Genetic association of angiogenesis- and hypoxia-related gene polymorphisms with osteonecrosis of the femoral head

Jung Min Hong,Hyun-Ju Kim,Tae-Ho Kim,Shin-Yoon Kim,Eun-Kyoung Yang,Eui-Kyun Park

doi:10.3858/emm.2010.42.5.039

Abstract

Multiple factors have been implicated in the development of osteonecrosis of the femoral head (ONFH). In particular, non-traumatic ONFH is directly or indirectly related to injury of the vascular supply to the femoral head. Thus, hypoxia in the femoral head caused by impaired blood flow may be an important risk factor for ONFH. In this study, we investigated whether genetic variations of angiogenesis- and hypoxia-related genes contribute to an increased risk for the development of ONFH. Candidate genes were selected based on known hypoxia and angiogenesis pathways. An association study was performed using an Affymetrix Targeted Genotyping 3K Chip array with 460 ONFH patients and 300 control subjects. We showed that single nucleotide polymorphisms (SNPs) in the genes TF, VEGFC, IGFBP3, and ACE were associated with an increased risk of ONFH. On the other hand, SNPs in the KDR and NRP1 genes were associated with protection against ONFH. The most important finding was that one SNP (rs2453839) in the IGFBP3 gene was significantly associated with a higher risk of ONFH (P=0.0061, OR 7.74). In subgroup analysis, most candidate gene variations that were associated with ONFH occurred in the idiopathic subgroup. Among other SNPs, ACE SNPs were associated with steroid-induced ONFH (P=0.0018-0.0037, OR>3). Collectively, our findings suggest that genetic variations in angiogenesis- and hypoxia-related genes may help to identify susceptibility factors for the development of ONFH in the Korean population.

Highlights

Osteonecrosis of the femoral head (ONFH) is a bone disorder that usually affects middle-aged men 30-50 yr of age (Jones, 1999; Glueck et al, 2003)
single nucleotide polymorphism (SNP) in these genes were selected based on a call rate (CR) > 0.90, minor allele frequency (MAF) > 0.05, and Hardy-Weinberg equilibrium (HWE) > 0.05 using a public database
Our results reveal that 6 candidate genes (TF, Kinase insert domain receptor (KDR), Vascular endothelial growth factor C (VEGFC), Insulin-like growth factor binding protein 3 (IGFBP3), Neuropilin 1 (NRP1) and Angiotensin I converting enzyme (ACE)) are significantly associated with osteonecrosis of the femoral head (ONFH) (Supplemental Data Table S2)

Summary

Introduction

Osteonecrosis of the femoral head (ONFH) is a bone disorder that usually affects middle-aged men 30-50 yr of age (Jones, 1999; Glueck et al, 2003). The exact pathogenesis of non-traumatic ONFH is largely unknown, it has been associated with corticosteroid usage, alcoholism, infections, marrow infiltrating diseases, and coagulation defects (Jones, 1999; Glueck et al, 2003; Childs, 2005). Most of these risk factors are closely related to direct or indirect injury to the vascular supply of the femoral head. Many studies have proposed that a pathogenetic mechanism, such as coagulation and angiogenesis, seems to be major risk factor for osteonecrosis (ON)

Methods

Results

Conclusion