VEGF and eNOS genetic polymorphisms and their interactions with steroid and the risk of osteonecrosis of the femoral head

This study investigated the effects of vascular endothelial growth factor (VEGF) -634G>C and endothelial nitric oxide synthase (eNOS) 894G>T genetic polymorphisms, their gene-gene interaction and their interactions with steroid use on the risk of osteonecrosis of the femoral head (ONFH). An age-matched case-control study was conducted with 174 cases and 174 controls. VEGF and eNOS genotypes were determined by polymerase chain reaction (PCR) and sequencing. The effects were evaluated by the adjusted odds ratio (OR) and 95% confidence interval (CI) derived from logistic regression analyses. VEGF CC and eNOS GT genotypes were both found to be independently related to the increased risk for ONFH, with ORs of 4.53 (95% CI 1.20-17.10) and 2.53 (95% CI 1.23-5.22), respectively. Further, compared with individuals having both VEGF GG and eNOS GG, the adjusted OR (95% CI) for those with both VEGF CC and eNOS GT was 4.87 (2.33-10.18) in all subjects. A statistically significant gene-gene interaction existed between the two polymorphisms (P<0.001). Furthermore, statistically significant interactions between the two polymorphisms and steroid use were found (VEGF P<0.001 and eNOS P=0.001). Heavy steroid users with VEGF CC and with eNOS GT both had significantly increased risks for ONFH, with ORs of 4.00 (95% CI 2.04-7.84) and 3.46 (95% CI 1.84-6.50), respectively. In conclusion, our results suggest a synergism between VEGF -634G>C and eNOS 894G>T genetic polymorphisms and their gene-environment interactions with steroid use in the ONFH risk.