Plasminogen Activator Inhibitor-1 4G/5G Polymorphism Contributes to Osteonecrosis of the Femoral Head Susceptibility: Evidence from a Systematic Review and Meta-analysis

Document Type : SYSTEMATIC REVIEW

Authors

1 Department of Orthopedics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

2 Department of Orthopedics, Afshar Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

3 Department of Pathology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

4 Department of Radiology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

5 Department of Emergency Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

6 Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

Abstract

Background: The Plasminogen Activator Inhibitor-1 gene 4G/5G (PAI-1 4G/5G) polymorphism has been suggested
to be associated with osteonecrosis of the femoral head (ONFH) susceptibility; however, the results are conflicting and
inconclusive. We have carried out a comprehensive meta-analysis to derive a more precise estimation of the association.
Methods: A comprehensive search in PubMed, EMBASE, Google Scholar, and ISI Web of Knowledge databases
was conducted to identify all eligible case-control publications investigating the association between PAI-1 4G/5G
polymorphism and ONFH risk. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were used to
assess the association.
Results: A total of six studies with 456 cases and 1,019 controls were included in this review. Three studies were
from Caucasian descendants and the three others were from East Asian descendants. Overall analysis suggests
a significant association between PAI-1 4G/5G polymorphism and ONFH risk under the allele model (4G vs. 5G:
OR =1.540, 95% CI =1.055-2.248, P=0.025) and the recessive model (4G4G vs. 4G5G+5G5G: OR=1.931, 95% CI:
1.162-3.207, P=0.011). When stratified by ethnicity, we have found a significant association between PAI-1 4G/5G
polymorphism and ONFH risk among the Caucasian (4G5G vs. 5G5G: OR=1.806, 95% CI: 1.064-3.067, P=0.029) and
East Asians (4G4G vs. 5G5G: OR=1.619, 95% CI: 1.025-2.556, P=0.039 and 4G4G vs. 4G5G+5G5G: OR=1.665, 95%
CI: 1.207-2.297, P=0.002).
Conclusion: The present meta-analysis suggested that PAI-1 4G/5G (rs1799889) polymorphism is a potential risk
factor for development of ONFH. However, large-scale and well-designed case-control studies in different ethnicities
are required to validate these results.
Level of evidence: II

Keywords

Main Subjects

References

1. Schmitt-Sody M, Kirchhoff C, Mayer W, Goebel M,
Jansson V. Avascular necrosis of the femoral head:
inter- and intraobserver variations of Ficat and
ARCO classifications. Int Orthop. 2008; 32(3):283-7.
2. Heidari B. Knee osteoarthritis prevalence, risk factors,
pathogenesis and features: part I. Caspian J Intern
Med. 2011; 2(2):205-12.
3. Yuan HF, Zhang J, Guo CA, Yan ZQ. Clinical outcomes
of osteonecrosis of the femoral head after autologous
bone marrow stem cell implantation: a metaanalysis
of seven case-control studies. Clinics. 2016;
71(2):110-3.
4. Pouya F, Kerachian MA. Avascular necrosis of the
femoral head: are any genes involved? Arch Bone Jt
Surg. 2015; 3(3):149-55.
5. Gagala J, Buraczynska M, Mazurkiewicz T, Ksiazek
A. Prevalence of genetic risk factors related with
thrombophilia and hypofibrinolysis in patients with
osteonecrosis of the femoral head in Poland. BMC
Musculoskelet Disord. 2013; 14(1):264.
6. Choi HR, Steinberg ME, Cheng E. Osteonecrosis of the
femoral head: diagnosis and classification systems.
Curr Rev Musculoskelet Med. 2015; 8(3):210-20.
7. Sen RK. Management of avascular necrosis of femoral
head at pre-collapse stage. Indian J Orthop. 2009;
43(1):6-16.
8. Wu B, Dong Z, Li S, Song H. Steroid-induced ischemic
bone necrosis of femoral head: treatment strategies.
Pak J Med Sci. 2015; 31(2):471-6.
9. Chang JD, Hur M, Lee SS, Yoo JH, Lee KM. Genetic
background of nontraumatic osteonecrosis of the
femoral head in the Korean population. Clin Orthop
Relat Res. 2008; 466(5):1041-6.
10. Zeng Z, Wang B, Pan H. Relation between
osteonecrosis of the femoral head and PAI-1 4G/5G
gene polymorphism: a meta-analysis. Int J Clin Exp
Med. 2015; 8(11):20337-42.
11. Liang XN, Xie L, Cheng JW, Tan Z, Yao J, Liu Q, et al.
Association between PAI-1 4G/5G Polymorphisms
and osteonecrosis of femoral head: a meta-analysis.
Thromb Res. 2013; 132(2):158-63.
12. Kamali M, Hantoushzadeh S, Borna S, Neamatzadeh
H, Mazaheri M, Noori-Shadkam M, et al. Association
between thrombophilic genes polymorphisms and
recurrent pregnancy loss susceptibility in the Iranian
population: a systematic review and meta-analysis.
Iran Biomed J. 2018; 22(2):78-89.
13. Tsantes AE, Nikolopoulos GK, Bagos PG, Bonovas
S, Kopterides P, Vaiopoulos G. The effect of
the plasminogen activator inhibitor-1 4G/5G
polymorphism on the thrombotic risk. Thromb Res.
2008; 122(6):736-42.
14. Bouchard L, Vohl MC, Lebel S, Hould FS, Marceau
P, Bergeron J, et al. Contribution of genetic and
metabolic syndrome to omental adipose tissue PAI-1
gene mRNA and plasma levels in obesity. Obes Surg.
2010; 20(4):492-9.
15. Onalan O, Balta G, Oto A, Kabakci G, Tokgozoglu L,
Aytemir K, et al. Plasminogen activator inhibitor-1
4G4G genotype is associated with myocardial
infarction but not with stable coronary artery disease.
J Thromb Thrombolysis. 2008; 26(3):211-7.
16. French D, Hamilton LH, Mattano LA Jr, Sather HN,
Devidas M, Nachman JB, et al. A PAI-1 (SERPINE1)
polymorphism predicts osteonecrosis in children
with acute lymphoblastic leukemia: a report from
the Children’s Oncology Group. Blood. 2008;
111(9):4496-9.
17. Ferrari P, Schroeder V, Anderson S, Kocovic L, Vogt
B, Schiesser D, et al. Association of plasminogen
activator inhibitor-1 genotype with avascular
osteonecrosis in steroid-treated renal allograft
recipients. Transplantation. 2002; 74(8):1147-52.
18. Asano T, Takahashi KA, Fujioka M, Inoue S, Ueshima
K, Hirata T, et al. Relationship between postrenal
transplant osteonecrosis of the femoral head and
gene polymorphisms related to the coagulation
and fibrinolytic systems in Japanese subjects.
Transplantation. 2004; 77(2):220-5.
19. Glueck CJ, Fontaine RN, Gruppo R, Stroop D, Sieve-
Smith L, Tracy T, et al. The plasminogen activator
inhibitor-1 gene, hypofibrinolysis, and osteonecrosis.
Clin Orthop Relat Res. 1999; 366(1):133-46.
20. Sun W, Li Z, Shi Z, Wang B, Gao F, Yang Y, et al.
Relationship between post-SARS osteonecrosis and
PAI-1 4G/5G gene polymorphisms. Eur J Orthop Surg
Traumatol. 2014; 24(4):525-9.
21. Kim H, Cho C, Cho Y, Cho S, Yoon K, Kim K. Significant
associations of PAI-1 genetic polymorphisms with
osteonecrosis of the femoral head. BMC Musculoskelet
Disord. 2011; 12(1):160.
22. Srzentić S, Nikčević G, Spasovski D, Baščarević Z,
Ž􀆽 ivković Z, Terzic-Š􀆽upić Z, et al. Predictive genetic
markers of coagulation, inflammation and apoptosis
in Perthes disease—Serbian experience. Eur J Pediatr.
2015; 174(8):1085-92.
23. Ghale-Noie ZN, Hassani M, Kachooei AR, Kerachian
MA. High serum alpha-2-macroglobulin level in
patients with osteonecrosis of the femoral head. Arch
Bone Jt Surg. 2018; 6(3):219-24.
24. Zintzaras E, Ioannidis JP. HEGESMA: genome
search meta-analysis and heterogeneity testing.
Bioinformatics. 2005; 21(18):3672-3.
25. Khoram-Abadi KM, Forat-Yazdi M, Kheirandish S,
Saeidi N, Zarezade Z, Mehrabi N, et al. DNMT3B -149
C>T and -579 G>T polymorphisms and risk of gastric
and colorectal cancer: a meta-analysis. Asian Pac J
Cancer Prev. 2016; 17(6):3015-20.
26. Jafari Nedooshan J, Forat Yazdi M, Neamatzadeh
H, Zare Shehneh M, Kargar S, Seddighi N. Genetic
association of XRCC1 gene rs1799782, rs25487 and
rs25489 polymorphisms with risk of thyroid cancer:
a systematic review and meta-analysis. Asian Pac J
Cancer Prev. 2017; 18(1):263-70.
27. Mantel N, Haenszel W. Statistical aspects of the
analysis of data from retrospective studies of disease.
J Natl Cancer Inst. 1959; 22(4):719-48.
28. DerSimonian R, Laird N. Meta-analysis in clinical
trials. Control Clin Trials. 1986; 7(3):177-88.
29. Namazi A, Forat-Yazdi M, Jafari M, Farahnak S, Nasiri
R, Foroughi E, et al. Association of interleukin-10
-1082 A/G (RS1800896) polymorphism with
susceptibility to gastric cancer: meta-analysis of
6,101 cases and 8,557 controls. Arq Gastroenterol.
2018; 55(1):33-40.
30. Begg CB, Mazumdar M. Operating characteristics of a
rank correlation test for publication bias. Biometrics.
1994; 50(4):1088-101.
31. Egger M, Davey Smith G, Schneider M, Minder C. Bias
in meta-analysis detected by a simple, graphical test.
BMJ. 1997; 315(7109):629-34.
32. Zhao L, Huang P. Plasminogen activator inhibitor-1
4G/5G polymorphism is associated with type 2
diabetes risk. Int J Clin Exp Med. 2013; 6(8):632-40.
33. Schafer K, Müller K, Hecke A, Mounier E, Goebel
J, Loskutoff DJ, et al. Enhanced thrombosis in
atherosclerosis-prone mice is associated with
increased arterial expression of plasminogen
activator inhibitor-1. Arterioscler Thromb Vasc Biol.
2003; 23(11):2097-103.
34. Xie X, Shi X, Xun X, Rao L. Endothelial nitric oxide
synthase gene single nucleotide polymorphisms
and the risk of hypertension: a meta-analysis
involving 63,258 subjects. Clin Exp Hypertens. 2017;
39(2):175-82.
35. Cesari M, Pahor M, Incalzi RA. Plasminogen activator
inhibitor-1 (PAI-1): a key factor linking fibrinolysis
and age-related subclinical and clinical conditions.
Cardiovasc Ther. 2010; 28(5):e72-91.
36. Meigs JB, Dupuis J, Liu C, O’Donnell CJ, Fox CS,
Kathiresan S, et al. PAI-1 gene 4G/5G polymorphism
and risk of type 2 diabetes in a population-based
sample. Obesity. 2006; 14(5):753-8.
37. Yazdi MM, Jamalaldini MH, Sobhan MR, Jafari M,
Mazaheri M, Zare-Shehneh M, et al. Association
of ESRα gene Pvu II T>C, XbaI A>G and BtgI
G>A polymorphisms with knee osteoarthritis
susceptibility: a systematic review and metaanalysis
based on 22 case-control studies. Arch Bone
Jt Surgery. 2017; 5(6):351-62.
38. Sobhan MR, Mahdinezhad-Yazdi M, Jafari M, Mazaheri
M, Neamatzadeh H, Daliri K. Association of ESRα XbaI
A>G, PvuII T>C and ESRβ AlwNI T>C polymorphisms
with the risk of adolescent idiopathic scoliosis: a
systematic review and genetic meta-analysis. Rev
Bras Ortop. 2018; In Press.
39. Sobhan MR, Forat Yazdi M, Mazaheri M, Zare Shehneh
M, Neamatzadeh H. Association between the DNA
repair gene XRCC3 rs861539 polymorphism and
risk of osteosarcoma: A systematic review and
meta-analysis. Asian Pac J Cancer Prev. 2017;
18(2):549-55.
40. Mehdinejad M, Sobhan MR, Mazaheri M, Shehneh
MZ, Neamatzadeh H, Kalantar SM. Genetic
association between ERCC2, NBN, RAD51 gene
variants and osteosarcoma risk: A systematic
review and meta-analysis. Asian Pac J Cancer Prev.
2017; 18(5):1315-21.
41. Sobhan MR, Mehdinejad M, Jamaladini MH, Mazaheri
M, Zare-Shehneh M, Neamatzadeh H. Association
between aspartic acid repeat polymorphism of
the asporin gene and risk of knee osteoarthritis: a
systematic review and meta-analysis. Acta Orthop
Traumatol Turc. 2017; 51(5):409-15.
The Archives of Bone and Joint Surgery
Volume 6, Issue 6
November 2018
Pages 468-477

Files

History

  • Receive Date: 22 May 2018
  • Revise Date: 31 July 2018
  • Accept Date: 23 September 2018

Share

How to cite

Statistics