Abstract
BackgroundThe pathogenesis of osteonecrosis of the femoral head (ONFH) has been implicated in hypofibrinolysis and blood supply interruption. Previous studies have demonstrated that decreased fibrinolytic activity due to elevated plasminogen activator inhibitor-1 (PAI-1) levels correlates with ONFH pathogenesis. The -675 4G/5G single nucleotide polymorphism (SNP rs1799889) in the PAI-1 gene promoter is associated with PAI-1 plasma level. We investigated whether rs1799889 and two other SNPs of the PAI-1 gene (rs2227631, -844 G/A in the promoter; rs11178, +10700 C/T in the 3'UTR) are associated with increased ONFH risk.MethodsThree SNPs in PAI-1 were genotyped in 206 ONFH patients and 251 control subjects, using direct sequencing and a TaqMan® 5' allelic discrimination assay. We performed association analysis for genotyped SNPs and haplotypes with ONFH.ResultsThe 4G allele of rs1799889, A allele of rs2227631, and C allele of rs11178 were significantly associated with increased ONFH risk (p = 0.03, p = 0.003, and p = 0.002, respectively). When we divided the population according to gender, an association between the three SNPs and increased risk of ONFH was found only in men. In another subgroup analysis based on the etiology of ONFH, rs2227631 (A allele) and rs11178 (C allele) in the idiopathic subgroup (p = 0.007 and p = 0.021) and rs1799889 (4G allele) and rs11178 (C allele) in the alcohol-induced subgroup (p = 0.042 and p = 0.015) were associated with increased risk of ONFH. In addition, a certain haplotype (A-4G-C) of PAI-1 was also significantly associated with ONFH (p < 0.001).ConclusionOur findings demonstrated that three SNPs (rs1799889, rs2227631, and rs11178) of the PAI-1 gene were associated with ONFH risk. This study also suggests that PAI-1 SNPs may play an important role in ONFH.
Highlights
The pathogenesis of osteonecrosis of the femoral head (ONFH) has been implicated in hypofibrinolysis and blood supply interruption
To identify if plasminogen activator inhibitor-1 (PAI-1) single nucleotide polymorphism (SNP) were involved in susceptibility to (osteonecrosis of the femoral head) (ONFH), three SNPs in the promoter and 3’UTR were selected based on a minor allele frequency (MAF) > 0.05 and Hardy-Weinberg equilibrium (HWE) > 0.05 using a public database http://www.ncbi.nlm.nih.gov/
These results suggest that the minor alleles of rs2227631 (A), rs1799889 (4G), and rs11178 (C) in the PAI-1 gene contribute to an increase in ONFH risk (Table 3)
Summary
The pathogenesis of osteonecrosis of the femoral head (ONFH) has been implicated in hypofibrinolysis and blood supply interruption. The -675 4G/5G single nucleotide polymorphism (SNP rs1799889) in the PAI-1 gene promoter is associated with PAI-1 plasma level. We investigated whether rs1799889 and two other SNPs of the PAI-1 gene (rs2227631, -844 G/A in the promoter; rs11178, +10700 C/T in the 3’UTR) are associated with increased ONFH risk. An increased tendency for intravascular coagulation is proposed as the pathogenetic mechanism responsible for interruption of the osseous blood supply and ONFH, and a significantly higher prevalence of coagulation abnormalities is reported in patients with ONFH [1,3]. Mainly attributable to increased levels of PAI-1, is associated with ONFH development [7,8]. PAI-1 levels were reported to be regulated by a common transcription-altering insertion/deletion single nucleotide polymorphism (SNP; rs1799889) of four or five guanine (4G/ 5G) nucleotides that is 675 bp upstream of the transcription start site. Subjects who are homozygous for the 4G allele (4G/4G genotype) have plasma PAI-1
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