Abstract
The pathology of non-traumatic osteonecrosis of the femoral head (ONFH) is complex. Several studies have linked some polymorphisms of vascular endothelial growth factors A (VEGFA) with ONFH, but the results are not consistent and are even conflicting. In the study, 22 single nucleotide polymorphisms (SNPs) in VEGFA were genotyped in 1,762 subjects (489 cases and 1,273 controls). Genetic association analyses were performed in single markers and haplotype levels. Stratification analysis was conducted for ONFH patients. Gene by environment interactions were tested between VEGFA and the smoking status of the subjects. Gene expression and eQTL data of significant SNPs were extracted from GTEx to examine their potential biological function. The SNP, rs2010963, was identified to be significantly associated with ONFH (χ2 = 11.66, P = 0.0006, OR = 1.29). Haplotypes including rs2010963 were also identified to be correlated with ONFH in the haplotype-based analyses. After stratifying by the causes of ONFH, a significant signal from rs2010963 could only be identified in alcohol-induced patients (Pallelic = 0.0009) but not in steroid-induced patients (Pallelic = 0.055). No significant results were obtained from the gene by environmental interaction analyses. Significant expression differences of VEGFA were identified in multiple human tissues for different genotypes of rs2010963. Our findings indicate that SNP rs2010963 is significantly associated with ONFH.
Highlights
Osteonecrosis of the femoral head (ONFH) is a complex bone disorder characterized by the death of bone cells due to insufficient blood flow
Through genotyping several pre-selected genetic markers covering vascular endothelial growth factor A (VEGFA) in our study subjects, we examined the statistical association between genetic polymorphisms and ONFH in both single-marker and haplotype-based methods
VEGFA encodes a heparin-binding protein that is an important member of the vascular endothelial growth factors (VEGFs) growth factor family[21,22,23,24,25]
Summary
Osteonecrosis of the femoral head (ONFH) is a complex bone disorder characterized by the death of bone cells due to insufficient blood flow. The death of bone cells can, in turn, lead to pain and collapse of particular areas of bone[1,2] Several causes of this disorder have been identified through clinical and epidemiology studies, and the two most important causes for non-traumatic ONFH are high-dose corticosteroid medications and excessive alcohol consumption[1]. Several previous studies have linked multiple genetic polymorphisms within the promoter region of VEGFA to the disease status of non-traumatic ONFH12–14. Several different variants located in the promoter region of VEGFA have been shown to contribute to the risk of ONFH; the roles of these SNPs are still unclear. Combined with relevant bioinformatics tools, we aimed to examine the potential biological function of the significant SNPs identified in the association analysis
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