that collagen XII may
be considered an influential component in ligament
and tendon strength and flexibility.
This assumption seems to be indirectly confirmed
by the fact that the key elements of tendons’
stretch-responsiveness have been identified in regulatory
regions of the COL12A1 gene. Additionally,
earlier studies indicated that collagen XII significantly
promotes the contraction of collagen gels (such as
tenascin C) and consequently modulates the cellular
response of tissue to mechanical stress [26-28]. Furthermore,
September et al. [8] suggested collagen
XII may be involved in similar biological processes
as both tenascin C and type V collagen, i.e., regulation
of the assembly of fibrils (fibrillogenesis). The A9285G COL12A1 polymorphism within
exon 65, is a non synonymous coding variant, which
changes the amino acid at position 3058 from a serine
to a glycine. Although the wild type serine amino
acid is a neutral polar amino acid with a larger
side chain than the substituted non polar neutral glycine
amino acid, some investigators speculate that
this change in amino acid sequence may alter the
biomechanical properties of the collagen fibril [29].
On the other hand, it is not proven that this SNP has
any effect on protein expression or function.
The first report concerning the possible importance
of COL12A1variants for achilles tendon
injuries did not identify a statistically significant
difference in the genotype or allele distribution in
the A9285G COL12A1 polymorphism [29]. On the
other hand, the same investigators showed that the
A9285G COL12A1 polymorphism is associated with
ACL ruptures in females [29]. The obtained results
suggested that females with an AA genotype are at
increased risk for ACL ruptures (AA vs. GT+GG;
OR = 2.4; 95% CI 1.0-5.5; p <0.05). Additionally,
September et al. [13] observed a trend for the AA
genotype to be overrepresented (AA vs. GA+GG;
p = 0.08) in female participants with a family history
of ligament injury. The ambiguity of the results
obtained by September et al. [13] and Posthumus
et al. [29] and a lack of other studies concerning
the role A9285G COL12A1 in ACL injures may be
considered as one of the most important reasons to
conduct repeated investigations in order to identify
the genetic background of individuals predisposed
to tendon and ligament injury.
Our results were contrary to the hypothesis that
the A9285G COL12A1 polymorphism is associated
with ACL injuries. We did not find any statistical
difference in the A9285G genotype and allele frequencies
in male football players with surgically
confirmed primary ACL ruptures compared to injury-
free athletes. To summarize, considering we only
investigated male subjects, we reached a similar
conclusion as September et al. [13].
In our investigation, the ACL injury group
closely resembled the control group of injury-free
athletes in numerous aspects, being of similar ages
and ethnicities and identical athletic disciplines. The
last of these is a key component due to the variability
of inciting events among different disciplines.
Participants from the control group in our study had
the similar internal and external risk factors relating
to the examined phenotype, overcoming a known
limitation of case-control studies.
We investigated male football players with surgically
confirmed primary ACL rupture, who were
qualified for an ACL reconstruction procedure. The
control group comprised of only males of the same
ethnicity, similar in age, participating in the same
sport, their knee joints being exposed to comparable
forces and movements, controlling the many internal
and external risk factors. Thanks to this solution
in our investigations cases and controls are similar
in variables that may be related to the phenotype
that is under examination, as well as the inciting
events is very difficult, a known limitation of casecontrol
studies.
The homogeneity of the investigated groups
seems to be a strength of this study, however, this
fact may be considered as a limitation, because we
did not manage to confirm or deny the important
role of the investigated polymorphism with regard
to the risk of ACL injury in women. We included
only male participants, but it should be noted that
women are 2-3 times more likely to sustain an ACL
injury than men [18]. A number of intrinsic risk
factors classified as anatomical, hormonal, or neuromuscular,
have been linked to this observed phenomenon.
In the case of female patients, each of the
aforementioned factors may be more likely to affect
the gene environmental interaction, causing significantly
higher incidence of this polymorphism’s association
with ACL injuries [30,31], a relationship
that is not seen as clearly in men.
In conclusion, this study found that there is no
association between the A9285G COL12A1 polymorphism
and ACL ruptures in men. On the other
hand, the lack of statistical significance in genotype
and allele distribution of A9285G COL12A1 shown
in our investigation, does not necessarily mean that
the investigated polymorphism has no effect on ACL
injuries. Tendon and ligament injuries are complex,
multifactorial conditions, caused by interactions of
a number of different proteins, encoded by different
genes on different chromosomes (gene-gene interactions),
and the interactions of these genetic components
with different environmental factors (geneenvironment
interactions) [13]. Thus, our findings
should be supported with more experimental studies
on COL12A1 polymorphisms including their interaction with other genes. Additionally, our results
need to be confirmed in a larger sample of subjects.
Lastly, it should be noted that genetic association
studies must always be interpreted with caution.
Declaration of Interest. The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of this article.
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