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

Abstract

Abbreviations: HWE, Hardy-Weinberg equilibrium; LD, linkage disequilibrium; MAF, minor allele frequency; ONFH, osteonecrosis of the femoral head; SNP, single nucleotide polymorphism AbstractMultiple 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.

Association between vascular endothelial growth factor gene polymorphisms and the risk of osteonecrosis of the femoral head: Systematic review

“…Liu et al (6) carried out the same tests in the Chinese population; however, the focus was only on -634G/C. VEGF gene polymorphisms, such as rs1485766, were observed to contribute to identifying genetic susceptibly factors of ONFH in Korea by Hong et al (9). The present meta-analysis of 3 studies, including 687 cases and 877 controls, systematically evaluated the association between -634G/C polymorphism in the VEGF gene and ONFH risk.…”

The genetic profile of bone repair

“…Certain polymorphisms close to four specific genes were also found to attribute the majority of the genetic risk for Paget's disease (25); and even for the pathophysiology of stress fractures, specific genetic "profiles" have also been suggested as potential predisposing factors for increased fracture risk within military recruits (26). Moreover, certain genetic variants in angiogenesis-and hypoxia-related genes were found to be associated with an increased risk for development of non-traumatic ONFH (27) and three other variants with the development of post-traumatic HO (28). Finally, specific genetic "profiles" with several genetic variations within different genes (like VDR, IL-6, BMP-2) have also been associated with various spinal conditions, such as disc degeneration, adolescent idiopathic scoliosis, and ossification of the posterior longitudinal ligament (29)(30)(31).…”

Impact of VEGF‐C Gene Polymorphisms and Environmental Factors on Oral Cancer Susceptibility in Taiwan

“…In this research, a case-control study was performed on five SNPs, which are located in the intron or downstream of the VEGF-C gene. Some of these SNPs were reported to be correlated with the risk of preeclampsia [34], osteonecrosis of the femoral head [35], or the survival rate with ovarian cancer [36]. In this study, we analyzed associations among VEGF-C gene SNPs, environment risk factors, and oral cancer susceptibility.…”