Anterior cruciate ligament (ACL) rupture is a very common and severe knee injury that predominantly occurs while participating in sports. It incurs high costs and has disastrous clinical consequences. Studies in recent years have suggested that genetic predisposition is an important factor in its etiology. |
This is the first systematic review with a best-evidence synthesis regarding associations between genetic variants and ACL rupture. We found some potential genetic variants that require further investigation, especially since we identified large heterogeneity in the broad genetic variants studied and outcome definitions. |
More research with large samples, phenotype homogeneity, and less bias is needed for a better understanding of the etiology of ACL rupture. This would allow us to take appropriate measures to screen for and prevent this injury and its clinical consequences. |
1 Introduction
2 Methods and Materials
2.1 Protocol
2.2 Eligibility Criteria
2.3 Information Sources and Search
2.4 Study Selection
2.5 Data-Collection Process
2.6 Risk-of-Bias Assessment
# | Criterion | Question |
---|---|---|
1 | Case | Are the cases defined clearly and adequately? |
2 | Control | Are the controls defined clearly and adequately? |
3 | Selection bias | Is selection bias excluded sufficiently? |
4 | Defined exposure | Is the exposure defined clearly, and is the method used to assess this exposure appropriate? |
5 | Determination | Was blinding to exposure status maintained before determination of disease? |
6 | Confounding | Are the main confounders identified and taken into account adequately for the design and analysis? |
2.7 Summary Measures
2.8 Synthesis of Results
3 Results
3.1 Study Selection
3.2 Study Characteristics
Study | Design | Patients with ACL rupture (n) | Controls (n) | Gene | Product | Variant |
---|---|---|---|---|---|---|
Ficek et al. [28] 2013 | Case–control | 91 | 143 |
COL1A1
| Collagen | rs1800012 |
rs1107946 | ||||||
Ficek et al. [29] 2014 | Case–control | 91 | 143 |
COL12A1
| Collagen | rs970547 |
Khoschnau et al. [30] 2008 | Case–control | 233 | 325 |
COL1A1
| Collagen | rs1800012 |
Khoury et al. [31] 2015 | Case–control | 141 | 219 |
ELN
| Elastin | rs2071307 |
FBN2
| Fibrillin | rs331079 | ||||
Malila et al. [32] 2011 | Case–control | 86 | 100 |
MMP3
| Matrix metalloproteinase | –1612 |
Mannion et al. [33] 2014 | Case–control | 227 | 234 |
ACAN
| Proteoglycans | rs2351491 |
rs1042631 | ||||||
rs1516797 | ||||||
BGN
| rs1126499 | |||||
rs1042103 | ||||||
DCN
| rs13312816 | |||||
rs516115 | ||||||
FMOD
| rs7543148 | |||||
rs10800912 | ||||||
LUM
| rs2268578 | |||||
O’Connell et al. [34]a 2015 | Case–control | 242b
| 235b
|
COL3A1
| Collagen | rs1800255 |
91c
| 91c
|
COL6A1
| rs35796750 | |||
Posthumus et al. [35] 2009 | Case–control | 117 | 130 |
COL1A1
| Collagen | rs1800012 |
Posthumus et al. [36] 2009 | Case–control | 129 | 216 |
COL5A1
| Collagen | rs13946 |
rs12722 | ||||||
Posthumus et al. [37] 2010 | Case–control | 129 | 216 |
COL12A1
| Collagen | rs240736 |
rs970547 | ||||||
Posthumus et al. [38] 2012 | Case–control | 129 | 216 |
MMP1
| Matrix metalloproteinase | rs1799750 |
MMP3
| rs679620 | |||||
MMP10
| rs486055 | |||||
MMP12
| rs2276109 | |||||
Rahim et al. [39] 2014 | Case–control | 227 | 227 |
VEGFA
| Angiogenesis-associated signaling cascade genes | rs699947 |
rs1570360 | ||||||
rs2010963 | ||||||
KDR
| rs1870377 | |||||
rs2071559 | ||||||
NGFB
| rs6678788 | |||||
HIF1A
| rs11549465 | |||||
Raleigh et al. [40] 2013 | Case–control | 126 | 216 |
GDF5
| Growth differentiation factor | rs143383 |
Stępień-Słodkowska et al. [41] 2013 | Case–control | 138 | 183 |
COL1A1
| Collagen | rs1800012 |
Stępień-Słodkowska et al. [42] 2015 | Case–control | 138 | 183 |
COL3A1
| Collagen | rs1800255 |
Stępień-Słodkowska et al. [43] 2015 | Case–control | 138 | 183 |
COL5A1
| Collagen | rs13946 |
rs12722 |
3.3 Risk of Bias
Study | Case (1) | Control (2) | Selection bias (3) | Defined exposure (4) | Determination exposure (5) | Confounding (6) | Overallb
|
---|---|---|---|---|---|---|---|
Ficek et al. [28] 2013 | + | + | ? | + | ? | + | ? |
Ficek et al. [29] 2014 | + | + | ? | + | ? | + | ? |
Khoschnau et al. [30] 2008 | + | ? | + | + | + | − | − |
Khoury et al. [31] 2015 | + | + | ? | + | ? | − | − |
Malila et al. [32] 2011 | + | + | ? | + | ? | − | − |
Mannion et al. [33] 2014 | + | + | ? | + | ? | − | − |
O’Connell et al. [34] 2015 | + | ? | ? | + | + | − | − |
Posthumus et al. [35] 2009 | + | + | ? | + | ? | − | − |
Posthumus et al. [36] 2009 | + | + | ? | + | ? | + | ? |
Posthumus et al. [37] 2010 | + | + | ? | + | ? | − | − |
Posthumus et al. [38] 2012 | + | + | ? | + | ? | + | ? |
Rahim et al. [39] 2014 | + | ? | ? | + | ? | - | − |
Raleigh et al. [40] 2013 | + | + | ? | + | ? | + | ? |
Stępień-Słodkowska et al. [41] 2013 | + | + | ? | + | ? | ? | ? |
Stępień-Słodkowska et al. [42] 2015 | + | + | ? | + | ? | ? | ? |
Stępień-Słodkowska et al. [43] 2015 | + | + | ? | + | ? | ? | ? |
3.4 Results of Association Studies in the Complete Populations
Study | Gene | Protein | Variant | Genetic analysis | OR (95% CI) |
p-Value | Risk of bias |
---|---|---|---|---|---|---|---|
Ficek et al. [28] 2013 |
COL1A1
| Collagen type I | rs1800012 | GG vs. GT + TT | Not shown | >0.05 | Unclear |
GT vs. GG + TT | Not shown | >0.05 | |||||
TT vs. GG + GT | Not shown | >0.05 | |||||
rs1107946 | GG vs. GT + TT | Not shown | >0.05 | ||||
GT vs. GG + TT | Not shown | >0.05 | |||||
TT vs. GT + GG | Not shown | >0.05 | |||||
Ficek et al. [29] 2014 |
COL12A1
| Collagen type XII | rs970547 | GG vs. GA + AA | Not shown | >0.05 | Unclear |
GA vs. GG + AA | Not shown | >0.05 | |||||
AA vs. GG + GA | Not shown | >0.05 | |||||
Khoschnau et al. [30] 2008 |
COL1A1
| Collagen type I | rs1800012 | GG vs. GG | 1 | >0.05 | High |
GT vs. GG | 1.19 (0.82–1.75) | >0.05 | |||||
TT vs. GG | 0.12 (0.02–0.92) |
<0.05
d
| |||||
Khoury et al. [31] 2015 |
ELN
| Elastin | rs2071307 | GG vs. GA + AA | Not shown | >0.05 | High |
GA vs. GG + AA | Not shown | >0.05 | |||||
AA vs. GG + GA | Not shown | >0.05 | |||||
FBN2
| Fibrillin-2 | rs331079 | GG vs. GC + CC | Not shown | >0.05 | ||
GC vs. GG + CC | Not shown | >0.05 | |||||
CC vs. GG + GC | Not shown | >0.05 | |||||
Malila et al. [32] 2011 |
MMP3
| Matrix metalloproteinase type 3 | –1612 | 5A+ vs. 5A− | 1.39 (0.72–2.67) | >0.05 | High |
5A− vs. 5A+ | 0.72 (0.37–1.38) | >0.05 | |||||
Mannion et al. [33] 2014 |
DCN
| Decorin | rs516115 | GG vs. GA + AA | 9.23 (1.17–73.01)e
|
0.015
| High |
GA vs. GG + AA | Not shown | >0.05 | |||||
AA vs. GG + GA | Not shown | >0.05 | |||||
rs13312816 | AA vs. AT + TT | Not shown | >0.05 | ||||
AT vs. AA + TT | Not shown | >0.05 | |||||
TT vs. AA + AT | Not shown | >0.05 | |||||
ACAN
| Aggrecan | rs2351491 | CT vs. CC + TT | Not shown | >0.05 | ||
CC vs. CT + TT | Not shown | >0.05 | |||||
TT vs. CT + CC | Not shown | >0.05 | |||||
rs1042631 | TT vs. CT + CC | Not shown | >0.05 | ||||
CT vs. TT + CC | Not shown | >0.05 | |||||
CC vs. CT + TT | Not shown | >0.05 | |||||
rs1516797 | TT vs. GT + GG | Not shown | >0.05 | ||||
GT vs. GG + TT | Not shown | >0.05 | |||||
GG vs. GT + TT | Not shown | >0.05 | |||||
BGN
| Biglycan | rs1126499 | CC vs. CT + TT | Not shown | >0.05 | ||
CT vs. CC + TT | Not shown | >0.05 | |||||
TT vs. CC + CT | Not shown | >0.05 | |||||
rs1042103 | GG vs. GA + AA | Not shown | >0.05 | ||||
GA vs. GG + AA | Not shown | >0.05 | |||||
AA vs. GG + GA | Not shown | >0.05 | |||||
FMOD
| Fibromodulin | rs7543148 | GG vs. GA + AA | Not shown | >0.05 | ||
GA vs. GG + AA | Not shown | >0.05 | |||||
AA vs. GG + GA | Not shown | >0.05 | |||||
rs10800912 | CC vs. CT + TT | Not shown | >0.05 | ||||
CT vs. CC + CT | Not shown | >0.05 | |||||
TT vs. CC + CT | Not shown | >0.05 | |||||
LUM
| Lumican | rs2268578 | TT vs. TC + CC | Not shown | >0.05 | ||
TC vs. TT + CC | Not shown | >0.05 | |||||
CC vs. CT + TT | Not shown | >0.05 | |||||
O’Connell et al. [34]a 2015 |
COL3A1
| Collagen type IIIb
| rs1800255 | AA vs. GA + GG | Not shown | >0.05 | High |
GA vs. GG + AA | Not shown | >0.05 | |||||
GG vs. AA + GA | Not shown | >0.05 | |||||
Collagen type IIIc
| AA vs. GA + GG | 3.8 (1.1–12.8) |
0.036
| ||||
GA vs. AA + GG | Not shown | >0.05 | |||||
GG vs. AA + GA | Not shown | >0.05 | |||||
Collagen type VIb
| rs35796750 | TT vs. TC + CC | Not shown | >0.05 | |||
TC vs. CC + TC | Not shown | >0.05 | |||||
CC vs. TT + CT | Not shown | >0.05 | |||||
Posthumus et al. [35] 2009 |
COL1A1
| Collagen type I | rs1800012 | TT vs. GT + GG | 0.08 (<0.01–1.46) |
0.031
| High |
GT vs. TT + GG | Not shown | >0.05 | |||||
GG vs. GG + GT | Not shown | >0.05 | |||||
Posthumus et al. [36] 2009 |
COL5A1
| Collagen type V | rs12722 | TT vs. CT + CC | Not shown | >0.05 | Unclear |
CT vs. TT + CC | Not shown | >0.05 | |||||
CC vs. TT + CT | Not shown | >0.05 | |||||
rs13946 | TT vs. CT + CC | Not shown | >0.05 | ||||
CT vs. TT + CC | Not shown | >0.05 | |||||
CC vs. TT + CT | Not shown | >0.05 | |||||
Posthumus et al. [37] 2010 |
COL12A1
| Collagen type XII | rs970547 | GG vs. GA + AA | Not shown | >0.05 | High |
GA Vs. AA + GG | Not shown | >0.05 | |||||
AA VS. GG + GA | Not shown | >0.05 | |||||
rs240736 | TT vs. CT + CC | Not shown | >0.05 | ||||
CT vs. TT + CC | Not shown | >0.05 | |||||
CC vs. TT + CT | Not shown | >0.05 | |||||
Posthumus et al. [38] 2012 |
MMP1
| Matrix metalloproteinase type 1 | rs1799750 | CC vs. CT + TT | Not shown | >0.05 | Unclear |
CT vs. CC + TT | Not shown | >0.05 | |||||
TT vs. CC + CT | Not shown | >0.05 | |||||
MMP3
| Matrix metalloproteinase type 3 | rs679620 | 1G1G vs. 1G2G + 2G2G | Not shown | >0.05 | ||
1G2G vs. 1G1G + 2G2G | Not shown | >0.05 | |||||
2G2G vs. 1G1G + 1G2G | Not shown | >0.05 | |||||
MMP10
| Matrix metalloproteinase type 10 | rs486055 | GG vs. GA + AA | Not shown | >0.05 | ||
GA vs. GG + AA | Not shown | >0.05 | |||||
AA vs. GG + GA | Not shown | >0.05 | |||||
MMP12
| Matrix metalloproteinase type 12 | rs2276109 | AA vs. AG + GG | Not shown | >0.05 | ||
AG vs. AA + GG | Not shown | >0.05 | |||||
GG vs. AA + AG | Not shown | >0.05 | |||||
Rahim et al. [39] 2014 |
VEGFA
| Vascular endothelial growth factor A | rs699947 | CC vs. CA + AA | Not shown | >0.05 | High |
CA vs. CC + AA | Not shown | >0.05 | |||||
AA vs. CC + CA | Not shown | >0.05 | |||||
rs1570360 | GG vs. GA + AA | Not shown | >0.05 | ||||
GA vs. GG + AA | 1.70 (1.16–2.50) |
0.007
| |||||
AA vs. GG + GA | Not shown | >0.05 | |||||
rs2010963 | GG vs. GC + CC | Not shown | >0.05 | ||||
GC vs. GG + CC | Not shown | >0.05 | |||||
CC vs. GC + GG | Not shown | >0.05 | |||||
KDR
| Kinase insert domain receptor | rs1870377 | TT vs. TA + AA | Not shown | >0.05 | ||
TA vs. TT + AA | Not shown | >0.05 | |||||
AA vs. TT + AT | Not shown | >0.05 | |||||
rs2071559 | GG vs. GA + AA | Not shown | >0.05 | ||||
GA vs. GG + AA | Not shown | >0.05 | |||||
AA vs. GA + GG | Not shown | >0.05 | |||||
NGFB
| Nerve growth factor beta | rs6678788 | CC vs. CT + TT | Not shown | >0.05 | ||
CT vs. GG + TT | Not shown | >0.05 | |||||
TT vs. GT + CC | Not shown | >0.05 | |||||
HIF1A
| Hypoxia-inducible factor 1-alpha | rs11549465 | CC vs. CT + CC | Not shown | >0.05 | ||
CT vs. CC + TT | Not shown | >0.05 | |||||
TT vs. CT + CC | Not shown | >0.05 | |||||
Raleigh et al. [40] 2013 |
GDF5
| Growth-differentiation hormone factor | rs143383 | TT vs. CT + CC | Not shown | >0.05 | Unclear |
CT vs. TT + CC | Not shown | >0.05 | |||||
CC vs. TT + CT | Not shown | >0.05 | |||||
Stępień-Słodkowska et al. [41] 2013 |
COL1A1
| Collagen type I | rs1800012 | GG vs. GT + TT | Not shown |
0.046
| Unclear |
GT vs. GG + TT | Not shown | >0.05 | |||||
TT vs. GT + GG | Not shown | >0.05 | |||||
Stępień-Słodkowska et al. [42] 2015 |
COL3A1
| Collagen type III | rs1800255 | GG vs. GA + AA | 0.78 (0.49–1.24) | >0.05 | Unclear |
GA vs. GG + AA | Not shown | >0.05 | |||||
AA vs. GG + GA | 5.05 (1.62–15.78) |
0.003
| |||||
Stępień-Słodkowska et al. [43] 2015 |
COL5A1
| Collagen type V | rs13946 | CC vs. CT + TT | Not shown | >0.05 | Unclear |
CT vs. CC + TT | Not shown | >0.05 | |||||
TT vs. CC + CT | Not shown | >0.05 | |||||
rs12722 | CC vs. CT + TT | Not shown | >0.05 | ||||
CT vs. CC + TT | Not shown | >0.05 | |||||
TT vs. CC + CT | Not shown | >0.05 |