Protocol

In this study, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used for reporting (Moher et al., 2009). This systematic review was registered in the PROSPERO database and the registration number is CRD42022368810.

Eligibility Criteria

Studies were considered for inclusion in the systematic review if they satisfied the following criteria: a case-control, cohort, cross-section and randomized controlled experiment that investigated genetic influences on the ACL injury in humans. Studies with previous systematic reviews, animal studies, book chapters, letters, editorials, conference abstracts, and review articles were disregarded. Furthermore, studies not written in English, without full-text were eliminated. Also studies with fewer than ten participants were not taken into consideration.

Search Strategy

The electronic databases PubMed Central, Web of Science, Cochran Library, Embase and Scopus were searched from the 1^st of January, 2017 to the 18^th of September, 2022 without language restriction, however, only articles in English were taken into consideration. The following search strategy was applied: ('anterior cruciate ligament injury'/exp OR 'anterior cruciate ligament injur*':ti,ab,kw OR 'acl injur*':ti,ab,kw OR 'anterior cruciate ligament tear*':ti,ab,kw OR 'acl tear*':ti,ab,kw OR 'anterior cruciate ligament rupture*':ti,ab,kw OR 'acl rupture*':ti,ab,kw) AND ('heredity'/exp OR 'genetic determinism':ti,ab,kw OR 'genetic effect':ti,ab,kw OR 'genetic factor':ti,ab,kw OR 'genetic phenomena':ti,ab,kw OR 'genetic processes':ti,ab,kw) AND (2018:py OR 20 1 9:py OR 2020:py OR 2021:py OR 2022:py).

Selection Process

Using the aforementioned search strategy, results were searched by the first author, and all of the results were imported into a reference manager (Endnote Vision X9.3.3) to remove duplicates. Two authors independently reviewed the results. Titles and abstracts were used as the initial criteria for selecting suitable studies. If an abstract did not provide sufficient information, full-texts were examined. In the event of discrepancies between two authors, the final decision was made by a third reviewer.

Data Management

Study Selection

From all databases, a total of 392 studies were retrieved. Two authors independently assessed the titles and abstracts of 291 papers after 101 duplicates were eliminated. Next, 242 and then 25 records were excluded after reading the title/abstract and the full text, respectively. Finally, 24 full text studies that met the criteria for inclusion were examined (Figure 1).

Figure 1

PRISMA flowchart showing the study-selection process.

Study Characteristics

This systematic review included twenty-four papers published between 2017 and 2022 in English, with summary features presented in Table 1. The total number of participants in the case and control groups was 5377 and 4343, respectively, and they could be classified into Asians, Caucasians, and colored people. Twenty-one case-control studies, two cross-sectional studies, and one cohort study were included. In the Feldmann et al.'s (2022) study, three cohorts were considered: Sweden, Poland, and Australia, while in the Suijkerbuijk et al.'s (2019) study, two cohorts were examined: Sweden and South Africa (European Caucasian ancestry). Additionally, within the studies included in the analysis, there are several independent studies conducted in South Africa (n = 9), Poland (n = 7), China (n = 1), Thailand (n = 1), India (n = 1), Brazil (n = 1), Norway (n = 1), and Sweden (n = 1). In total, thirty-one genes and sixty-two genetic variations have been reported.

Risk of Bias

The NOS was utilized to assess the study's quality, and the rating greater than six indicated exceptional quality. Three papers received eight points, eleven articles received seven points, seven studies received 6 points, and only three studies were rated as of low quality (Table 2).

Influence of Genetic Factors on the ACLR

Ten studies investigated seven different collagens and ten single nucleotide polymorphisms (SNPs) with regard to the ACLR. Some studies showed the same results with no significant difference in the association of the COL1A1 rs1800012 (Gibbon et al., 2020; Manish Shukla et al., 2020; Perini et al., 2022; Sivertsen et al., 2019; Zhao et al., 2020) and rs1107946 (Gibbon et al., 2020; Perini et al., 2022) variant with the risk of ACL ruptures (p > 0.05). However, when individuals of European ancestry (Swedish, South African, Polish, Norwegian and Finnish; all those participants self-identified as being of white European ancestry) were combined, the rs1800012 TT genotype (TT vs. GT + GG) was significantly over-represented in the control group compared to the ACLR group (p = 0.040; OR = 2.8), which confirmed a strong link between rs1800012 and the ACL risk (Gibbon et al., 2020). The A allele of rs1800012 in the COL1A1 gene was more prevalent in the Norwegian than in the Finnish cohort (minor allele frequency: 0.18 vs. 0.14; p < 0.03) (Sivertsen et al., 2019). Perini et al. (2022) observed that the COL1A1 SNP (rs1107946, GG or TT) was a protective association with ACLR (OR = 0.25) when the three COL1A2 SNPs (rs412777, rs42524, and rs2621215) were all wildtype.

Perini et al. (2022) reported that COL1A2 rs42524 (OR = 5.73 [1.22–26.95], and rs2621215 (4.29 [1.26–14.61) SNPs contributed significantly to the ACL risk between 146 ACLR patients and 192 healthy subjects. Sivertsen et al. (2019) showed a failed association of the COL3A1rs1800255 polymorphism and ACL injury in both Norwegian and Finnish female athletes. No COL27A1 variants were significantly associated with the risk of ACLR in South African people (European Caucasian ancestry) (Gibbon et al., 2018). Thus, there are currently insufficient evidence to support such an approach.

No significant differences were found in the genotype frequencies for the COL5A1 rs12722 polymorphism (Lulinska-Kuklik et al., 2018; Sivertsen et al., 2019; Suijkerbuijk et al., 2019; Willard et al., 2018; Zhao et al., 2020) and rs3922912, rs4841926, and rs3124299 within COL5A1 (Laguette et al., 2020). However, the frequency distributions of allele combinations may pose a risk of the ACL injury. Willard et al. (2018) showed that when all participants or only female participants were analyzed, the COL5A1 (rs12722) and DCN (rs516115) allele combination associated with an increased risk of the ACL injury (p = 0.006). COL5A1-IL1B-IL6 allele T-C-G combination was significantly underrepresented (p = 0.034) in the Swedish male cohort control group (Suijkerbuijk et al., 2019). Contradictory evidence was revealed for COL5A1 rs13946 polymorphisms (Lulinska-Kuklik et al., 2018; Sivertsen et al., 2019; Zhao et al., 2020).

COL12A1 rs970547 and rs240736 may present a high risk of the ACLR in the Chinese male population (Zhao et al., 2020), but not in the European population (Sivertsen et al., 2019). The AA genotypes of COL12A1 rs970547 were at the level of 49.3% and 27.5% in the patient and control groups, respectively (p = 0.026), and rs240736 of COL12A1 played a significant role in the ACL injury in Chinese men (Zhao et al., 2020). Sivertsen et al. (2019) examined 851 female Norwegian and Finnish elite athletes and found no significant differences between the ACL injury and control groups for COL12A1 rs970547 genotypes. This suggests that COL12A1 rs970547 may increase the risk of the ACL injury in males only.

The evidence was insufficient to support the influence of MMP genes on the non-contact ACL rupture risk. Lulińska et al. (2020) found no significant differences between case and control groups for the polymorphism of MMP10 (C/T rs486055), MMP12 (T/C rs2276109), and MMP1 (-/G rs1799750). Similar results were reported for rs 679620 (A/G), rs591058 (T/C) and rs650108 (G/A) in a study by Gibbon et al. (2017). In the same cohort (Lulińska-Kuklik et al., 2019d; Rahim et al., 2019), the MMP3 rs679620 G and rs591058 C alleles were significantly over-represented in cases compared to controls (OR = 1.38 [1.05–1.81], p = 0.021), however, no association was found for MMP8 (rs11225395C/T), and TIMP2 (rs4789932 G/A) regarding the ACL injury.

Four studies (Lulinska-Kuklik et al., 2019c; Maculewicz et al., 2019; Rahim et al., 2017, 2022; Suijkerbuijk et al., 2019) indicated the lack of significant differences in the genotype and allele frequencies for IL6R rs2228145, IL6 rs1800795, IL1B rs16944 and rs1143627 when all participants (female and male) from the control and the ACL injury group were analyzed. Only the female cohort had a significantly different genotype frequency distribution for IL1B rs16944 when compared with participants in non-contact subgroups (p = 0.039, OR = 3.06) (Rahim et al., 2017).

Conflicting evidence was found for polymorpsims rs2010963, rs699947 of VEGFA gene in different studies. Lulińska-Kuklik et al. (2019b), Rahim et al. (2022) and Feldmann et al. (2022) found a potential correlation between the VEGFA rs2010963 (G/C) polymorphism and the ACLR risk. However, for the associations between rs699947 and the ACLR, different results were observed (Cięszczyk et al., 2017; Feldmann et al., 2022; Lulińska-Kuklik et al., 2019b; Rahim et al., 2018, 2022; Shukla et al., 2020). There were no significant differences in the genotype or allele frequency distributions for the rs1570360 of VEGFA (Feldmann et al., 2022; Lulińska-Kuklik et al., 2019b; Rahim et al., 2018, 2022). Shukla et al. (2020) observed that the ID and II genotypes, as well as the I allele (rs35569394), were associated with a 1.64-fold increased risk of the ACL rupture compared to the control group. Rahim et al. (2022) and Feldmann et al. (2022) investigated polymorphisms of the KDR gene rs2071559 A/G and rs1870377 A/T. However, their findings did not indicate that those two SNPs had an independent relationship with the ACL injury.

Two studies analyzed the relationship between the TNC gene and the ACL risk. Lulińska-Kuklik et al. (2019a) found that the genotype and allele frequencies of TNC variants (rs1330363 C/T, rs2104772 T/A, rs13321 G/C) did not differ between cases and controls. However, another study (Gibbon et al., 2018) showed that when females were examined separately, the TNC rs2104772 (A/T) variant's AA genotype was significantly associated with the ACL rupture (p = 0.035, OR = 2.3).

When gender was considered, conflicting results were found for the BGN rs1042103 and rs1126499 (Cięszczyk et al., 2017; Willard et al., 2018). Cięszczyk et al. (2017) observed a significant difference in the ACAN rs1516797 genotype frequencies between the control and ACLR groups (p = 0.041) in Polish participants. When female and male participants were analyzed together, no significant differences in the genotype and allele distributions were noted for the DCN rs516115. In the male ACLR group, the A allele of rs1042103 (OR = 1.5) was found to be significantly over-represented, however, there were no reported significant genotype differences for the ACAN rs1516797.

Two studies investigated the effects of transforming the growth factor and tumor necrosis factor Adipokine and cytokine on ACL injury. Rahim et al. (2017) did not find any significant difference between the ACL injury and healthy groups for TGFB2 (rs7550232), TNF (rs1799964, rs1800629) and TNFRSF1B (rs1061622) when all participants (males and females) were analyzed. The TGFB rs7550232 SNP appeared to influence male weight and female height, which can provide further information to describe the genetic risk to ACL injury. Laguette et al. (2020) observed a significant difference in the frequency distribution of the rs1805113 G>A genotype (p = 0.033) between the two groups. The GG genotype was more prevalent in the control group than in the ACL group (p = 0.010, OR = 0.48). However, there were no significant differences in the genotype or allele frequency for TGFBR3 rs1805117 T > C between all groups and after sex stratification.

The limited evidence was found for the lack of association between CASP8 (rs3834129 ins/Del, rs1045485, rs13113) (Rahim et al., 2017; Seale et al., 2020), B-fibrinogenrs (rs1800789, rs1800791) (Zhao et al., 2020), PTGER4 (rs4495224) (Rahim et al., 2017) and TIMP2 (rs4789932 ) (Lulinska-Kuklik et al., 2019d; Rahim et al., 2019) variants and ACL injury. In addition, there was insufficient evidence to link Adiponectin rs1501299 (OR = 1.91) and B-fibrinogenrs (1800787, rs1800788, rs1800790, rs2227389) (Zhao et al., 2020) to the ACL injury.